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Sample records for host cytokine response

  1. Plasmodium genetic loci linked to host cytokine and chemokine responses

    PubMed Central

    Pattaradilokrat, Sittiporn; Li, Jian; Wu, Jian; Qi, Yanwei; Eastman, Richard T.; Zilversmit, Martine; Nair, Sethu C.; Huaman, Maria Cecilia; Quinones, Mariam; Jiang, Hongying; Li, Na; Zhu, Jun; Zhao, Keji; Kaneko, Osamu; Long, Carole A.; Su, Xin-zhuan

    2014-01-01

    Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CC) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1β, IP-10, IFN-γ, MCP-1, and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12, and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosome 7 and 13 had significant (p < 0.005) additive effects on IL-1β, IL-5, and IP-10 responses, and the chromosome 9 and 12 loci had significant (p = 0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection. PMID:24452266

  2. Plasmodium genetic loci linked to host cytokine and chemokine responses.

    PubMed

    Pattaradilokrat, S; Li, J; Wu, J; Qi, Y; Eastman, R T; Zilversmit, M; Nair, S C; Huaman, M C; Quinones, M; Jiang, H; Li, N; Zhu, J; Zhao, K; Kaneko, O; Long, C A; Su, X-z

    2014-01-01

    Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate the effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CCs) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1β, IP-10, IFN-γ, MCP-1 and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12 and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosomes 7 and 13 had significant (P<0.005) additive effects on IL-1β, IL-5 and IP-10 responses, and the chromosome 9 and 12 loci had significant (P=0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for a better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.

  3. The frustrated host response to Legionella pneumophila is bypassed by MyD88-dependent translation of pro-inflammatory cytokines.

    PubMed

    Asrat, Seblewongel; Dugan, Aisling S; Isberg, Ralph R

    2014-07-01

    Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its host cytosol through its type IV protein secretion machinery. At least 5 of the bacterial translocated effectors interfere with the function of host cell elongation factors, blocking translation and causing the induction of a unique host cell transcriptional profile. In addition, L. pneumophila also interferes with translation initiation, by preventing cap-dependent translation in host cells. We demonstrate here that protein translation inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes involved in the pathway are transcribed but fail to be translated due to the bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory cytokines, such as IL-1α and IL-1β, bypass this inhibition and get synthesized in the presence of Legionella effectors. We show that the selective synthesis of these genes requires MyD88 signaling and takes place in both infected cells that harbor bacteria and neighboring bystander cells. Our findings offer a perspective of how host cells are able to cope with pathogen-encoded activities that disrupt normal cellular process and initiate a successful inflammatory response.

  4. Mycobacterium tuberculosis PPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

    PubMed Central

    Zeng, Jie; Abdalla, Abualgasim Elgaili; Xie, Jianping

    2016-01-01

    Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis. PMID:27634911

  5. Differential IFN-γ and TNF-α driven cytokine response distinguishes acute infection of a metatherian host with Toxoplasma gondii and Neospora caninum.

    PubMed

    Donahoe, Shannon L; Phalen, David N; McAllan, Bronwyn M; O'Meally, Denis; McAllister, Milton M; Ellis, John; Šlapeta, Jan

    2017-03-27

    Toxoplasma gondii and Neospora caninum (both Apicomplexa) are closely related cyst-forming coccidian parasites that differ significantly in their host range and ability to cause disease. Unlike eutherian mammals, Australian marsupials (metatherian mammals) have long been thought to be highly susceptible to toxoplasmosis and neosporosis because of their historical isolation from the parasites. In this study, the carnivorous fat-tailed dunnart (Sminthopsis crassicaudata) was used as a disease model to investigate the immune response and susceptibility to infection of an Australian marsupial to T. gondii and N. caninum Disease outcome was more severe in N. caninum infected dunnarts than in T. gondii infected dunnarts, as shown by the severity of clinical and histopathological features of disease and a higher tissue parasite burden in the tissues evaluated. Transcriptome sequencing (RNA-seq) of spleens from infected dunnarts and mitogen-stimulated dunnart splenocytes was used to define the cytokine repertoire. Changes in mRNA expression during the time course of infection was measured using quantitative reverse transcription PCR (qRT-PCR) for key Th1 (IFNγ, TNFα), Th2 (IL-4, IL-6), and Th17 (IL-17A) cytokines. The results show qualitative differences in cytokine responses by the fat-tailed dunnart to infection with N. caninum and T. gondii Dunnarts infected with T. gondii were capable of mounting a more effective Th1 immune response than those infected with N. caninum, indicating the role of the immune response in the outcome scenarios of parasite infection in this marsupial mammal.

  6. Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice▿

    PubMed Central

    Szretter, Kristy J.; Gangappa, Shivaprakash; Lu, Xuihua; Smith, Chalanda; Shieh, Wun-Ju; Zaki, Sherif R.; Sambhara, Suryaprakash; Tumpey, Terrence M.; Katz, Jacqueline M.

    2007-01-01

    Highly pathogenic avian H5N1 influenza viruses are now widespread in poultry in Asia and have recently spread to some African and European countries. Interspecies transmission of these viruses to humans poses a major threat to public health. To better understand the basis of pathogenesis of H5N1 viruses, we have investigated the role of proinflammatory cytokines in transgenic mice deficient in interleukin-6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1α), IL-1 receptor (IL-1R), or tumor necrosis factor receptor 1 (TNFR1) by the use of two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. The course of disease and the extent of virus replication and spread in IL-6- and MIP-1α-deficient mice were not different from those observed in wild-type mice during acute infection with 1,000 50% mouse infective doses of either H5N1 virus. However, with HK/486 virus, IL-1R-deficient mice exhibited heightened morbidity and mortality due to infection, whereas no such differences were observed with the more virulent HK/483 virus. Furthermore, TNFR1-deficient mice exhibited significantly reduced morbidity following challenge with either H5N1 virus but no difference in viral replication and spread or ultimate disease outcome compared with wild-type mice. These results suggest that TNF-α may contribute to morbidity during H5N1 influenza virus infection, while IL-1 may be important for effective virus clearance in nonlethal H5N1 disease. PMID:17182684

  7. Cytokines in Radiobiological Responses: A Review

    PubMed Central

    Schaue, Dörthe; Kachikwu, Evelyn L.; McBride, William H.

    2013-01-01

    Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). “Self” molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, “driver” cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly

  8. Lack of a Role of Cytotoxic Necrotizing Factor 1 Toxin from Escherichia coli in Bacterial Pathogenicity and Host Cytokine Response in Infected Germfree Piglets

    PubMed Central

    Fournout, S.; Dozois, C. M.; Odin, M.; Desautels, C.; Pérès, S.; Hérault, F.; Daigle, F.; Segafredo, C.; Laffitte, J.; Oswald, E.; Fairbrother, J. M.; Oswald, I. P.

    2000-01-01

    the CNF1-producing strain, M623, is pathogenic and induces inflammatory cytokine expression in germfree, colostrum-deprived piglets. Nevertheless, in this model, the CNF1 toxin does not appear to be a major factor for pathogenicity or cytokine response, as demonstrated by the use of an isogenic cnf1 mutant. PMID:10639454

  9. Kinetic and organ-specific patterns of cytokine expression in acute graft-versus-host disease.

    PubMed

    Baker, K S; Allen, R D; Roths, J B; Sidman, C L

    1995-04-01

    Although many cytokines have been previously implicated in graft-versus-host disease (GVHD), no study to date has comprehensively evaluated their expression over time or in different tissues affected by GVHD. Using a semi-quantitative reverse transcriptase-PCR technique and a murine model of acute GVHD, we have evaluated the expression levels of mRNA for a wide range of cytokines in spleen, gut and liver tissues at weekly intervals after bone marrow transfer. The earliest cytokine responses seen were increases in IL-2, IL-10, IFN-gamma, MIP-1 alpha and TNF-alpha in the spleen, suggesting a primarily Th1 pathway. Other cytokines (IL-1 alpha, IL-10 and MIP-1 alpha) were persistently elevated in GVHD mice, but were variable depending on the tissue. These data demonstrate that a wide range of cytokines are involved in the GVHD response and that their kinetic pattern of expression is different in various affected tissues.

  10. Cytokines and Immune Responses in Murine Atherosclerosis.

    PubMed

    Kusters, Pascal J H; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and regulation of inflammation. In recent years, many studies have investigated the role of these molecules in experimental models of atherosclerosis. While some cytokines such as TNF or IFNγ clearly had atherogenic effects, others such as IL-10 were found to be atheroprotective. However, studies investigating the different cytokines in experimental atherosclerosis revealed that the cytokine system is complex with both disease stage-dependent and site-specific effects. In this review, we strive to provide an overview of the main cytokines involved in atherosclerosis and to shed light on their individual role during atherogenesis.

  11. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa

    PubMed Central

    Savva, Athina; Kersten, Brigit; Pistiki, Aikaterini; van de Veerdonk, Frank L.; Netea, Mihai G.; van der Meer, Jos W.; Giamarellos-Bourboulis, Evangelos J.

    2015-01-01

    Background Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). Methods Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. Results CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8. Conclusions Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF. PMID:26091259

  12. Early cytokine responses during intestinal parasitic infections.

    PubMed Central

    Ishikawa, N; Goyal, P K; Mahida, Y R; Li, K F; Wakelin, D

    1998-01-01

    Infections with gastro-intestinal nematodes elicit immune and inflammatory responses mediated by cytokines released from T-helper type-2 (Th2) cells. In vitro assays of cells from the mesenteric lymph nodes (MLN) of experimentally infected rodents confirm that, after about 1 week, the dominant cytokine responses to mitogens and antigens are those associated with this Th-cell subset. Polarization of the Th response in this way implies an initial local cytokine environment that favours Th2 development. However, experimental infections with Trichinella spiralis and Nippostrongylus brasiliensis show that, within 2 days of worms reaching the intestine, MLN cells (MLNC) respond with a Th1 rather than a Th2 response [i.e. there is an increase in mRNA for the type 1 cytokine interferon-gamma (IFN-gamma), and mitogen-stimulated MLNC release IFN-gamma rather than interleukin-5 (IL-5)]. Antigen stimulation at this time does not elicit IFN-gamma release and the MLNC cannot adoptively transfer immunity. Within a few days the MLNC phenotype changes. There is a Th2 response (IL-5 release) to both mitogen and antigen stimulation and MLNC can adoptively transfer immunity. Early release of IFN-gamma is T-cell dependent, with CD4+ T cells playing the major role. The data are discussed in relation to factors regulating the mucosal response to invasion by parasites. PMID:9616376

  13. A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

    PubMed Central

    Sulaiman, Azad A.; Zolnierczyk, Katarzyna; Japa, Ornampai; Owen, Jonathan P.; Maddison, Ben C.; Hodgkinson, Jane E.; Gough, Kevin C.

    2016-01-01

    effector response targeting juvenile parasites which we demonstrate extends to an abrogation of the ADCC response. Thus suggesting that FhTLM is a stage specific evasion molecule that utilises host cytokine receptors. These findings are the first to clearly demonstrate the interaction of a helminth cytokine with a host receptor complex resulting in immune modifications that facilitate the non-protective chronic immune response which is characteristic of F. hepatica infection. PMID:27806135

  14. Host Intracellular Signaling Events and Pro-inflammatory Cytokine Production in African Trypanosomiasis

    PubMed Central

    Kuriakose, Shiby M.; Singh, Rani; Uzonna, Jude E.

    2016-01-01

    Pathogens, such as bacteria, viruses, and parasites, possess specific molecules or proteins that are recognized by several host innate immune receptors, leading to the activation of several intracellular signaling molecules and pathways. The magnitude and quality of these events significantly affect the outcome of infection. African trypanosomes, including Trypanosoma congolense, are capable of manipulating the host immune response, including the activity of macrophages, which are the key immune cells that contribute to the immunopathogenesis of African trypanosomiasis. Although it is known that immune hyperactivation and excessive pro-inflammatory cytokine production are the hallmarks of African trypanosomiasis, the mechanisms through which these events are triggered are poorly defined. However, it is known that macrophages may play a significant role in these processes, because phagocytosis of trypanosomes by macrophages initiates intracellular signal transduction cascades that lead to the release of pro-inflammatory cytokines and alteration in cell function. This review highlights recent progress in our understanding of the innate immune receptors, signaling pathways, and transcription factors involved in T. congolense-induced pro-inflammatory cytokine production in macrophages. It will reveal the existence of complex signaling events through which the parasite modulates the host immune response, thus identifying novel targets that could aid in designing strategies to effectively control the disease. PMID:27242788

  15. Mnk Kinases in Cytokine Signaling and Regulation of Cytokine Responses

    PubMed Central

    Joshi, Sonali; Platanias, Leonidas C.

    2013-01-01

    The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed. PMID:23710261

  16. Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

    PubMed Central

    Henderson, B; Poole, S; Wilson, M

    1996-01-01

    Cytokines are a diverse group of proteins and glycoproteins which have potent and wide-ranging effects on eukaryotic cell function and are now recognized as important mediators of tissue pathology in infectious diseases. It is increasingly recognized that for many bacterial species, cytokine induction is a major virulence mechanism. Until recent years, the only bacterial component known to stimulate cytokine synthesis was lipopolysaccharide (LPS). It is only within the past decade that it has been clearly shown that many components associated with the bacterial cell wall, including proteins, glycoproteins, lipoproteins, carbohydrates, and lipids, have the capacity to stimulate mammalian cells to produce a diverse array of cytokines. It has been established that many of these cytokine-inducing molecules act by mechanisms distinct from that of LPS, and thus their activities are not due to LPS contamination. Bacteria produce a wide range of virulence factors which cause host tissue pathology, and these diverse factors have been grouped into four families: adhesins, aggressins, impedins, and invasins. We suggest that the array of bacterial cytokine-inducing molecules represents a new class of bacterial virulence factor, and, by analogy with the known virulence families, we suggest the term "modulin" to describe these molecules, because the action of cytokines is to modulate eukaryotic cell behavior. This review summarizes our current understanding of cytokine biology in relation to tissue homeostasis and disease and concisely reviews the current literature on the cytokine-inducing molecules produced by gram-negative and gram-positive bacteria, with an emphasis on the cellular mechanisms responsible for cytokine induction. We propose that modulins, by controlling the host immune and inflammatory responses, maintain the large commensal flora that all multicellular organisms support. PMID:8801436

  17. Host response mechanisms in periodontal diseases

    PubMed Central

    SILVA, Nora; ABUSLEME, Loreto; BRAVO, Denisse; DUTZAN, Nicolás; GARCIA-SESNICH, Jocelyn; VERNAL, Rolando; HERNÁNDEZ, Marcela; GAMONAL, Jorge

    2015-01-01

    Periodontal diseases usually refer to common inflammatory disorders known as gingivitis and periodontitis, which are caused by a pathogenic microbiota in the subgingival biofilm, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola that trigger innate, inflammatory, and adaptive immune responses. These processes result in the destruction of the tissues surrounding and supporting the teeth, and eventually in tissue, bone and finally, tooth loss. The innate immune response constitutes a homeostatic system, which is the first line of defense, and is able to recognize invading microorganisms as non-self, triggering immune responses to eliminate them. In addition to the innate immunity, adaptive immunity cells and characteristic cytokines have been described as important players in the periodontal disease pathogenesis scenario, with a special attention to CD4+ T-cells (T-helper cells). Interestingly, the T cell-mediated adaptive immunity development is highly dependent on innate immunity-associated antigen presenting cells, which after antigen capture undergo into a maturation process and migrate towards the lymph nodes, where they produce distinct patterns of cytokines that will contribute to the subsequent polarization and activation of specific T CD4+ lymphocytes. Skeletal homeostasis depends on a dynamic balance between the activities of the bone-forming osteoblasts (OBLs) and bone-resorbing osteoclasts (OCLs). This balance is tightly controlled by various regulatory systems, such as the endocrine system, and is influenced by the immune system, an osteoimmunological regulation depending on lymphocyte- and macrophage-derived cytokines. All these cytokines and inflammatory mediators are capable of acting alone or in concert, to stimulate periodontal breakdown and collagen destruction via tissue-derived matrix metalloproteinases, a characterization of the progression of periodontitis as a stage that

  18. The Role of Cytokine PF4 in the Antiviral Immune Response of Shrimp

    PubMed Central

    Chen, Yulei; Cao, Jiao; Zhang, Xiaobo

    2016-01-01

    During viral infection in vertebrates, cytokines play important roles in the host defense against the virus. However, the function of cytokines in invertebrates has not been well characterized. In this study, shrimp cytokines involved in viral infection were screened using a cytokine antibody microarray. The results showed that three cytokines, the Fas receptor (Fas), platelet factor 4 (PF4) and interleukin-22 (IL-22), were significantly upregulated in the white spot syndrome virus (WSSV)-challenged shrimp, suggesting that these cytokines played positive regulatory roles in the immune response of shrimp against the virus. Further experiments revealed that PF4 had positive effects on the antiviral immunity of shrimp by enhancing the shrimp phagocytic activity and inhibiting the apoptotic activity of virus-infected hemocytes. Therefore, our study presented a novel mechanism of cytokines in the innate immunity of invertebrates. PMID:27631372

  19. Monitoring host responses to the gut microbiota.

    PubMed

    Lichtman, Joshua S; Sonnenburg, Justin L; Elias, Joshua E

    2015-09-01

    The gastrointestinal (GI) ecosystem is increasingly understood to be a fundamental component of health, and has been identified as a new focal point for diagnosing, correcting and preventing countless disorders. Shotgun DNA sequencing has emerged as the dominant technology for determining the genetic and microbial composition of the gut microbiota. This technology has linked microbiota dysbioses to numerous GI diseases including inflammatory bowel disease, obesity and allergy, and to non-GI diseases like autism and depression. The importance of establishing causality in the deterioration of the host-microbiota relationship is well appreciated; however, discovery of candidate molecules and pathways that underlie mechanisms remains a major challenge. Targeted approaches, transcriptional assays, cytokine panels and imaging analyses, applied to animals, have yielded important insight into host responses to the microbiota. However, non-invasive, hypothesis-independent means of measuring host responses in humans are necessary to keep pace with similarly unbiased sequencing efforts that monitor microbes. Mass spectrometry-based proteomics has served this purpose in many other fields, but stool proteins exist in such diversity and dynamic range as to overwhelm conventional proteomics technologies. Focused analysis of host protein secretion into the gut lumen and monitoring proteome-level dynamics in stool provides a tractable route toward non-invasively evaluating dietary, microbial, surgical or pharmacological intervention efficacies. This review is intended to guide GI biologists and clinicians through the methods currently used to elucidate host responses in the gut, with a specific focus on mass spectrometry-based shotgun proteomics applied to the study of host protein dynamics within the GI ecosystem.

  20. [Cytokines in bone diseases. What is cytokine?].

    PubMed

    Murakami, Yousuke; Kohsaka, Hitoshi

    2010-10-01

    Cytokines have an essential role for cell-cell communication. They can regulate cell proliferation, differentiation, survival, and function. Interaction of cell surface receptor with cytokines is necessary for control of physiological responses. Activation of cytokine receptors transduces specific signal in the receptor-expressing cells, resulting that cytokines can regulate specific cell population. Thus, cytokines contribute directly or indirectly to morphogenesis, host defense and immune response, play critical roles for homeostasis and development.

  1. Distinct cytokine pattern in response to different bacterial pathogens in human brain abscess.

    PubMed

    Bajpai, Anamika; Prasad, Kashi Nath; Mishra, Priyanka; Singh, Aloukick Kumar; Gupta, Rakesh Kumar; Ojha, Bal Krishan

    2014-08-15

    Brain abscess is a focal suppurative process. Host inflammatory response in Gram type and specific bacteria has not been studied in brain abscess. A total of 57 brain abscess patients with monomicrobial infections were studied for Th1 (TNF-α, IFN-γ, IL1-β), Th2 (IL-4, IL-10) and Th17 (IL-17, IL-23) cytokine response by reverse-transcriptase PCR and ELISA. Th1 and Th17 cytokines were significantly elevated in Gram positive (Staphylococcus aureus and Streptococcus intermedius) and Th2 cytokine (IL-10) in Gram negative (Bacteroides fragilis and Escherichia coli) infections (p<0.05). Cytokine levels were significantly higher in abscess than blood (p<0.001). Elevated levels of several inflammatory cytokines (TNF-α, IFN-γ, IL1-β, IL-17 and IL-23) were associated with the duration of symptoms; predisposing factors also influenced the levels of several cytokines. The expression of inflammatory cytokines in abscess was influenced by the bacterial pathogen, duration of symptoms and predisposing factors. Local milieu of brain plays significant role in secretion of various cytokines.

  2. Role of inflammatory cytokines in the response of solid cancers to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai; Cecic, Ivana; Dougherty, Graeme J.

    2001-04-01

    Photodynamic therapy (PDT) elicits a strong acute inflammatory response that has both local and systemic (acute phase response) attributes. The insult mediated by PDT-induced oxidative stress at the targeted site triggers a complex multifactorial response engaging host defence mechanisms associated with the inflammatory process to participate in the eradication of the treated tumor. Inflammatory cytokines are important mediators of critical events in this process as they regulate the activity of inflammatory, endothelial and other cells. The initial stimulus for enhanced production and release of cytokines likely originates from several types of events, such as activated transcription factors and complement deposition. The PDT-induced complement activation appears to be directly linked to the enhanced expression of various cytokines, including chemokines such as KC (in mouse models), and classic inflammatory cytokines such as IL-1β, TNF-α , IL-6 and IL-10. A variety of interventions that modulate the activity of particular cytokines performed in conjunction with PDT were shown to influence the therapy outcome. The treatments such as using blocking antibodies and local or systemic cytokine delivery may either reduce or dramatically improve the curative effect of PDT. The inflammatory and related cytokines that at present appear particularly interesting and merit further investigation for use as adjuvants to PDT are IL-3, IL-8, IL-15, TNF-α, IFN-γ, G-CSF and GM-CSF.

  3. Host response, obesity, and oral health

    PubMed Central

    Słotwiński, Robert

    2015-01-01

    Proper food choices are part of preventing or reducing the risk of dental caries and periodontal disease. A significant association has been proven between oral diseases and the incidence of systemic diseases. Obesity, just like smoking, is one of the major risk factors for oral disease and is a serious social problem that has reached epidemic proportions in many developed countries. The results of studies on periodontitis confirm the relationship between the values of body mass index (BMI) and the prevalence of periodontal diseases. Adipose tissue is an active endocrine organ and it performs many important functions in the body, such as thermal isolation and protection, storage, and secretion. Many cytokines are secreted proportionally to the amount of fat present and are actively involved in the metabolism of the whole system, including the functioning of the immune system. Therefore, obesity may alter the response of the host to the antigens derived from bacterial plaque, and thus cause disturbances in the inflammatory response in the course of periodontal disease. PMID:26557035

  4. Pseudomonas aeruginosa and Its Bacterial Components Influence the Cytokine Response in Thymocytes and Splenocytes

    PubMed Central

    Zimmermann, Corinna; Mausberg, Anne K.; Dehmel, Thomas; Kieseier, Bernd C.; Hartung, Hans-Peter; Hofstetter, Harald H.

    2016-01-01

    Infections with Pseudomonas aeruginosa may cause many different diseases. The spectrum of such infections in general includes inflammation and bacterial sepsis. Hospital-acquired pneumonia, naturally resistant to a wide range of antibiotics, is associated with a particularly high mortality rate in mechanically ventilated patients. The pathogenesis of P. aeruginosa is complex and mediated by several virulence factors, as well as cell-associated factors. We have previously demonstrated that stimulation with different bacteria triggers the cytokine response of thymocytes. In this study, we investigated the effect of P. aeruginosa and its different components on the cytokine production of immature and mature immune cells. We found that the induced cytokine pattern in the thymus and the spleen after infections with P. aeruginosa is primarily mediated by lipopolysaccharide (LPS) of the outer cell membrane, but other components of the bacterium can influence the cytokine secretion as well. Stimulation with heat-killed P. aeruginosa and LPS does not influence the amount of cytokine-producing CD4+ T cells but instead suppresses the emergence of Th17 cells. However, stimulation with P. aeruginosa or its components triggers the interleukin-17 (IL-17) response both in thymocytes and in splenocytes. We conclude that infections with P. aeruginosa affect the cytokine secretion of immature and mature cells and that IL-17 and Th17 cells play only a minor role in the development of pathological systemic inflammatory disease conditions during P. aeruginosa infections. Therefore, other inflammatory immune responses must be responsible for septic reactions of the host. PMID:26902726

  5. Human cytokine responses induced by Gram-positive cell walls of normal intestinal microbiota

    PubMed Central

    Chen, T; Isomäki, P; Rimpiläinen, M; Toivanen, P

    1999-01-01

    The normal microbiota plays an important role in the health of the host, but little is known of how the human immune system recognizes and responds to Gram-positive indigenous bacteria. We have investigated cytokine responses of peripheral blood mononuclear cells (PBMC) to Gram-positive cell walls (CW) derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (Eu.a.), Eubacterium limosum(Eu.l.), Lactobacillus casei(L.c.), and Lactobacillus fermentum (L.f.). Our results indicate that Gram-positive CW of the normal intestinal microbiota can induce cytokine responses of the human PBMC. The profile, level and kinetics of these responses are similar to those induced by lipopolysaccharide (LPS) or CW derived from a pathogen, Streptococcus pyogenes (S.p.). Bacterial CW are capable of inducing production of a proinflammatory cytokine, tumour necrosis factor-alpha (TNF-α), and an anti-inflammatory cytokine, IL-10, but not that of IL-4 or interferon-gamma (IFN-γ). Monocytes are the main cell population in PBMC to produce TNF-α and IL-10. Induction of cytokine secretion is serum-dependent; both CD14-dependent and -independent pathways are involved. These findings suggest that the human cytokine responses induced by Gram-positive CW of the normal intestinal microbiota are similar to those induced by LPS or Gram-positive CW of the pathogens. PMID:10540188

  6. A Secreted MIF Cytokine Enables Aphid Feeding and Represses Plant Immune Responses.

    PubMed

    Naessens, Elodie; Dubreuil, Géraldine; Giordanengo, Philippe; Baron, Olga Lucia; Minet-Kebdani, Naïma; Keller, Harald; Coustau, Christine

    2015-07-20

    Aphids attack virtually all plant species and cause serious crop damages in agriculture. Despite their dramatic impact on food production, little is known about the molecular processes that allow aphids to exploit their host plants. To date, few aphid salivary proteins have been identified that are essential for aphid feeding, and their nature and function remain largely unknown. Here, we show that a macrophage migration inhibitory factor (MIF) is secreted in aphid saliva. In vertebrates, MIFs are important pro-inflammatory cytokines regulating immune responses. MIF proteins are also secreted by parasites of vertebrates, including nematodes, ticks, and protozoa, and participate in the modulation of host immune responses. The finding that a plant parasite secretes a MIF protein prompted us to question the role of the cytokine in the plant-aphid interaction. We show here that expression of MIF genes is crucial for aphid survival, fecundity, and feeding on a host plant. The ectopic expression of aphid MIFs in leaf tissues inhibits major plant immune responses, such as the expression of defense-related genes, callose deposition, and hypersensitive cell death. Functional complementation analyses in vivo allowed demonstrating that MIF1 is the member of the MIF protein family that allows aphids to exploit their host plants. To our knowledge, this is the first report of a cytokine that is secreted by a parasite to modulate plant immune responses. Our findings suggest a so-far unsuspected conservation of infection strategies among parasites of animal and plant species.

  7. Host immune response in returning travellers infected with malaria

    PubMed Central

    2012-01-01

    Background Clinical observations suggest that Canadian-born (CB) travellers are prone to more severe malaria, characterized by higher parasite density in the blood, and severe symptoms, such as cerebral malaria and renal failure, than foreign-born travellers (FB) from areas of malaria endemicity. It was hypothesized that host cytokine and chemokine responses differ significantly in CB versus FB patients returning with malaria, contributing to the courses of severity. A more detailed understanding of the profiles of cytokines, chemokines, and endothelial activation may be useful in developing biomarkers and novel therapeutic approaches for malaria. Materials and methods The patient population for the study (n = 186) was comprised of travellers returning to Toronto, Canada between 2007 and 2011. The patient blood samples’ cytokine, chemokine and angiopoietin concentrations were determined using cytokine multiplex assays, and ELISA assays. Results Significantly higher plasma cytokine levels of IL-12 (p40) were observed in CB compared to FB travellers, while epidermal growth factor (EGF) was observed to be higher in FB than CB travellers. Older travellers (55 years old or greater) with Plasmodium vivax infections had significantly higher mean cytokine levels for IL-6 and macrophage colony-stimulating factor (M-CSF) than other adults with P. vivax (ages 18–55). Patients with P. vivax infections had significantly higher mean cytokine levels for monocyte chemotactic protein-1 (MCP-1), and M-CSF than patients with Plasmodium falciparum. Angiopoietin 2 (Ang-2) was higher for patients infected with P. falciparum than P. vivax, especially when comparing just the FB groups. IL-12 (p40) was higher in FB patients with P. vivax compared to P. falciparum. Il-12 (p40) was also higher in patients infected with P. vivax than those infected with Plasmodium ovale. For patients travelling to West Africa, IFN-γ and IL-6 was lower than for patients who were in other regions of Africa

  8. Clinical associations of host genetic variations in the genes of cytokines in critically ill patients.

    PubMed

    Belopolskaya, O B; Smelaya, T V; Moroz, V V; Golubev, A M; Salnikova, L E

    2015-06-01

    Host genetic variations may influence a changing profile of biochemical markers and outcome in patients with trauma/injury. The objective of this study was to assess clinical associations of single nucleotide polymorphisms (SNPs) in the genes of cytokines in critically ill patients. A total of 430 patients were genotyped for SNPs in the genes of pro- (IL1B, IL6, IL8) and anti-inflammatory (IL4, IL10, IL13) cytokines. The main end-points were sepsis, mortality and adult respiratory distress syndrome (ARDS). We evaluated the dynamic levels of bilirubin, blood urea nitrogen, creatine kinase, creatinine and lactate dehydrogenase in five points of measurements (between 1 and 14 days after admission) and correlated them with SNPs. High-producing alleles of proinflammatory cytokines protected patients against sepsis (IL1B -511A and IL8 -251A) and mortality (IL1B -511A). High-producing alleles of anti-inflammatory cytokines IL4 -589T and IL13 431A (144Gln) were less frequent in ARDS patients. The carriers of IL6 -174C/C genotypes were prone to the increased levels of biochemical markers and acute kidney and liver insufficiency. Genotype-dependent differences in the levels of biochemical indicators gradually increased to a maximal value on the 14th day after admission. These findings suggest that genetic variability in pro- and anti-inflammatory cytokines may contribute to different clinical phenotypes in patients at high risk of critical illness.

  9. Pro-inflammatory Cytokines Impair Vitamin D-induced Host Defense in Cultured Airway Epithelial Cells.

    PubMed

    Schrumpf, Jasmijn A; Amatngalim, Gimano D; Veldkamp, Joris B; Verhoosel, Renate M; Ninaber, Dennis K; Ordonez, Soledad R; van der Does, Anne M; Haagsman, Henk P; Hiemstra, Pieter S

    2017-02-23

    Vitamin D is a regulator of host defense against infections and induces expression of the antimicrobial peptide hCAP18/LL-37. Vitamin D deficiency is associated with chronic inflammatory lung diseases and respiratory infections. However, it is incompletely understood if and how (chronic) airway inflammation affects vitamin D metabolism and action. We hypothesized that long-term exposure of primary bronchial epithelial cells (PBEC) to pro-inflammatory cytokines alters their vitamin D metabolism, antibacterial activity and expression of hCAP18/LL-37. To investigate this, PBEC were differentiated at the air-liquid interphase for 14 days in presence of the pro-inflammatory cytokines TNF-α and IL-1β (TNF-α/IL-1β), and subsequently exposed to vitamin D (inactive 25(OH)D3 and active 1,25(OH)2D3). Expression of hCAP18/LL-37, vitamin D receptor (VDR) and enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) was determined using qPCR, Western blot and immunofluorescence staining. Furthermore, vitamin D-mediated antibacterial activity was assessed using non-typeable Haemophilus influenzae (NTHi). We found that TNF-α/IL-1β treatment reduced vitamin D-induced expression of hCAP18/LL-37 and killing of NTHi. In addition, CYP24A1 (a vitamin D-degrading enzyme) was increased by TNF-α/IL-1β, whereas CYP27B1 (that converts 25(OH)D3 to its active form) and VDR expression remained unaffected. Furthermore, we demonstrated that the TNF-α/IL-1β-mediated induction of CYP24A1 was at least in part mediated by the transcription factor specific protein 1 (Sp1) and the EGFR-MAPK-pathway. These findings indicate that TNF-α/IL-1β decreases vitamin D-mediated antibacterial activity and hCAP18/LL-37 expression via induction of CYP24A1, and suggests that chronic inflammation impairs protective responses induced by vitamin D.

  10. Modeling Systems-Level Regulation of Host Immune Responses

    PubMed Central

    Thakar, Juilee; Pilione, Mylisa; Kirimanjeswara, Girish; Harvill, Eric T; Albert, Réka

    2007-01-01

    Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections; we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods. PMID:17559300

  11. Tear cytokine response to multipurpose solutions for contact lenses

    PubMed Central

    Kalsow, Carolyn M; Reindel, William T; Merchea, Mohinder M; Bateman, Kirk M; Barr, Joseph T

    2013-01-01

    Purpose An increased risk of corneal infiltrative events has been noted with the use of certain contact lenses and multipurpose solutions (MPS). This study was designed to evaluate tear cytokine assay as a sensitive, objective, and quantitative measure of the ocular surface response to contact lens/MPS and to consider the assay’s clinical relevance in the context of other measures of ocular surface response. Methods Two MPS, ReNu® Fresh™ (RNF) and Opti-Free® RepleniSH (OFR), were used with daily wear silicone hydrogel contact lenses in a randomized, prospective crossover study involving 26 subjects. Clinical data collection (conjunctival hyperemia, ocular surface sensitivity, solution induced corneal staining (SICS) test score, and subjective responses) and tear cytokine assays were conducted masked. Responses were tracked as change from baseline throughout the experimental schedule. Results Similar response patterns for several inflammatory cytokines were seen throughout both phases: subjects who received OFR in Phase I had mean tear concentrations that were generally higher than those of the RNF Phase I group. OFR Phase I subjects had significant (P < 0.01) increases over baseline at day 1 and/or following washout for 13 cytokines (cc chemokine ligands [CCL] 3, CCL5, CCL11, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [INF]-γ, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-13, IL-15, IL-17, tumor necrosis factor [TNF]-α). These changes were not observed in RNF Phase I subjects, even though SICS test scores increased. Phase I OFR subjects also had increased dryness, while RNF Phase I subjects had decreased bulbar hyperemia. No changes were detected with respect to limbal hyperemia or surface sensitivity thresholds. Conclusion The tear cytokine assay can detect and differentiate contact lens/MPS induced increases in inflammatory cytokines. Changes in cytokine levels were consistent with measurement of hyperemia and dryness but not with

  12. Mycobacterium tuberculosis and the host response

    PubMed Central

    Kaufmann, Stefan H.E.; Cole, Stewart T.; Mizrahi, Valerie; Rubin, Eric; Nathan, Carl

    2005-01-01

    Mycobacterium tuberculosis remains a leading cause of morbidity and mortality worldwide. Advances reported at a recent international meeting highlight insights and controversies in the genetics of M. tuberculosis and the infected host, the nature of protective immune responses, adaptation of the bacillus to host-imposed stresses, animal models, and new techniques. PMID:15939785

  13. LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse

    SciTech Connect

    Islam, Zahidul; Pestka, James J. . E-mail: pestka@msu.edu

    2006-02-15

    Simultaneous exposure to lipopolysaccharide (LPS) markedly amplifies induction of proinflammatory cytokine expression as well as IL-1-driven lymphocyte apoptosis by trichothecene deoxynivalenol (DON) in the mouse. The purpose of this research was to test the hypothesis that LPS priming will sensitize a host to DON-induced proinflammatory cytokine induction and apoptosis. In mice primed with LPS (1 mg/kg bw) ip. and treated 8 h later with DON po., the minimum DON doses for inducing IL-1{alpha}, IL-1{beta}, IL-6 and TNF-{alpha} serum proteins and splenic mRNAs were significantly lower than the DON doses required for vehicle-primed mice. LPS priming also decreased onset time and dramatically increased magnitude and duration of cytokine responses. LPS-primed mice maintained heightened sensitivity to DON for up to 24 h. LPS priming doses as low as 50 {mu}g/kg bw evoked sensitization. DNA fragmentation analysis and flow cytometry also revealed that mice primed with LPS (1 mg/kg) for 8 h and exposed to DON (12.5 mg/kg) exhibited massive thymocyte loss by apoptosis 12 h later compared to mice exposed to DON or LPS alone. LPS priming decreased DON-induced p38 and ERK 1/2 phosphorylation suggesting that enhanced mitogen-activated protein kinase activation was not involved in increased cytokine responses. Taken together, exposure to LPS rendered mice highly susceptible to DON induction of cytokine expression and this correlated with increased apoptosis in the thymus.

  14. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

    Turroni, Francesca; Taverniti, Valentina; Ruas-Madiedo, Patricia; Duranti, Sabrina; Guglielmetti, Simone; Lugli, Gabriele Andrea; Gioiosa, Laura; Palanza, Paola; Margolles, Abelardo; van Sinderen, Douwe

    2014-01-01

    Here, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, with Bifidobacterium bifidum PRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure to B. bifidum PRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest that Bifidobacterium bifidum PRL2010 modulates the innate immune response of the host. PMID:24242237

  15. Protective host immune responses to Salmonella infection.

    PubMed

    Pham, Oanh H; McSorley, Stephen J

    2015-01-01

    Salmonella enterica serovars Typhi and Paratyphi are the causative agents of human typhoid fever. Current typhoid vaccines are ineffective and are not widely used in endemic areas. Greater understanding of host-pathogen interactions during Salmonella infection should facilitate the development of improved vaccines to combat typhoid and nontyphoidal Salmonellosis. This review will focus on our current understanding of Salmonella pathogenesis and the major host immune components that participate in immunity to Salmonella infection. In addition, recent findings regarding host immune mechanisms in response to Salmonella infection will be also discussed, providing a new perspective on the utility of improved tools to study the immune response to Salmonella infections.

  16. Immune response to the cestode Hymenolepis nana: cytokine production during infection with eggs or cysts.

    PubMed

    Conchedda, M; Bortoletti, G; Gabriele, F; Wakelin, D; Palmas, C

    1997-03-01

    Analysis of cytokine production (IFN-gamma, IL-2, IL-3, IL-4, IL-5) by in vitro Con A-stimulated mesenteric lymph node cells measured daily after egg or cyst infection of mice with Hymenolepis nana showed that cytokine production varies during parasite development and between different host strains (BALB/c and C3H/He mice). Egg infection stimulates a rapid increase in IFN-gamma, independent of mouse strain. In addition, in BALB/c mice a Th2-like response (IL-4, IL-5 secretion) was stimulated 4-5 days p.i., when the parasites are thought to begin their lumenal phase. After infection with cysts significant increases in IFN-gamma, IL-2, IL-4 and IL-5 were observed at the time when autoinfection with eggs is thought to occur. The level of IFN-gamma paralleled that seen after a primary egg infection. This suggests that there is a predominantly Th1-type response during the tissue phase of H. nana development and that, in BALB/c mice, a Th2 polarization occurs during the first few days of the lumenal phase. The cytokine patterns observed are discussed in relation to host responses during chronic helminth infection.

  17. Cytokines in Drosophila immunity.

    PubMed

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity.

  18. Host cell autophagy in immune response to zoonotic infections.

    PubMed

    Skendros, Panagiotis; Mitroulis, Ioannis

    2012-01-01

    Autophagy is a fundamental homeostatic process in which cytoplasmic targets are sequestered within double-membraned autophagosomes and subsequently delivered to lysosomes for degradation. Accumulating evidence supports the pivotal role of autophagy in host defense against intracellular pathogens implicating both innate and adaptive immunity. Many of these pathogens cause common zoonotic infections worldwide. The induction of the autophagic machinery by innate immune receptors signaling, such as TLRs, NOD1/2, and p62/SQSTM1 in antigen-presenting cells results in inhibition of survival and elimination of invading pathogens. Furthermore, Th1 cytokines induce the autophagic process, whereas autophagy also contributes to antigen processing and MHC class II presentation, linking innate to adaptive immunity. However, several pathogens have developed strategies to avoid autophagy or exploit autophagic machinery to their advantage. This paper focuses on the role of host cell autophagy in the regulation of immune response against intracellular pathogens, emphasizing on selected bacterial and protozoan zoonoses.

  19. Pathogen-associated porin turns IL-10 competent B-1a cells toward proinflammatory cytokine response.

    PubMed

    Ghosh, Amlan Kanti; Sinha, Debolina; Biswas, Ratna; Biswas, Tapas

    2016-12-01

    Shigellosis is a major problem in the developing countries causing mortality and morbidity particularly among the children. Shigella spp. harbours the epithelial cells of the human colon to infect the host and spread the disease. We analyzed the response of B-1a cells, the major component of the mucosal immune system to porin of Shigella dysenteriae type 1. We show that porin while proliferating B-1a cells, deplete Siglec-G, the inhibitory molecule present on B-1a cells. Adjuvanticity of porin has been shown to govern innate signaling for promoting host adaptive immune response. Up-regulation of CD69 and CD40 denotes activation of the cells parallel to abrogation of Siglec-G. As a result of cell activation, porin stimulated the inflammatory cytokines of CD5(+) B-1a cells, otherwise rich in IL-10. The work shows B-1a cell responses promote the immunopotentiating activity of porin.

  20. PTEN functions as a melanoma tumor suppressor by promoting host immune response.

    PubMed

    Dong, Y; Richards, J-Ae; Gupta, R; Aung, P P; Emley, A; Kluger, Y; Dogra, S K; Mahalingam, M; Wajapeyee, N

    2014-09-18

    Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.

  1. Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates

    PubMed Central

    Li, Jinrong; Li, Hong; Mao, Huawei; Yu, Meixing; Yang, Fan; Feng, Ting; Fan, Yingying; Lu, Qiao; Shen, Chongyang; Yin, Zhongwei; Mao, Meng; Tu, Wenwei

    2013-01-01

    The neonates, particularly small-for-gestational-age (SGA) ones, are susceptible to various microbial infections. Natural killer (NK) cells are critical components of host innate immunity system and the main source of the inflammatory cytokines, which provide critical protection during the early phase of viral infections before the development of an appropriate adaptive immune response. However, little is known about the antiviral effects of NK cells in neonates especially the SGA population. Herein, a prospective descriptive study was performed to determine the differences of NK cell immunity among adults, appropriate-for gestational-age (AGA) and SGA neonates. Adults have much higher NK cell number in peripheral blood than that in cord blood from neonates. In response to influenza virus stimulation, neonatal NK cells, especially SGA baby cells, expressed significantly lower antiviral cytokines including perforin, interferon (IFN)-γ and tumor-necrosis factor (TNF)-α responses than adult NK cells. In addition, the antiviral cytokine responses of NK cells were positively correlated with neonatal birth weight. Our data suggested that the depressed antiviral activity and less frequency of NK cells are likely to be responsible for the high susceptibility to microbial infection in neonates, at least in part. Improving the function of innate immunity may provide a new way to defend virus infection. PMID:23872919

  2. Yersinia type III effectors perturb host innate immune responses

    PubMed Central

    Pha, Khavong; Navarro, Lorena

    2016-01-01

    The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia

  3. Proteomic analysis of Fasciola hepatica excretory and secretory products (FhESPs) involved in interacting with host PBMCs and cytokines by shotgun LC-MS/MS.

    PubMed

    Liu, Qing; Huang, Si-Yang; Yue, Dong-Mei; Wang, Jin-Lei; Wang, Yujian; Li, Xiangrui; Zhu, Xing-Quan

    2017-02-01

    Fasciola hepatica is a helminth parasite with a worldwide distribution, which can cause chronic liver disease, fasciolosis, leading to economic losses in the livestock and public health in many countries. Control is mostly reliant on the use of drugs, and as a result, drug resistance has now emerged. The identification of F. hepatica genes involved in interaction between the parasite and host immune system is utmost important to elucidate the evasion mechanisms of the parasite and develop more effective strategies against fasciolosis. In this study, we aimed to identify molecules in F. hepatica excretory and secretory products (FhESPs) interacting with the host peripheral blood mononuclear cells (PBMCs), Th1-like cytokines (IL2 and IFN-γ), and Th17-like cytokines (IL17) by Co-IP combined with tandem mass spectrometry. The results showed that 14, 16, and 9 proteins in FhESPs could bind with IL2, IL17, and IFN-γ, respectively, which indicated that adult F. hepatica may evade the host immune responses through directly interplaying with cytokines. In addition, nine proteins in FhESPs could adhere to PBMCs. Our findings provided potential targets as immuno-regulators, and will be helpful to elucidate the molecular basis of host-parasite interactions and search for new potential proteins as vaccine and drug target candidates.

  4. Moxibustion activates host defense against herpes simplex virus type I through augmentation of cytokine production.

    PubMed

    Takayama, Yuko; Itoi, Manami; Hamahashi, Takashi; Tsukamoto, Noriyuki; Mori, Kazuya; Morishita, Daisuke; Wada, Kumiko; Amagai, Takashi

    2010-09-01

    Moxibustion is a technique used in traditional oriental medicine, the aim of which is to cure and/or prevent illness by activating a person's ability for self-healing. In this study, we assessed how moxibustion would affect the immune system and whether it would augment protective immunity. Mice were treated with moxibustion at Zusanli (ST36) acupoints; we analyzed mortality and cytokine activity in sera after infection with herpes simplex virus type 1 (HSV-1), and cytokine gene expression in the skin and the spleen without a virus challenge. Our study demonstrates that pretreatment of BALB/c mice with moxibustion resulted in a marked increase in the survival rate after infection with lethal doses of HSV-1, and elevated serum levels of IL-1β and IFN-γ on days 1 and 6 post-infection with HSV-1. Semi-quantitative RT-PCR assay showed that moxibustion treatment augmented the expression of IL-1α, IL-1β, IL-6, universal-IFN-α, MIP-1α, and TNF-α mRNA in the skin, and IL-1α, IL-1β, IL-12p40, IL-15, u-IFN-α, MIP-1α, and TNF-α mRNA in the spleen. Moreover, moxibustion induces augmentation of natural killer cell activity. Collectively, our study demonstrates that moxibustion activates protective responses against HSV-1 infection through the activation of cytokine production including IFN, and of NK cells.

  5. The Role of Virus Infection in Deregulating the Cytokine Response to Secondary Bacterial Infection.

    PubMed

    Mehta, Divya; Petes, Carlene; Gee, Katrina; Basta, Sameh

    2015-12-01

    Proinflammatory cytokines are produced by macrophages and dendritic cells (DCs) after infection to stimulate T helper (Th) cells, linking innate and adaptive immunity. Virus infections can deregulate the proinflammatory cytokine response like tumor necrosis factor-α and interleukin (IL)-2, making the host more susceptible to secondary bacterial infections. Studies using various viruses such as lymphocytic choriomeningitis virus, influenza A virus, and human immunodeficiency virus have revealed several intriguing mechanisms that account for the increased susceptibility to several prevalent bacterial infections. In particular, type I interferons induced during a virus infection have been observed to play a role in suppressing the production of some key antibacterial proinflammatory cytokines such as IL-23 and IL-17. Other suppressive mechanisms as a result of cytokine deregulation by viral infections include reduced function of immune cells such as DC, macrophage, natural killer, CD4(+), and CD8(+) T cells leading to impaired clearance of secondary bacterial infections. In this study, we highlight some of the immune mechanisms that become deregulated by viral infections, and can thus become defective during secondary bacterial infections.

  6. Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

    PubMed

    Hempstead, Andrew D; Isberg, Ralph R

    2015-12-08

    Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

  7. Recent progress in understanding host immunity to Avian Coccidiosis: Role of IL-17 Family Cytokines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Host-pathogen interaction leading to protection against coccidiosis is complex, involving many aspects of innate and adaptive immunity to intracellular parasites. Recent application of global gene expression microarray analysis to investigate gut innate immune response to Eimeria infections led to t...

  8. Endocrine dysfunction in sepsis: a beneficial or deleterious host response?

    PubMed

    Gheorghiţă, Valeriu; Barbu, Alina Elena; Gheorghiu, Monica Livia; Căruntu, Florin Alexandru

    2015-03-01

    Sepsis is a systemic, deleterious inflammatory host response triggered by an infective agent leading to severe sepsis, septic shock and multi-organ failure. The host response to infection involves a complex, organized and coherent interaction between immune, autonomic, neuroendocrine and behavioral systems. Recent data have confirmed that disturbances of the autonomic nervous and neuroendocrine systems could contribute to sepsis-induced organ dysfunction. Through this review, we aimed to summarize the current knowledge about the endocrine dysfunction as response to sepsis, specifically addressed to vasopressin, copeptin, cortisol, insulin and leptin. We searched the following readily accessible, clinically relevant databases: PubMed, UpToDate, BioMed Central. The immune system could be regarded as a "diffuse sensory organ" that signals the presence of pathogens to the brain through different pathways, such as the vagus nerve, endothelial activation/dysfunction, cytokines and neurotoxic mediators and the circumventricular organs, especially the neurohypophysis. The hormonal profile changes substantially as a consequence of inflammatory mediators and microorganism products leading to inappropriately low levels of vasopressin, sick euthyroid syndrome, reduced adrenal responsiveness to ACTH, insulin resistance, hyperglycemia as well as hyperleptinemia. In conclusion, clinical diagnosis of this "pan-endocrine illness" is frequently challenging due to the many limiting factors. The most important benefits of endocrine markers in the management of sepsis may be reflected by their potential to be used as biomarkers in different scoring systems to estimate the severity of the disease and the risk of death.

  9. Inflammasomes in host response to protozoan parasites.

    PubMed

    Zamboni, Dario S; Lima-Junior, Djalma S

    2015-05-01

    Inflammasomes are multimeric complexes of proteins that are assembled in the host cell cytoplasm in response to specific stress signals or contamination of the cytoplasm by microbial molecules. The canonical inflammasomes are composed of at least three main components: an inflammatory caspase (caspase-1, caspase-11), an adapter molecule (such as ASC), and a sensor protein (such as NLRP1, NLRP3, NLRP12, NAIP1, NAIP2, NAIP5, or AIM2). The sensor molecule determines the inflammasome specificity by detecting specific microbial products or cell stress signals. Upon activation, these molecular platforms facilitate restriction of microbial replication and trigger an inflammatory form of cell death called pyroptosis, thus accounting for the genesis of inflammatory processes. Inflammasome activation has been widely reported in response to pathogenic bacteria. However, recent reports have highlighted the important role of the inflammasomes in the host response to the pathogenesis of infections caused by intracellular protozoan parasites. Herein, we review the activation and specific roles of inflammasomes in recognition and host responses to intracellular protozoan parasites such as Trypanosoma cruzi, Toxoplasma gondii, Plasmodium spp., and Leishmania spp.

  10. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  11. Role of interleukin-12 family cytokines in the cellular response to mycobacterial disease.

    PubMed

    Méndez-Samperio, Patricia

    2010-05-01

    Interleukin (IL)-12 is a multifunctional cytokine acting as a key regulator of cell-mediated immune responses through the differentiation of naïve CD4+ T cells into type 1 helper T cells (Th1) producing interferon-gamma. As our knowledge of IL-12 family members is rapidly growing, it will be important to specify their involvement in the regulation of mycobacterial infection. This article is a review of the current knowledge regarding the functions of the IL-12 family cytokines in the immune host defense system against mycobacteria. Specifically, this review aims to describe recent scientific evidence concerning the protective role of some members of the IL-12 family cytokines for the control of mycobacterial infection, as well as to summarize knowledge of the potential use of the IL-12 family members as potent adjuvants in the prevention and treatment of mycobacterial infectious diseases. In addition, recent data supporting the importance of the IL-12 family members in mycobacterial diseases in relation to Th17 function are discussed. This examination will help to improve our understanding of the immune response to mycobacterial infection and also improve vaccine design and immunotherapeutic intervention against tuberculosis.

  12. Infection with arginase deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis1

    PubMed Central

    Muleme, Helen M; Reguera, Rosa M; Berard, Alicia; Azinwi, Richard; Jia, Ping; Okwor, Ifeoma B; Beverley, Stephen; Uzonna, Jude E

    2009-01-01

    The balance between the products of L-arginine metabolism in macrophages regulates the outcome of Leishmania major infection. L-arginine can be oxidized by host inducible nitric oxide synthase (iNOS) to produce nitric oxide (NO), which contributes to parasite killing. In contrast, L-arginine hydrolysis by host arginase blocks NO generation and provides polyamines, which can support parasite proliferation. Additionally, Leishmania encode their own arginase which has considereable potential to modulate infectivity and disease pathogenesis. Here, we compare the infectivity and impact on host cellular immune response in vitro and in vivo of wild-type (WT) L. major with that of a parasite arginase null mutant (arg-). We found that arg- L. major are impaired in their macrophage infectivity in vitro independent of host iNOS activities. As with in vitro results, the proliferation of arg- L. major in animal infections was also significantly impaired in vivo resulting in delayed onset of lesion development, attenuated pathology and low parasite burden. Despite this attenuated pathology, the production of cytokines by cells from the draining lymph node of mice infected with WT and arg- L. major was similar at all times tested. Interestingly, in vitro and in vivo arginase levels were significantly lower in arg- than in WT infected cases and were directly correlated with parasite numbers inside infected cells. These results suggest that Leishmania-encoded arginase enhances disease pathogenesis by augmenting host cellular arginase activities leading and that contrary to previous in vitro studies, the host cytokine response does not influence host arginase activity. PMID:19923451

  13. Identification of host response signatures of infection.

    SciTech Connect

    Branda, Steven S.; Sinha, Anupama; Bent, Zachary

    2013-02-01

    Biological weapons of mass destruction and emerging infectious diseases represent a serious and growing threat to our national security. Effective response to a bioattack or disease outbreak critically depends upon efficient and reliable distinguishing between infected vs healthy individuals, to enable rational use of scarce, invasive, and/or costly countermeasures (diagnostics, therapies, quarantine). Screening based on direct detection of the causative pathogen can be problematic, because culture- and probe-based assays are confounded by unanticipated pathogens (e.g., deeply diverged, engineered), and readily-accessible specimens (e.g., blood) often contain little or no pathogen, particularly at pre-symptomatic stages of disease. Thus, in addition to the pathogen itself, one would like to detect infection-specific host response signatures in the specimen, preferably ones comprised of nucleic acids (NA), which can be recovered and amplified from tiny specimens (e.g., fingerstick draws). Proof-of-concept studies have not been definitive, however, largely due to use of sub-optimal sample preparation and detection technologies. For purposes of pathogen detection, Sandia has developed novel molecular biology methods that enable selective isolation of NA unique to, or shared between, complex samples, followed by identification and quantitation via Second Generation Sequencing (SGS). The central hypothesis of the current study is that variations on this approach will support efficient identification and verification of NA-based host response signatures of infectious disease. To test this hypothesis, we re-engineered Sandia's sophisticated sample preparation pipelines, and developed new SGS data analysis tools and strategies, in order to pioneer use of SGS for identification of host NA correlating with infection. Proof-of-concept studies were carried out using specimens drawn from pathogen-infected non-human primates (NHP). This work provides a strong foundation for

  14. Cytokines in sleep regulation.

    PubMed

    Krueger, J M; Takahashi, S; Kapás, L; Bredow, S; Roky, R; Fang, J; Floyd, R; Renegar, K B; Guha-Thakurta, N; Novitsky, S

    1995-01-01

    The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the host's response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.

  15. New insights about host response to smallpox using microarray data

    PubMed Central

    Esteves, Gustavo H; Simoes, Ana CQ; Souza, Estevao; Dias, Rodrigo A; Ospina, Raydonal; Venancio, Thiago M

    2007-01-01

    Background Smallpox is a lethal disease that was endemic in many parts of the world until eradicated by massive immunization. Due to its lethality, there are serious concerns about its use as a bioweapon. Here we analyze publicly available microarray data to further understand survival of smallpox infected macaques, using systems biology approaches. Our goal is to improve the knowledge about the progression of this disease. Results We used KEGG pathways annotations to define groups of genes (or modules), and subsequently compared them to macaque survival times. This technique provided additional insights about the host response to this disease, such as increased expression of the cytokines and ECM receptors in the individuals with higher survival times. These results could indicate that these gene groups could influence an effective response from the host to smallpox. Conclusion Macaques with higher survival times clearly express some specific pathways previously unidentified using regular gene-by-gene approaches. Our work also shows how third party analysis of public datasets can be important to support new hypotheses to relevant biological problems. PMID:17718913

  16. Lymphotropism and host responses during acute wild-type canine distemper virus infections in a highly susceptible natural host.

    PubMed

    Nielsen, Line; Søgaard, Mette; Jensen, Trine Hammer; Andersen, Mads Klindt; Aasted, Bent; Blixenkrone-Møller, Merete

    2009-09-01

    The mechanisms behind the in vivo virulence of immunosuppressive wild-type morbillivirus infections are still not fully understood. To investigate lymphotropism and host responses, we have selected the natural host model of canine distemper virus (CDV) infection in mink. This model displays multisystemic infection, similar to measles virus and rinderpest virus infections in their susceptible natural hosts. The wild-type CDVs investigated provoked marked virulence differences, inducing mild versus marked to severe acute disease. The mildly virulent wild-type virus induced transient lymphopenia, despite the development of massive infection of peripheral blood mononuclear cells (PBMCs) exceeding that determined for the highly virulent wild-type virus, indicating an inverse relationship between acute virulence and the extent of viraemia in the investigated wild-type viruses. Single-cell cytokine production in PBMCs was investigated throughout the acute infections. We observed Th1- and Th2-type cytokine responses beginning in the prodromal phase, and late inflammatory responses were shared between the wild-type infections.

  17. Gut Microbial Metabolites Fuel Host Antibody Responses.

    PubMed

    Kim, Myunghoo; Qie, Yaqing; Park, Jeongho; Kim, Chang H

    2016-08-10

    Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.

  18. Nasal cytokine responses to natural colds in asthmatic children

    PubMed Central

    Lewis, Toby C.; Henderson, Tiffany A.; Carpenter, Ashley R.; Ramirez, Ixsy A.; McHenry, Christina L.; Goldsmith, Adam M.; Ren, Xiaodan; Mentz, Graciela B.; Mukherjee, Bhramar; Robins, Thomas G.; Joiner, Terence A.; Mohammad, Layla S.; Nguyen, Emily R.; Burns, Mark A.; Burke, David T.; Hershenson, Marc B.

    2014-01-01

    Background The mechanisms by which viruses induce asthma exacerbations are not well-understood. Objective We characterized fluctuations in nasal aspirate cytokines during naturally-occurring respiratory viral infections in children with asthma. Methods Sixteen children underwent home collections of nasal aspirates when they were without cold symptoms and again during self-reported respiratory illnesses. The presence of viral infection was ascertained by multiplex PCR. Cytokines were measured by multiplex immune assay. mRNA expression for selected markers of viral infection was measured by RT-PCR. A cumulative respiratory symptom score was calculated for each day of measurement. Generalized estimated equations were used to evaluate associations between viral infection and marker elevation, and between marker elevation and symptom score. Results The 16 patients completed a total of 37 weeks of assessment (15 “well” weeks; 22 self-assessed “sick” weeks). Viral infections were detected in three of the “well” weeks and 17 of the “sick” weeks (10 rhinovirus, 3 coronavirus, 2 influenza A, 2 influenza B, 2 respiratory syncytial virus, 1 parainfluenza). Compared to virus-negative well weeks, nasal aspirate IFN-γ, CXCL8/IL-8, CXCL10/IP-10, CCL5/RANTES, CCL11/eotaxin-1, CCL2/MCP-1, CCL4/MIP-1β, CCL7/MCP-3 and CCL20/MIP3α protein levels increased during virus-positive sick weeks. Only a subset of cytokines (IFN-γ, CXCL8, CCL2, CCL4, CCL5 and CCL20) correlated with self-reported respiratory tract symptoms. While many aspirates were dilute and showed no mRNA signal, viral infection significantly increased the number of samples that were positive for IFN-λ1, IFN-λ2/3, TLR3, RIG-I and IRF7 mRNA. Conclusions & Clinical Relevance We conclude that, in children with asthma, naturally-occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs and IFN-responsive genes. PMID:23181789

  19. PDT-induced inflammatory and host responses.

    PubMed

    Firczuk, Małgorzata; Nowis, Dominika; Gołąb, Jakub

    2011-05-01

    Photodynamic therapy (PDT) is used in the management of neoplastic and nonmalignant diseases. Its unique mechanisms of action include direct cytotoxic effects exerted towards tumor cells, destruction of tumor and peritumoral vasculature and induction of local acute inflammatory reaction. The latter develops in response to (1) damage to tumor and stromal cells that leads to the release of cell death-associated molecular patterns (CDAMs) or damage associated molecular patterns (DAMPs), (2) early vascular changes that include increased vascular permeability, vascular occlusion, and release of vasoactive and proinflammatory mediators, (3) activation of alternative pathway of complement leading to generation of potent chemotactic factors, and (4) induction of signaling cascades and transcription factors that trigger secretion of cytokines, matrix metalloproteinases, or adhesion molecules. The majority of studies indicate that induction of local inflammatory response contributes to the antitumor effects of PDT and facilitates development of systemic immunity. However, the degree of PDT-induced inflammation and its subsequent contribution to its antitumor efficacy depend on multiple parameters, such as chemical nature, concentration and subcellular localization of the photosensitizers, the spectral characteristics of the light source, light fluence and fluence rate, oxygenation level, and tumor type. Identification of detailed molecular mechanisms and development of therapeutic approaches modulating PDT-induced inflammation will be necessary to tailor this treatment to particular clinical conditions.

  20. Impact of host genetic polymorphisms on vaccine induced antibody response

    PubMed Central

    Linnik, Janina E.; Egli, Adrian

    2016-01-01

    ABSTRACT Many host- and vaccine-specific factors modulate an antibody response. Host genetic polymorphisms, in particular, modulate the immune response in multiple ways on different scales. This review article describes how information on host genetic polymorphisms and corresponding immune cascades may be used to generate personalized vaccine strategies to optimize the antibody response. PMID:26809773

  1. Systems approach to characterizing cell signaling in host-pathogen response to staphylococcus toxin.

    SciTech Connect

    Ambrosiano, J. J.; Gupta, G.; Gray, P. C.; Hush, D. R.; Fugate, M. L.; Cleland, T. J.; Roberts, R. M.; Hlavacek, W. S.; Smith, J. L.

    2002-01-01

    The mammalian immune system is capable of highly sensitive and specific responses when challenged by pathogens. It is believed that the human immune repertoire - the total number of distinct antigens that can be recognized - is between 10{sup 9} and 10{sup 11}. The most specific responses are cell mediated and involve complex and subtle communications among the immune cells via small proteins known as cytokines. The details of host-pathogen response are exceedingly complex, involving both intracellular and extracellular mechanisms. These include the presentation of antigen by B cells to helper T cells and subsequent stimulation of signal transduction pathways and gene expression within both B and T-cell populations. These in turn lead to the secretion of cytokines and receptor expression. Intercellular cytokine signaling can trigger a host of immune responses including the proliferation and specialization of naive immune cells and the marshaling of effector cells to combat infection. In the ever-evolving game of threat and countermeasure played out by pathogens and their intended hosts, there are direct assaults aimed at subverting the immune system's ability to recognize antigens and respond effectively to challenge by pathogens. Staphylococcus is one of these. Staph bacteria secrete a variety of toxins known generically as superantigens. Superantigen molecules bind simultaneously to the MHC receptors of antigen presenting cells and the TCR receptors of helper T cells, locking them in place and leading to overstimulation. This strategy can effectively burn out the immune system in a matter of days.

  2. Cytokine response after severe RSV bronchiolitis in early life

    PubMed Central

    Castro, Mario; Schweiger, Toni; Yin-DeClue, Huiquing; Ramkumar, Thiruvamoor P; Christie, Chandrika; Zheng, Jie; Cohen, Rebecca; Schechtman, Kenneth B; Strunk, Robert; Bacharier, Leonard B.

    2008-01-01

    Background Immune response following viral infection usually involves Th1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a Th2-predominant phenotype. Objective To understand the early and subsequent immunologic response to a serious RSV infection in children over time. Methods 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life (RBEL) study. Peripheral blood T cells were obtained immediately following RSV infection and at 2, 4 and 6 years of age, stimulated with PMA and ionomycin, and analyzed for interleukin (IL)-2, -4, and - 13 and interferon-γ (IFN-γ) by flow cytometry and real time PCR. Results 48% (n=97) of the children developed asthma (physician-diagnosed) and 48% (n=97) had eczema by age 6. 32% (n=48 of 150) developed allergic sensitization by 3 yrs of age. Children with asthma had lower IL-13 expression at 6 yrs of age than those without (p=0.001). IFN-γ, IL-2 and -4 levels did not differ by asthma or eczema status during follow-up (all p>0.05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all p>0.05). Conclusion Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema or allergic sensitization was not associated with a Th2 phenotype in the peripheral blood. PMID:18760461

  3. Early Cytokine Response to Infection with Pathogenic vs Non-Pathogenic Organisms in a Mouse Model of Endodontic Infection

    PubMed Central

    Matsui, Aritsune; Stephens, Danielle; Kantarci, Alpdogan; Rittling, Susan R.

    2015-01-01

    Using the subcutaneous chamber model of infection, we showed previously that a mixture of four endodontic pathogens (EP: P. intermedia, F. nucleatum, S. intermedius and P. micra) are able to persist without clearance for up to seven days, while a non-pathogenic oral species, S. mitis, was substantially cleared in this time. Here we have compared the cytokine response inside the chambers against these microorganisms. A majority of cytokines tested (17/24) showed different patterns of expression. Several cytokines had a peak of expression at 2 h after infection in response to the EP, while none showed this pattern in S. mitis infections. Chemokines were uniformly present at similar or higher levels in response to S. mitis, with redundant expression of CXCR2 ligands, while several growth/survival factors were present at higher levels in EP infections. Protease activity expressed by EP may be responsible for the lower levels of some chemokines. T-cell associated cytokines were in general expressed at extremely low levels, and did not differ between the two infections. The inflammatory markers IL-6, IL-1α and IL1-β were expressed at similar levels in both infections at early times, while TNFα was preferentially present in S. mitis infections. In EP infected chambers, reciprocal changes in levels of IL-6 and IL-1α were observed at later times suggesting a switch in the inflammatory response. Analysis of the cytokine response to infection with the individual species from the EP mix suggests that P. intermedia drives this inflammatory switch. Together these results show a surprising level of divergence of the host response to pathogenic and non-pathogenic organisms associated with oral infections, and supports a dominant effect of P. intermedia in polymicrobial endodontic infections. PMID:26171605

  4. In Vivo Cytokine-Associated Responses to Biomaterials

    PubMed Central

    Schutte, RJ; Xie, L; Klitzman, B; Reichert, WM

    2008-01-01

    Cytokines, chemokines, and growth factors were analyzed periodically over eight weeks from the wound exudate fluid surrounding biomaterials implanted subcutaneously within stainless steel mesh cages. TNF-α, MCP-1, MIP-1α, IL-2, IL-6, IL-1β, VEGF, IL-4, and IL-10 were measured from exudate samples collected from cages containing specimens of polyethylene (PE), polyurethane (PU), or organo-tin polyvinyl chloride (ot-PVC). Empty cages served as negative controls, and lipopolysaccharide (LPS) served as a positive control. Cytokine, chemokine, and growth factor concentrations decreased from the time of implantation to eight weeks post-implantation, and there was an overall increase in cytokine, chemokine, and growth factor production for material-containing cages compared to empty cages. However, cytokine production was only modestly affected by the different surface chemistries of the three implanted polymeric materials. PMID:18849070

  5. In vivo cytokine-associated responses to biomaterials.

    PubMed

    Schutte, Robert J; Xie, Lola; Klitzman, Bruce; Reichert, William M

    2009-01-01

    Cytokines, chemokines, and growth factors were analyzed periodically over eight weeks from the wound exudate fluid surrounding biomaterials implanted subcutaneously within stainless steel mesh cages. TNF-alpha, MCP-1, MIP-1alpha, IL-2, IL-6, IL-1beta, VEGF, IL-4, and IL-10 were measured from exudate samples collected from cages containing specimens of polyethylene (PE), polyurethane (PU), or organotin polyvinyl chloride (ot-PVC). Empty cages served as negative controls, and lipopolysaccharide (LPS) served as a positive control. Cytokine, chemokine, and growth factor concentrations decreased from the time of implantation to eight weeks post-implantation, and there was an overall increase in cytokine, chemokine, and growth factor production for material-containing cages compared to empty cages. However, cytokine production was only modestly affected by the different surface chemistries of the three implanted polymeric materials.

  6. Systemic cytokine and interferon responsiveness Patterns in HIV and HCV mono and co-infections.

    PubMed

    Fernandez-Botran, Rafael; Joshi-Barve, Swati; Ghare, Smita; Barve, Shirish; Young, Mary; Plankey, Michael; Bordon, Jose

    2014-11-01

    The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV(+)/HCV(+)), HCV mono-infected (HIV(-)/HCV(+)), HIV mono-infected (HIV(+)/HCV(-)) female patients and HIV- and HCV-uninfected women (HIV(-)/HCV(-)) who had enrolled in the Women's Interagency HIV Study (WIHS). HIV(+)/HCV(+) women had higher plasma levels of pro-inflammatory cytokines as well as caspase-1 compared with other groups. Both HIV(+)/HCV(+) and HIV(+)/HCV(-) women had significantly higher sCD14 levels compared with other groups. Peripheral blood mononuclear cells from HCV mono-infected patients had reduced levels of phosphorylation of STAT1 compared with other groups as well as lower basal levels of expression of the IFN-stimulated genes, OAS1, ISG15, and USP18 (UBP43). Basal expression of USP18, a functional antagonist of ISG15, as well as USP18/ISG15 ratios were increased in the HIV(+)/HCV(+) group compared with HIV(-)/HCV(+) and HIV(+)/HCV(-) groups. A more pronounced systemic inflammatory profile as well as increased expression ratios of USP18 to ISG15 may contribute to the more rapid progression of liver disease in HIV(+)/HCV(+) individuals.

  7. Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus

    PubMed Central

    Uematsu, Takayuki; Fujita, Tomoko; Nakaoka, Hiroki J.; Hara, Toshiro; Kobayashi, Noritada; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

    2016-01-01

    Influenza virus (IFV) infection is a common cause of severe pneumonia. Studies have suggested that excessive activation of the host immune system including macrophages is responsible for the severe pathologies mediated by IFV infection. Here, we focused on the X11 protein family member Mint3/Apba3, known to promote ATP production via glycolysis by activating hypoxia inducible factor-1 (HIF-1) in macrophages, and examined its roles in lung pathogenesis and anti-viral defence upon IFV infection. Mint3-deficient mice exhibited improved influenza pneumonia with reduced inflammatory cytokines/chemokine levels and neutrophil infiltration in the IFV-infected lungs without alteration in viral burden, type-I interferon production, or acquired immunity. In macrophages, Mint3 depletion attenuated NF-κB signalling and the resultant cytokine/chemokine production in response to IFV infection by increasing IκBα and activating the cellular energy sensor AMPK, respectively. Thus, Mint3 might represent one of the likely therapeutic targets for the treatment of severe influenza pneumonia without affecting host anti-viral defence through suppressing macrophage cytokine/chemokine production. PMID:27883071

  8. Host response to synthetic mesh in women with mesh complications

    PubMed Central

    Nolfi, Alexis L.; Brown, Bryan N.; Liang, Rui; Palcsey, Stacy L.; Bonidie, Michael J.; Abramowitch, Steven D.; Moalli, Pamela A.

    2016-01-01

    BACKGROUND Despite good anatomic and functional outcomes, urogynecologic polypropylene meshes that are used to treat pelvic organ prolapse and stress urinary incontinence are associated with significant complications, most commonly mesh exposure and pain. Few studies have been performed that specifically focus on the host response to urogynecologic meshes. The macrophage has long been known to be the key cell type that mediates the foreign body response. Conceptually, macrophages that respond to a foreign body can be dichotomized broadly into M1 proinflammatory and M2 proremodeling subtypes. A prolonged M1 response is thought to result in chronic inflammation and the formation of foreign body giant cells with potential for ongoing tissue damage and destruction. Although a limited M2 predominant response is favorable for tissue integration and ingrowth, excessive M2 activity can lead to accelerated fibrillar matrix deposition and result in fibrosis and encapsulation of the mesh. OBJECTIVE The purpose of this study was to define and compare the macrophage response in patients who undergo mesh excision surgery for the indication of pain vs a mesh exposure. STUDY DESIGN Patients who were scheduled to undergo a surgical excision of mesh for pain or exposure at Magee-Womens Hospital were offered enrollment. Twenty-seven mesh-vagina complexes that were removed for the primary complaint of a mesh exposure (n = 15) vs pain in the absence of an exposure (n = 12) were compared with 30 full-thickness vaginal biopsy specimens from women who underwent benign gynecologic surgery without mesh. Macrophage M1 proinflammatory vs M2 proremodeling phenotypes were examined via immunofluorescent labeling for cell surface markers CD86 (M1) vs CD206 (M2) and M1 vs M2 cytokines via enzyme-linked immunosorbent assay. The amount of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) proteolytic enzymes were quantified by zymography and substrate degradation assays, as an

  9. Using host response modifiers in the treatment of periodontal disease.

    PubMed

    Novak, M John; Donley, Timothy G

    2002-01-01

    Periodontal disease is the result of a complex interaction between microbial plaque, the host's inflammatory response to the plaque, and host modifying factors (e.g., smoking, diabetes, genetics) that may have an impact on the disease process. It is known that plaque initiates periodontal disease but that the host response is responsible for the destruction of periodontal tissues. This article describes why host response modifiers may be used to help control inflammation and tissue destruction as part of the initial phase of periodontal therapy in selected patient groups.

  10. B cells responses and cytokine production are regulated by their immune microenvironment.

    PubMed

    Vazquez, Monica I; Catalan-Dibene, Jovani; Zlotnik, Albert

    2015-08-01

    The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.

  11. Comparison of cytokine responses between dogs with sepsis and dogs with immune-mediated hemolytic anemia.

    PubMed

    Johnson, Valerie; Burgess, Brandy; Morley, Paul; Bragg, Ryan; Avery, Anne; Dow, Steven

    2016-11-01

    Cytokine abnormalities have been described previously in dogs with varied immune mediated and inflammatory conditions such as IMHA and sepsis. The purpose of this study was to establish references ranges for cytokine levels in dogs and to compare cytokine levels in normal dogs and dogs with two common inflammatory diseases (sepsis and IMHA). We hypothesized that cytokine response profiles in dogs with sepsis would be significantly different from those in dogs with IMHA due to the very different etiologies of the two diseases. Concentrations of 14 different cytokines in serum were measured and values grouped according to cytokine function. Serum from clinically normal dogs was used to establish cytokine concentration reference ranges. Rank values for each of the 4 cytokine groups were then compared statistically between healthy control, septic and IMHA dogs. This analysis revealed differences in cytokine groups between dogs with sepsis and IMHA when compared to healthy control dogs but no difference between dogs with either of these conditions. In conclustion, dogs in the early stage of sepsis and IMHA have similar circulating cytokines despite different etiologies suggesting activation of common immunologic pathways. This may have implications for immunotherapy of immune mediated diseases in dogs of varying etiology.

  12. CYTOKINE PROFILES DO NOT PREDICT ANTIBODY RESPONSES AND RESPIRATORY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO ISOCYANATES

    EPA Science Inventory

    Rationale: Cytokine profiling of local lymph node responses following dermal exposure has been proposed as a test to identify chemicals that pose a risk of occupational asthma. The present study tested the hypothesis that relative differences in cytokine profiles for dini...

  13. Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis.

    PubMed

    Lewis, Eric R G; David, Victoria R; Doyle, Adina L; Rajabi, Khadijeh; Kiefer, Jeffrey A; Pirrotte, Patrick; Barker, Bridget M

    2015-10-01

    Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.

  14. Proteomic Characterization of Host Response to Yersinia pestis

    SciTech Connect

    Chromy, B; Perkins, J; Heidbrink, J; Gonzales, A; Murhpy, G; Fitch, J P; McCutchen-Maloney, S

    2004-05-11

    Host-pathogen interactions result in protein expression changes within both the host and the pathogen. Here, results from proteomic characterization of host response following exposure to Yersinia pestis, the causative agent of plague, and to two near neighbors, Y. pseudotuberculosis and Y. enterocolitica, are reported. Human monocyte-like cells were chosen as a model for macrophage immune response to pathogen exposure. Two-dimensional electrophoresis followed by mass spectrometry was used to identify host proteins with differential expression following exposure to these three closely related Yersinia species. This comparative proteomic characterization of host response clearly shows that host protein expression patterns are distinct for the different pathogen exposures, and contributes to further understanding of Y. pestis virulence and host defense mechanisms. This work also lays the foundation for future studies aimed at defining biomarkers for presymptomatic detection of plague.

  15. Response of host plants to periodical cicada oviposition damage.

    PubMed

    Flory, S Luke; Mattingly, W Brett

    2008-06-01

    Insect oviposition on plants is widespread across many systems, but studies on the response of host plants to oviposition damage are lacking. Although patterns of oviposition vary spatially and temporally, ovipositing insects that exhibit outbreak characteristics may have strong effects on host plants during peak abundance. Periodical cicadas (Magicicada spp.), in particular, may reduce the performance of host plants when they synchronously emerge in massive numbers to mate and oviposit on host plants. Here we provide the first experimental manipulation of host plant use by periodical cicadas to evaluate the impact of cicada oviposition on plant performance across a diversity of host species within an ecologically relevant setting. Using a randomized block design, we established a plantation of three native and three exotic host plant species common to the successional forests in which cicadas occur. During the emergence of Brood X in 2004, we employed a highly effective cicada exclusion treatment by netting half of the host plants within each block. We assessed multiple measures of host plant performance, including overall plant growth and the growth and reproduction of individual branches, across three growing seasons. Despite our thorough assessment of potential host plant responses to oviposition damage, cicada oviposition did not generally inhibit host plant performance. Oviposition densities on unnetted host plants were comparable to levels documented in other studies, reinforcing the ecological relevance of our results, which indicate that cicada oviposition damage did not generally reduce the performance of native or exotic host plants.

  16. Cytokine responses in the common cold and otitis media.

    PubMed

    Wine, Todd M; Alper, Cuneyt M

    2012-12-01

    Cytokines are a group of diverse molecules that influence the function of every organ system. They are most well studied in their effects on the immune system and their integral role in mediating inflammation. The common cold and otitis media are two such disease states, and much has been learned about the various effects of cytokines in each disease. Most often the viruses isolated include rhinovirus (RV), respiratory syncytial virus (RSV), adenovirus, coronavirus, and picornavirus. Otitis media, sinusitis, bronchiolitis, pneumonia, and asthma exacerbation are commonly accepted as complications of viral upper respiratory tract infections. Furthermore, otitis media and upper respiratory infections are inextricably linked in that the majority (>70 %) of cases of acute otitis media occur as complications of the common cold. Cytokine polymorphisms have been associated with the severity of colds as well as the frequency of otitis media. This article attempts to update the reader on various studies that have recently been published regarding the role of cytokines in these two disease entities.

  17. Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus.

    PubMed

    Roberts, Kimberly K; Hill, Terence E; Davis, Melissa N; Holbrook, Michael R; Freiberg, Alexander N

    2015-07-01

    Rift Valley fever virus (RVFV) is the most pathogenic member of the genus Phlebovirus within the family Bunyaviridae, and can cause severe disease in humans and livestock. Until recently, limited information has been published on the cellular host response elicited by RVFV, particularly in macrophages and dendritic cells, which play critical roles in stimulating adaptive and innate immune responses to viral infection. In an effort to define the initial response of host immunomodulatory cells to infection, primary mouse bone marrow derived macrophages (BMDM) were infected with the pathogenic RVFV strain ZH501, or attenuated strains MP-12 or MP-12 based Clone13 type (rMP12-C13 type), and cytokine secretion profiles examined. The secretion of T helper (Th)1-associated antiviral cytokines, chemokines and various interleukins increased rapidly after infection with the attenuated rMP12-C13 type RVFV, which lacks a functional NSs virulence gene. In comparison, infection with live-attenuated MP-12 encoding a functional NSs gene appeared to cause a delayed immune response, while pathogenic ZH501 ablates the immune response almost entirely. These data demonstrate that NSs can inhibit components of the BMDM antiviral response and supports previous work indicating that NSs can specifically regulate the type I interferon response in macrophages. Furthermore, our data demonstrate that genetic differences between ZH501 and MP-12 reduce the ability of MP-12 to inhibit antiviral signalling and subsequently reduce virulence in BMDM, demonstrating that viral components other than NSs play a critical role in regulating the host response to RVFV infection.

  18. Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

    PubMed Central

    Roberts, Kimberly K.; Hill, Terence E.; Davis, Melissa N.; Holbrook, Michael R.

    2015-01-01

    Rift Valley fever virus (RVFV) is the most pathogenic member of the genus Phlebovirus within the family Bunyaviridae, and can cause severe disease in humans and livestock. Until recently, limited information has been published on the cellular host response elicited by RVFV, particularly in macrophages and dendritic cells, which play critical roles in stimulating adaptive and innate immune responses to viral infection. In an effort to define the initial response of host immunomodulatory cells to infection, primary mouse bone marrow derived macrophages (BMDM) were infected with the pathogenic RVFV strain ZH501, or attenuated strains MP-12 or MP-12 based Clone13 type (rMP12-C13 type), and cytokine secretion profiles examined. The secretion of T helper (Th)1-associated antiviral cytokines, chemokines and various interleukins increased rapidly after infection with the attenuated rMP12-C13 type RVFV, which lacks a functional NSs virulence gene. In comparison, infection with live-attenuated MP-12 encoding a functional NSs gene appeared to cause a delayed immune response, while pathogenic ZH501 ablates the immune response almost entirely. These data demonstrate that NSs can inhibit components of the BMDM antiviral response and supports previous work indicating that NSs can specifically regulate the type I interferon response in macrophages. Furthermore, our data demonstrate that genetic differences between ZH501 and MP-12 reduce the ability of MP-12 to inhibit antiviral signalling and subsequently reduce virulence in BMDM, demonstrating that viral components other than NSs play a critical role in regulating the host response to RVFV infection. PMID:25759029

  19. Metabolic host responses to infection by intracellular bacterial pathogens

    PubMed Central

    Eisenreich, Wolfgang; Heesemann, Jürgen; Rudel, Thomas; Goebel, Werner

    2013-01-01

    The interaction of bacterial pathogens with mammalian hosts leads to a variety of physiological responses of the interacting partners aimed at an adaptation to the new situation. These responses include multiple metabolic changes in the affected host cells which are most obvious when the pathogen replicates within host cells as in case of intracellular bacterial pathogens. While the pathogen tries to deprive nutrients from the host cell, the host cell in return takes various metabolic countermeasures against the nutrient theft. During this conflicting interaction, the pathogen triggers metabolic host cell responses by means of common cell envelope components and specific virulence-associated factors. These host reactions generally promote replication of the pathogen. There is growing evidence that pathogen-specific factors may interfere in different ways with the complex regulatory network that controls the carbon and nitrogen metabolism of mammalian cells. The host cell defense answers include general metabolic reactions, like the generation of oxygen- and/or nitrogen-reactive species, and more specific measures aimed to prevent access to essential nutrients for the respective pathogen. Accurate results on metabolic host cell responses are often hampered by the use of cancer cell lines that already exhibit various de-regulated reactions in the primary carbon metabolism. Hence, there is an urgent need for cellular models that more closely reflect the in vivo infection conditions. The exact knowledge of the metabolic host cell responses may provide new interesting concepts for antibacterial therapies. PMID:23847769

  20. Polyfunctional responses by human T cells result from sequential release of cytokines

    PubMed Central

    Han, Qing; Bagheri, Neda; Bradshaw, Elizabeth M.; Hafler, David A.; Lauffenburger, Douglas A.; Love, J. Christopher

    2012-01-01

    The release of cytokines by T cells defines a significant part of their functional activity in vivo, and their ability to produce multiple cytokines has been associated with beneficial immune responses. To date, time-integrated end-point measurements have obscured whether these polyfunctional states arise from the simultaneous or successive release of cytokines. Here, we used serial, time-dependent, single-cell analysis of primary human T cells to resolve the temporal dynamics of cytokine secretion from individual cells after activation ex vivo. We show that multifunctional, Th1-skewed cytokine responses (IFN-γ, IL-2, TNFα) are initiated asynchronously, but the ensuing dynamic trajectories of these responses evolve programmatically in a sequential manner. That is, cells predominantly release one of these cytokines at a time rather than maintain active secretion of multiple cytokines simultaneously. Furthermore, these dynamic trajectories are strongly associated with the various states of cell differentiation suggesting that transient programmatic activities of many individual T cells contribute to sustained, population-level responses. The trajectories of responses by single cells may also provide unique, time-dependent signatures for immune monitoring that are less compromised by the timing and duration of integrated measures. PMID:22160692

  1. Cytokine and Chemokine Responses of Lung Exposed to Surrogate Viral and Bacterial Infections

    PubMed Central

    Liberati, Teresa A; Trammell, Rita A; Randle, Michelle; Barrett, Sarah; Toth, Linda A

    2013-01-01

    The use of in vitro models of complex in vivo systems has yielded many insights into the molecular mechanisms that underlie normal and pathologic physiology. However although the reduced complexity of these models is advantageous with regard to some research questions, the simplification may obscure or eliminate key influences that occur in vivo. We sought to examine this possibility with regard to the lung's response to infection, which may be inherent to resident lung cells or related to the systemic response to pulmonary infection. We used the inbred mouse strains C57BL/6J, DBA/2J, and B6.129S2-IL6tm1Kopf, which differ in their response to inflammatory and infectious challenges, to assess in vivo responses of lung to surrogate viral and bacterial infection and compared these with responses of cultured lung slices and human A549 cells. Pulmonary cytokine concentrations were measured both after in vivo inoculation of mice and in vitro exposure of lung slices and A549 cells to surrogate viral and bacterial infections. The data indicate similarities and differences in early lung responses to in vivo compared with in vitro exposure to these inflammatory substances. Therefore, resident cells in the lung appear to respond to some challenges in a strain-independent manner, whereas some stimuli may elicit recruitment of peripheral inflammatory cells that generate the subsequent response in a genotype-related manner. These results add to the body of information pointing to host genotype as a crucial factor in mediating the severity of microbial infections and demonstrate that some of these effects may not be apparent in vitro. PMID:23582418

  2. Inflammatory Cytokines as Preclinical Markers of Adverse Responses to Chemical Stressors

    EPA Science Inventory

    Abstract: The in vivo cytokine response to chemical stressors is a promising mainstream tool used to assess potential systemic inflammation and immune function changes. Notably, new instrumentation and statistical analysis provide the selectivity and sensitivity to rapidly diff...

  3. Host Responses in Tissue Repair and Fibrosis

    PubMed Central

    Duffield, Jeremy S.; Lupher, Mark; Thannickal, Victor J.

    2013-01-01

    Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary “effector” cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis. PMID:23092186

  4. Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators

    PubMed Central

    McMahon-Pratt, Diane; Saravia, Nancy Gore

    2015-01-01

    Background Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. Methodology To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. Principal Findings Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine

  5. Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis.

    PubMed

    Yang, Wenmin; Deng, Wanyan; Zeng, Jie; Ren, Sai; Ali, Md Kaisar; Gu, Yinzhong; Li, Yangyuling; Xie, Jianping

    2017-04-01

    Mycobacterium tuberculosis PE/PPE family proteins, named after the presence of conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains at N-terminal, are prevalent in M. tuberculosis genome. The function of most PE/PPE family proteins remains elusive. To characterize the function of PE_PGRS18, the encoding gene was heterologously expressed in M. smegmatis, a nonpathogenic mycobacterium. The recombinant PE_PGRS18 is cell wall associated. M. smegmatis PE_PGRS18 recombinant showed differential response to stresses and altered the production of host cytokines IL-6, IL-1β, IL-12p40 and IL-10, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages. In summary, the study firstly unveiled the role of PE_PGRS18 in physiology and pathogenesis of mycobacterium.

  6. Impact of influenza vaccine formulation with a detailed analysis of the cytokine response.

    PubMed

    Szyszko, E; Brokstad, K; Cox, R J; Hovden, A-O; Madhun, A; Haaheim, L R

    2006-11-01

    Vaccination provides the most effective method of limiting the impact of influenza. Inactivated influenza vaccines are available in three formulations and more information needs to be generated on how antigen presented in different vaccine formulations influences the subsequent immune response. In the present study, we have investigated the effect of two different influenza vaccine formulations on the resulting antibody and cytokine responses and compared these responses with influenza infection. Mice were vaccinated intramuscularly with one or two doses of whole or split virus vaccine or alternatively intranasally infected with influenza virus. Lymphocytes were isolated from spleen cells and stimulated in vitro for 24 or 72 h for analysis of cytokine profile at the gene expression and at the protein level. Additionally, whole blood was collected and the serum antibody response investigated by haemagglutination inhibition (HI) and enzyme-linked immunosorbent assay (ELISA). We found that one dose of whole virus vaccine induced higher antibody and cytokine responses and thus was more immunogenic in unprimed mice than split virus vaccine. Whole virus vaccine induced a strong IFN-gamma (type 1) immune response after one dose of vaccine and a more mixed cytokine response after the second dose. Split virus vaccine induced a type 2 response, particularly after two vaccine doses. Our results show that two doses of vaccine (both vaccine formulation) were more effective in induction of Th2 type of cytokines and thus indicate that both the formulation and also the number of vaccine doses substantially influences the magnitude and quality of the immune response.

  7. Divergence in Olfactory Host Plant Preference in D. mojavensis in Response to Cactus Host Use

    PubMed Central

    Stensmyr, Marcus C.; Shann, Jodi; Hansson, Bill S.; Rollmann, Stephanie M.

    2013-01-01

    Divergence in host adaptive traits has been well studied from an ecological and evolutionary perspective, but identification of the proximate mechanisms underlying such divergence is less well understood. Behavioral preferences for host plants are often mediated by olfaction and shifts in preference may be accompanied by changes in the olfactory system. In this study, we examine the evolution of host plant preferences in cactophilic Drosophila mojavensis that feeds and breeds on different cacti throughout its range. We show divergence in electrophysiological responses and olfactory behavior among populations with host plant shifts. Specifically, significant divergence was observed in the Mojave Desert population that specializes on barrel cactus. Differences were observed in electrophysiological responses of the olfactory organs and in behavioral responses to barrel cactus volatiles. Together our results suggest that the peripheral nervous system has changed in response to different ecological environments and that these changes likely contribute to divergence among D. mojavensis populations. PMID:23936137

  8. Divergence in olfactory host plant preference in D. mojavensis in response to cactus host use.

    PubMed

    Date, Priya; Dweck, Hany K M; Stensmyr, Marcus C; Shann, Jodi; Hansson, Bill S; Rollmann, Stephanie M

    2013-01-01

    Divergence in host adaptive traits has been well studied from an ecological and evolutionary perspective, but identification of the proximate mechanisms underlying such divergence is less well understood. Behavioral preferences for host plants are often mediated by olfaction and shifts in preference may be accompanied by changes in the olfactory system. In this study, we examine the evolution of host plant preferences in cactophilic Drosophila mojavensis that feeds and breeds on different cacti throughout its range. We show divergence in electrophysiological responses and olfactory behavior among populations with host plant shifts. Specifically, significant divergence was observed in the Mojave Desert population that specializes on barrel cactus. Differences were observed in electrophysiological responses of the olfactory organs and in behavioral responses to barrel cactus volatiles. Together our results suggest that the peripheral nervous system has changed in response to different ecological environments and that these changes likely contribute to divergence among D. mojavensis populations.

  9. A conserved flagellar pocket exposed high mannose moiety is used by African trypanosomes as a host cytokine binding molecule.

    PubMed

    Magez, S; Radwanska, M; Stijlemans, B; Xong, H V; Pays, E; De Baetselier, P

    2001-09-07

    Trypanosomes use antigenic variation of their variant-specific surface glycoprotein (VSG) coat as defense against the host immune system. However, in order to sustain their growth, they need to expose conserved epitopes, allowing host macromolecule binding and receptor-mediated endocytosis. Here we show that Trypanosoma brucei uses the conserved chitobiose-oligomannose (GlcNAc(2)-Man(5-9)) moieties of its VSG as a binding ligand for tumor necrosis factor (TNF), a host cytokine with lectin-like properties. As endocytosis in trypanosomes is restricted to the flagellar pocket, we show that soluble flagellar pocket extracts, and in particular soluble VSG, inhibit the binding of (125)I-TNF to trypanosomes. The interaction between TNF and VSG is confirmed by affinity chromatography, biosensor, and dot-blot affinity measurements, and soluble VSG inhibition of TNF-mediated trypanolysis. In all approaches, removal of N-linked carbohydrates abrogates the TNF-VSG interaction. In addition, synthetic high mannose oligosaccharides can block TNF-VSG interactions, and a VSG glycopeptide carrying the GlcNAc(2)-Man(5-9) moiety is shown to inhibit TNF-mediated trypanosome killing in mixed parasite/macrophage cell cultures. Together, these results support the observation that TNF plays a role in growth control of trypanosomes and, moreover, suggest that, by the use of conserved VSG carbohydrates as lectin-binding epitopes, trypanosomes can limit the necessity to express large numbers of invariant surface exposed receptors.

  10. Cytokine and Growth Factor Responses After Radiotherapy for Localized Ependymoma

    SciTech Connect

    Merchant, Thomas E. Li Chenghong; Xiong Xiaoping; Gaber, M. Waleed

    2009-05-01

    Purpose: To determine the time course and clinical significance of cytokines and peptide growth factors in pediatric patients with ependymoma treated with postoperative radiotherapy (RT). Methods and Materials: We measured 15 cytokines and growth factors (fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor [VEGF], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-{gamma}, tumor necrosis factor-{alpha}, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-{alpha}) from 30 patients before RT and 2 and 24 h, weekly for 6 weeks, and at 3, 6, 9, and 12 months after the initiation of RT. Two longitudinal models for the trend of log-transformed measurements were fitted, one during treatment and one through 12 months. Results: During RT, log IL-8 declined at a rate of -0.10389/wk (p = 0.0068). The rate of decline was greater (p = 0.028) for patients with an infratentorial tumor location. The decline in IL-8 after RT was significant when stratified by infratentorial tumor location (p = 0.0345) and more than one surgical procedure (p = 0.0272). During RT, the decline in log VEGF was significant when stratified by the presence of a ventriculoperitoneal shunt. After RT, the log VEGF declined significantly at a rate of -0.06207/mo. The decline was significant for males (p = 0.0222), supratentorial tumors (p = 0.0158), one surgical procedure (p = 0.0222), no ventriculoperitoneal shunt (p = 0.0005), and the absence of treatment failure (p = 0.0028). Conclusion: The pro-inflammatory cytokine IL-8 declined significantly during RT and the decline differed according to tumor location. The angiogenesis factor VEGF declined significantly during the 12 months after RT. The decline was greater in males, those without a ventriculoperitoneal shunt, and in those with favorable disease factors, including one surgical procedure, supratentorial tumor location, and

  11. Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract

    PubMed Central

    Horvath, Dennis J.; Patel, Ashay S.; Mohamed, Ahmad; Storm, Douglas W.; Singh, Chandra; Li, Birong; Zhang, Jingwen; Koff, Stephen A.; Jayanthi, Venkata R.; Mason, Kevin M.

    2016-01-01

    ABSTRACT Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into

  12. Mycobacterium tuberculosis Co-operonic PE32/PPE65 Proteins Alter Host Immune Responses by Hampering Th1 Response

    PubMed Central

    Khubaib, Mohd; Sheikh, Javaid A.; Pandey, Saurabh; Srikanth, Battu; Bhuwan, Manish; Khan, Nooruddin; Hasnain, Seyed E.; Ehtesham, Nasreen Z.

    2016-01-01

    PE/PPE genes, present in cluster with ESAT-6 like genes, are suspected to have a role in antigenic variation and virulence of Mycobacterium tuberculosis. Their roles in immune evasion and immune modulation of host are also well documented. We present evidence that PE32/PPE65 present within the RD8 region are co-operonic, co-transcribed, and co-translated, and play role in modulating host immune responses. Experiments with macrophage cell lines revealed that this protein complex suppresses pro-inflammatory cytokines such as TNF-α and IL-6 whereas also inducing high expression of anti-inflammatory IL-10. Immunization of mice with these recombinant proteins dampens an effective Th1 response as evident from reduced frequency of IFN-γ and IL-2 producing CD4+ and CD8+ T cells. IgG sub-typing from serum of immunized mice revealed high levels of IgG1 when compared with IgG2a and IgG2b. Further IgG1/IgG2a ratio clearly demonstrated that the protein complex manipulates the host immune response favorable to the pathogen. Our results demonstrate that the co-transcribed and co-translated PE32 and PPE65 antigens are involved specifically in modulating anti-mycobacterial host immune response by hampering Th1 response. PMID:27242739

  13. Serum Cytokine Levels in Major Depressive Disorder and Its Role in Antidepressant Response

    PubMed Central

    Myung, Woojae; Lim, Shinn-Won; Woo, Hye In; Park, Jin Hong; Shim, Sanghong

    2016-01-01

    Objective Cytokines have been reported to have key roles in major depressive disorder (MDD). However, much less is known about cytokines in MDD and antidepressant treatment due to the diversity of cytokines and the heterogeneity of depression. We investigated the levels of cytokines in patients with MDD compared with healthy subjects and their associations with antidepressant response. Methods We investigated the changes of several cytokines (eotaxin, sCD40L, IL-8, MCP-1alpha, TNF-alpha, INF-gamma and MIP-1alpha) by Luminex assay in 66 patients with MDD and 22 healthy controls. The antidepressant response was assessed by 17-item Hamilton Rating Scale for Depression. Results We found the levels of sCD40L (p=0.001), IL-8 (p=0.004) and MCP-1 (p=0.03) of healthy controls were significantly higher than those of depressive patients. However, the level of eotaxin and TNF-alpha were not associated with MDD. In addition, we found the level of MCP-1 was significantly changed after antidepressant treatment (p=0.01). Conclusion These findings suggest the roles of cytokines in MDD are complex, and could vary according to the individual characteristics of each patient. Further studies regarding the relationship between cytokines and MDD will be required. PMID:27909456

  14. Rapid Detection of Neutrophil Oxidative Burst Capacity is Predictive of Whole Blood Cytokine Responses

    PubMed Central

    Vernon, Philip J.; Schaub, Leasha J.; Dallelucca, Jurandir J.; Pusateri, Anthony E.; Sheppard, Forest R.

    2015-01-01

    Background Maladaptive immune responses, particularly cytokine and chemokine-driven, are a significant contributor to the deleterious inflammation present in many types of injury and infection. Widely available applications to rapidly assess individual inflammatory capacity could permit identification of patients at risk for exacerbated immune responses and guide therapy. Here we evaluate neutrophil oxidative burst (NOX) capacity measured by plate reader to immuno-type Rhesus Macaques as an acute strategy to rapidly detect inflammatory capacity and predict maladaptive immune responses as assayed by cytokine array. Methods Whole blood was collected from anesthetized Rhesus Macaques (n = 25) and analyzed for plasma cytokine secretion (23-plex Luminex assay) and NOX capacity. For cytokine secretion, paired samples were either unstimulated or ex-vivo lipopolysaccharide (LPS)-stimulated (100μg/mL/24h). NOX capacity was measured in dihydrorhodamine-123 loaded samples following phorbol 12-myristate 13-acetate (PMA)/ionomycin treatment. Pearson’s test was utilized to correlate NOX capacity with cytokine secretion, p<0.05 considered significant. Results LPS stimulation induced secretion of the inflammatory molecules G-CSF, IL-1β, IL-1RA, IL-6, IL-10, IL-12/23(p40), IL-18, MIP-1α, MIP-1β, and TNFα. Although values were variable, several cytokines correlated with NOX capacity, p-values≤0.0001. Specifically, IL-1β (r = 0.66), IL-6 (r = 0.74), the Th1-polarizing cytokine IL-12/23(p40) (r = 0.78), and TNFα (r = 0.76) were strongly associated with NOX. Conclusion NOX capacity correlated with Th1-polarizing cytokine secretion, indicating its ability to rapidly predict inflammatory responses. These data suggest that NOX capacity may quickly identify patients at risk for maladaptive immune responses and who may benefit from immuno-modulatory therapies. Future studies will assess the in-vivo predictive value of NOX in animal models of immune-mediated pathologies. PMID

  15. Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients

    PubMed Central

    Hegen, Harald; Adrianto, Indra; Lessard, Christopher J.; Millonig, Alban; Bertolotto, Antonio; Comabella, Manuel; Giovannoni, Gavin; Guger, Michael; Hoelzl, Martina; Khalil, Michael; Fazekas, Franz; Killestein, Joep; Lindberg, Raija L.P.; Malucchi, Simona; Mehling, Matthias; Montalban, Xavier; Rudzki, Dagmar; Schautzer, Franz; Sellebjerg, Finn; Sorensen, Per Soelberg; Deisenhammer, Florian; Steinman, Lawrence

    2016-01-01

    Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)–β treatment in patients with multiple sclerosis (MS). Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups. Results: A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment. Conclusions: There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response. PMID:26894205

  16. Allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to Bacillus anthracis.

    PubMed

    Terra, Jill K; France, Bryan; Cote, Christopher K; Jenkins, Amy; Bozue, Joel A; Welkos, Susan L; Bhargava, Ragini; Ho, Chi-Lee; Mehrabian, Margarete; Pan, Calvin; Lusis, Aldons J; Davis, Richard C; LeVine, Steven M; Bradley, Kenneth A

    2011-12-01

    Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36-74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT.

  17. Enteropathogenic Escherichia coli Tir recruits cellular SHP-2 through ITIM motifs to suppress host immune response.

    PubMed

    Yan, Dapeng; Quan, Heming; Wang, Lin; Liu, Feng; Liu, Haipeng; Chen, Jianxia; Cao, Xuetao; Ge, Baoxue

    2013-09-01

    Immune responses to pathogens are regulated by immune receptors containing either an immunoreceptor tyrosine-based activation motif (ITAM) or an immunoreceptor tyrosine-based inhibitory motif (ITIM). The important diarrheal pathogen enteropathogenic Escherichia coli (EPEC) require delivery and insertion of the bacterial translocated intimin receptor (Tir) into the host plasma membrane for pedestal formation. The C-terminal region of Tir, encompassing Y483 and Y511, shares sequence similarity with cellular ITIMs. Here, we show that EPEC Tir suppresses the production of inflammatory cytokines by recruitment of SHP-2 and subsequent deubiquitination of TRAF6 in an ITIM dependent manner. Our findings revealed a novel mechanism by which the EPEC utilize its ITIM motifs to suppress and evade the host innate immune response, which could lead to the development of novel therapeutics to prevent bacterial infection.

  18. Alveolar macrophage cytokine response to air pollution particles: Oxidant mechanisms

    SciTech Connect

    Imrich, Amy; Ning Yaoyu; Lawrence, Joy; Coull, Brent; Gitin, Elena; Knutson, Mitchell; Kobzik, Lester . E-mail: lkobzik@hsph.harvard.edu

    2007-02-01

    Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-L-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 {mu}M) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H{sub 2}O{sub 2} generated by glucose oxidase, 10 {mu}M/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H{sub 2}O{sub 2}. The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H{sub 2}O{sub 2} but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H{sub 2}O{sub 2}-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H{sub 2}O{sub 2} released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.

  19. Regulation of local host-mediated anti-tumor mechanisms by cytokines: direct and indirect effects on leukocyte recruitment and angiogenesis.

    PubMed Central

    Watanabe, M.; McCormick, K. L.; Volker, K.; Ortaldo, J. R.; Wigginton, J. M.; Brunda, M. J.; Wiltrout, R. H.; Fogler, W. E.

    1997-01-01

    The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing recombinant human basic fibroblast growth factor (rhFGFb) and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recombinant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, suggesting that T, B, and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge after treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions. This potential mechanism could be dissociated from the known activities of these two cytokines to induce the

  20. Immunopathology and cytokine responses in commercial broiler chickens with gangrenous dermatitis.

    PubMed

    Li, Guangxing; Lillehoj, Hyun S; Lee, Kyung Woo; Lee, Sung Hyen; Park, Myeong Seon; Jang, Seung I; Bauchan, Gary R; Gay, Cyril G; Ritter, G Donald; Bautista, Daniel A; Siragusa, Gregory R

    2010-08-01

    Gangrenous dermatitis (GD) is an emerging disease of increasing economic importance in poultry resulting from infection by Clostridium septicum and Clostridium perfringens type A. Lack of a reproducible disease model has been a major obstacle in understanding the immunopathology of GD. To gain better understanding of host-pathogen interactions in GD infection, we evaluated various immune parameters in two groups of birds from a recent commercial outbreak of GD, the first showing typical disease signs and pathological lesions (GD-like birds) and the second lacking clinical signs (GD-free birds). Our results revealed that GD-like birds showed: reduced T-cell and B-cell mitogen-stimulated lymphoproliferation; higher levels of serum nitric oxide and alpha-1-acid glycoprotein; greater numbers of K55(+), K1(+), CD8(+), and MHC class II(+) intradermal lymphocytes, and increased K55(+), K1(+), CD8(+), TCR1(+), TCR2(+), Bu1(+), and MHC class II(+) intestinal intraepithelial lymphocytes; and increased levels of mRNAs encoding proinflammatory cytokines and chemokines in skin compared with GD-free chickens. These results provide the first evidence of altered systemic and local (skin and intestine) immune responses in GD pathogenesis in chickens.

  1. Preserved ex vivo inflammatory status and cytokine responses in naturally long-lived mice

    PubMed Central

    Arranz, Lorena; Lord, Janet M.

    2010-01-01

    Preserved immune cell function has been reported in mice that achieve extreme longevity. Since cytokines are major modulators of immune responses, we aimed to determine the levels of 21 cytokines secreted ex vivo by peritoneal leukocytes cultured under basal- and mitogen- (conconavalin A (ConA) and LPS) stimulated conditions in middle-aged (44 ± 4 weeks), old (69 ± 4 weeks), very old (92 ± 4 weeks), and extreme long-lived (125 ± 4 weeks) ICR (CD1) female mice. The secretion of cytokines was measured by multiplex luminometry. Increased basal levels of proinflammatory IL-1β, IL-6, IL-12 (p70), IFN-γ, and TNF-α were seen in the old and very old animals, accompanied by decreased IL-10. In contrast, the extreme long-lived mice maintained the overall cytokine profile of middle-aged mice, though the basal secretion of IL-2, IL-9, IL-10, IL-13, and IL-12 (p40) was raised. Under LPS- and/or ConA-stimulated conditions, leukocytes from old and very old animals showed a significantly impaired response with respect to secretion of Th1 cytokines IL-3, IL-12p70, IFN-γ, and TNF-α; Th2 cytokines IL-6, IL-4, IL-10, and IL-13; and the regulatory cytokines IL-2, IL-5, and IL-17. Extreme long-lived mice preserved the middle-aged-like cytokine profile, with the most striking effect seen for the IL-2 response to ConA, which was minimal in the old and very old mice but increased with respect to the middle-aged level in extreme long-lived mice. Chemokine responses in regard to KC, MCP-1, MIP1β, and RANTES were more variable, though similar secretion of LPS-induced KC and MCP-1 and ConA-induced MCP-1, MIP-1β, and RANTES was found in long-lived and middle-aged mice. Thus, extreme long-lived animals showed only a minimal inflammatory profile, much lower than the old and very old groups and also lower than the middle-aged, which is likely mediated by the increase of anti-inflammatory cytokines such as IL-10. This was coupled to a robust response to immune stimuli

  2. Cytokine responses in camels (Camelus bactrianus) vaccinated with Brucella abortus strain 19 vaccine.

    PubMed

    Odbileg, Raadan; Purevtseren, Byambaa; Gantsetseg, Dorj; Boldbaatar, Bazartseren; Buyannemekh, Tumurjav; Galmandakh, Zagd; Erdenebaatar, Janchivdorj; Konnai, Satoru; Onuma, Misao; Ohashi, Kazuhiko

    2008-02-01

    In the present study, we determined the levels of cytokines produced by camel (Camelus bactrianus) peripheral blood mononuclear cells (PBMCs) in response to live attenuated Brucella abortus (B. abortus) S19 vaccine. Seven camels were vaccinated with commercial B. abortus S19 vaccine, and their cytokine responses were determined using a real-time PCR assay. Cytokine responses to B. abortus S19 were examined at 6 hr, 48 hr and 1, 2 and 3 weeks post-vaccination. Serological tests were performed to further confirm these immune responses. The results revealed that IFN-gamma and IL-6 were upregulated during the first week post-vaccination. Low level expressions of IL-1alpha, IL-1beta, TNFalpha and IL-10 and no expression of IL-2 and IL-4 were observed compared with the control camels. The findings showed that B. abortus stimulates cell-mediated immunity by directly activating camel Th1 cells to secrete IFN-gamma. This quantification of cytokine expression in camels is essential for understanding of Camelidae disease development and protective immune responses. This is the first report of in vivo camel cytokine quantification after vaccination.

  3. In vitro lymphoproliferative response and cytokine production in mice with experimental disseminated candidiasis

    PubMed Central

    Khosravi, Ali Reza; Shokri, Hojjatollah; Eshghi, Shahin

    2017-01-01

    Objective(s): Systemic candidiasis is an infection of Candida albicans (C. albicans) causing disseminated disease and sepsis, invariably when host defenses are compromised. We investigated the histopathological changes as well as the lymphoproliferative responses and cytokine production of splenic cells after stimulation with Concanavalin A (Con A) and Pokeweed mitogen (PWM) in mice with disseminated candidiasis. Materials and Methods: Lymphoproliferative responses were stimulated in vitro with Con A (1 µg/ml) and PWM (1 µg/ml) mitogens in Roswell Park Memorial Institute (RPMI) 1640 media, and the production of interferon (IFN)-γ and interleukin-4 (IL-4) in the supernatants was measured by enzyme-linked immunosorbent assay (ELISA). Results: The results revealed that C. albicans organisms multiplied to a greater extent in the kidneys than in the liver and spleen of infected mice. The most predominant forms of C. albicans in different parts of the kidneys were yeast mixed with hyphal forms. Infected mice had a significantly increased proliferative response when splenocytes were stimulated with PWM (2.0±0.16) and Con A (1.9±0.19) (P<0.05). PWM and Con A-stimulated production of IFN-γ significantly tended to be higher in infected mice (PWM: 68.4±14.0 pg/ml; Con A: 53.7±17.3 pg/ml) when compared to controls (P<0.05). Stimulation with PWM and Con A showed no differences in IL-4 production between infected mice and controls. Conclusion: These findings demonstrated a significant increase in both cell proliferation and IFN-γ secretion in supernatants of PWM and Con A- stimulated splenocyte cultures obtained from mice with disseminated candidiasis. PMID:28293397

  4. Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Guérin.

    PubMed

    Liu, Xiaoxuan; Dowell, Alexander C; Patel, Prashant; Viney, Richard P; Foster, Michael C; Porfiri, Emilio; James, Nicholas D; Bryan, Richard T

    2014-06-01

    The most effective intravesical treatment of non-muscle-invasive bladder cancer is instillation of live Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG stimulates the release of cytokines, contributing directly or indirectly to its effectiveness. However, the function of specific cytokines is not well understood. We have undertaken a nonsystematic review of primary evidence regarding cytokine detection, activation and response in BCG patients. Cytokines IL-2, IL-8 and TNF-α appear to be essential for effective BCG therapy and nonrecurrence, while IL-10 may have an inhibitory effect on BCG responses. IL-2, IL-8, TRAIL and TNF-α are potentially predictive of response to BCG. Alterations in genes encoding cytokines may also affect responses. There are significant data showing the association of certain cytokines with successful BCG treatment, and which may be useful predictive markers. Isolating those cytokines mediating efficacy may hold the key to ameliorating BCG's side effects and improving efficacy and patient compliance.

  5. Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells

    PubMed Central

    2010-01-01

    Background Modulation of the immune system is one of the most plausible mechanisms underlying the beneficial effects of probiotic bacteria on human health. Presently, the specific probiotic cell products responsible for immunomodulation are largely unknown. In this study, the genetic and phenotypic diversity of strains of the Lactobacillus plantarum species were investigated to identify genes of L. plantarum with the potential to influence the amounts of cytokines interleukin 10 (IL-10) and IL-12 and the ratio of IL-10/IL-12 produced by peripheral blood mononuclear cells (PBMCs). Results A total of 42 Lactobacillus plantarum strains isolated from diverse environmental and human sources were evaluated for their capacity to stimulate cytokine production in PBMCs. The L. plantarum strains induced the secretion of the anti-inflammatory cytokine IL-10 over an average 14-fold range and secretion of the pro-inflammatory cytokine IL-12 over an average 16-fold range. Comparisons of the strain-specific cytokine responses of PBMCs to comparative genome hybridization profiles obtained with L. plantarum WCFS1 DNA microarrays (also termed gene-trait matching) resulted in the identification of 6 candidate genetic loci with immunomodulatory capacities. These loci included genes encoding an N-acetyl-glucosamine/galactosamine phosphotransferase system, the LamBDCA quorum sensing system, and components of the plantaricin (bacteriocin) biosynthesis and transport pathway. Deletion of these genes in L. plantarum WCFS1 resulted in growth phase-dependent changes in the PBMC IL-10 and IL-12 cytokine profiles compared with wild-type cells. Conclusions The altered PBMC cytokine profiles obtained with the L. plantarum WCFS1 mutants were in good agreement with the predictions made by gene-trait matching for the 42 L. plantarum strains. This study therefore resulted in the identification of genes present in certain strains of L. plantarum which might be responsible for the stimulation of anti

  6. Regulation of Host Epithelial Responses to Cryptosporidium Infection by MicroRNAs.

    PubMed

    Ming, Zhenping; Zhou, Rui; Chen, Xian-Ming

    2016-12-15

    Cryptosporidium species infect the gastrointestinal epithelium and other mucosal surfaces of vertebrate hosts. Epithelial cells provide the first line of defense against Cryptosporidium infection and play a critical role in the initiation, regulation, and resolution of both innate and adaptive immune reactions. Host miRNAs in mammalian cells have been shown to play crucial roles in cellular responses to infection by diverse pathogens, including viruses, parasites, and bacteria. Given the absence of RNAi machinery in Cryptosporidium, lack of miRNA expression in the parasite, and minimal invasion nature of infection, Cryptosporidium infection provides an ideal model for exploring miRNA-mediated epithelial cell defense, relevant to infection of mucosal epithelial cells by pathogens in general. Increasing evidence supports that miRNAs may modulate many stages of epithelial responses following Cryptosporidium infection, including activation of the intracellular signaling pathways, production of antimicrobial molecules, expression of cytokines/chemokines, release of epithelial cell-derived exosomes, and feedback regulation of immune homeostasis. On the other hand, this parasite may have developed strategies to modulate host miRNA-mediated cellular function for immune evasion. In this review, we will summarize the recent advances on miRNA regulation of epithelial responses to Cryptosporidium infection, with an emphasis on host defense and parasite immune evasion. This article is protected by copyright. All rights reserved.

  7. Modeling the NF-κB mediated inflammatory response predicts cytokine waves in tissue

    PubMed Central

    2011-01-01

    Background Waves propagating in "excitable media" is a reliable way to transmit signals in space. A fascinating example where living cells comprise such a medium is Dictyostelium D. which propagates waves of chemoattractant to attract distant cells. While neutrophils chemotax in a similar fashion as Dictyostelium D., it is unclear if chemoattractant waves exist in mammalian tissues and what mechanisms could propagate them. Results We propose that chemoattractant cytokine waves may naturally develop as a result of NF-κB response. Using a heuristic mathematical model of NF-κB-like circuits coupled in space we show that the known characteristics of NF-κB response favor cytokine waves. Conclusions While the propagating wave of cytokines is generally beneficial for inflammation resolution, our model predicts that there exist special conditions that can cause chronic inflammation and re-occurrence of acute inflammatory response. PMID:21771307

  8. Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis.

    PubMed

    Tharmalingam, J; Prabhakar, A T; Gangadaran, P; Dorny, P; Vercruysse, J; Geldhof, P; Rajshekhar, V; Alexander, M; Oommen, A

    2016-10-01

    Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single-cyst infection prevails in India. Single-cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4(+) T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single- and multicyst-infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium-endemic and T. solium-non-endemic regions and those with single-cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4(+) T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple-cyst infections to establish and persist.

  9. Adjuvant effect of Asparagus racemosus Willd. derived saponins in antibody production, allergic response and pro-inflammatory cytokine modulation.

    PubMed

    Tiwari, Nimisha; Gupta, Vivek Kumar; Pandey, Pallavi; Patel, Dinesh Kumar; Banerjee, Suchitra; Darokar, Mahendra Pandurang; Pal, Anirban

    2017-02-01

    The study manifests the immunoadjuvant potential of saponin rich fraction from Asparagus racemosus in terms of cellular and humoral immune response that can be exploited against microbial infections. Asparagus racemosus (AR) has been attributed as an adaptogen and rasayana in traditional medication systems for enhancing the host defence mechanism. Spectrophotometric and HPTLC analysis ensured the presence of saponins. The saponin rich fractions were tested for immunoadjuvant property in ovalbumin immunised mice for the humoral response, quantified in terms of prolonged antibody production upto a duration of 56days. Proinflammatory cytokines (IL-6 and TNF) were estimated for the cellular immune response in LPS stimulated primary murine macrophages. The safety evaluation in terms of cytotoxicity and allergic response has also been evaluated through in-vitro (MTT) and in-vivo (IgE) respectively. ARS significantly inhibited the pro-inflammatory cytokines, in LPS stimulated murine macrophages with no intrinsic cytotoxicity. The significant increase in IgG production infers the utility of ARS for prolonged humoral response. Further, the antigen specific response of IL-12 at early stage and IgE titres also suggests the generation of cellular immune response and low allergic reaction respectively, as compared to conventional adjuvants. IL-6 and TNF fluctuations in LPS stimulated and non-stimulated macrophages along with IgG and IL-12 also confirmed the Th1/Th2 modulating effect of ARS. The study indicates potential effect of ARS as an adjuvant for the stimulation of cellular immune response in addition to generating a sustained adaptive response without any adverse effects paving way for further validation with pathogenic organisms.

  10. Differential Biphasic Transcriptional Host Response Associated with Coevolution of Hemagglutinin Quasispecies of Influenza A Virus

    PubMed Central

    Manchanda, Himanshu; Seidel, Nora; Blaess, Markus F.; Claus, Ralf A.; Linde, Joerg; Slevogt, Hortense; Sauerbrei, Andreas; Guthke, Reinhard; Schmidtke, Michaela

    2016-01-01

    Severe influenza associated with strong symptoms and lung inflammation can be caused by intra-host evolution of quasispecies with aspartic acid or glycine in hemagglutinin position 222 (HA-222D/G; H1 numbering). To gain insights into the dynamics of host response to this coevolution and to identify key mechanisms contributing to copathogenesis, the lung transcriptional response of BALB/c mice infected with an A(H1N1)pdm09 isolate consisting HA-222D/G quasispecies was analyzed from days 1 to 12 post infection (p.i). At day 2 p.i. 968 differentially expressed genes (DEGs) were detected. The DEG number declined to 359 at day 4 and reached 1001 at day 7 p.i. prior to recovery. Interestingly, a biphasic expression profile was shown for the majority of these genes. Cytokine assays confirmed these results on protein level exemplarily for two key inflammatory cytokines, interferon gamma and interleukin 6. Using a reverse engineering strategy, a regulatory network was inferred to hypothetically explain the biphasic pattern for selected DEGs. Known regulatory interactions were extracted by Pathway Studio 9.0 and integrated during network inference. The hypothetic gene regulatory network revealed a positive feedback loop of Ifng, Stat1, and Tlr3 gene signaling that was triggered by the HA-G222 variant and correlated with a clinical symptom score indicating disease severity. PMID:27536272

  11. NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus.

    PubMed

    Silveira, Tatiana N; Gomes, Marco Túlio R; Oliveira, Luciana S; Campos, Priscila C; Machado, Gabriela G; Oliveira, Sergio C

    2017-01-01

    Brucella abortus is the causative agent of brucellosis, which causes abortion in domestic animals and undulant fever in humans. This bacterium infects and proliferates mainly in macrophages and dendritic cells, where it is recognized by pattern recognition receptors (PRRs) including Nod-like receptors (NLRs). Our group recently demonstrated the role of AIM2 and NLRP3 in Brucella recognition. Here, we investigated the participation of NLRP12 in innate immune response to B. abortus. We show that NLRP12 inhibits the early production of IL-12 by bone marrow-derived macrophages upon B. abortus infection. We also observed that NLRP12 suppresses in vitro NF-κB and MAPK signaling in response to Brucella. Moreover, we show that NLRP12 modulates caspase-1 activation and IL-1β secretion in B. abortus infected-macrophages. Furthermore, we show that mice lacking NLRP12 are more resistant in the early stages of B. abortus infection: NLRP12(-/-) infected-mice have reduced bacterial burdens in the spleens and increased production of IFN-γ and IL-1β compared with wild-type controls. In addition, NLRP12 deficiency leads to reduction in granuloma number and size in mouse livers. Altogether, our findings suggest that NLRP12 plays an important role in negatively regulating the early inflammatory responses against B. abortus.

  12. Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response.

    PubMed

    Kouwaki, Takahisa; Okamoto, Masaaki; Tsukamoto, Hirotake; Fukushima, Yoshimi; Oshiumi, Hiroyuki

    2017-03-20

    The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses.

  13. Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response

    PubMed Central

    Kouwaki, Takahisa; Okamoto, Masaaki; Tsukamoto, Hirotake; Fukushima, Yoshimi; Oshiumi, Hiroyuki

    2017-01-01

    The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses. PMID:28335522

  14. TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response

    PubMed Central

    Roca, Francisco J.; López-Muñoz, Azucena; Tyrkalska, Sylwia D.; Candel, Sergio; García-Moreno, Diana; Falco, Alberto; Meseguer, José

    2016-01-01

    TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections. PMID:27351838

  15. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

    PubMed Central

    2009-01-01

    Introduction Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. Methods We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. Results Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. Conclusions While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17

  16. Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients.

    PubMed

    Draborg, Anette Holck; Sandhu, Noreen; Larsen, Nanna; Lisander Larsen, Janni; Jacobsen, Søren; Houen, Gunnar

    2016-01-01

    We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired EBV-directed T-cell response. The concentrations of 14 cytokines (IL2, IL4, IL5, IL6, IL10, IL12, IL17, IL18, IL1β, IFNγ, TNFα, TNFβ, TGFβ, and GM-CSF) were quantified upon stimulation of whole blood with latent state antigen EBNA1, lytic cycle antigen EBV-EA/D, and the superantigen SEB. To avoid results affected by lack of lymphocytes, we focused on SLE patients with normal levels. Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels. Results substantiate the previously proposed impaired regulation of the immune response against latent and lytic cycle EBV infection in SLE patients without lymphopenia. Furthermore, results indicate general dysfunction of leukocytes and their cytokine regulations in SLE patients.

  17. Lactobacillus acidophilus and L. reuteri modulate cytokine responses in gnotobiotic pigs infected with human rotavirus

    PubMed Central

    Azevedo, M. S. P.; Zhang, W.; Wen, K.; Gonzalez, A. M.; Saif, L. J.; Yousef, A. E.; Yuan, L.

    2012-01-01

    Probiotic lactic acid bacteria (LAB) have been shown to alleviate inflammation, enhance the immunogenicity of rotavirus vaccines, or reduce the severity of rotavirus diarrhoea. Although the mechanisms are not clear, the differential Th1/Th2/Th3-driving capacities and modulating effects on cytokine production of different LAB strains may be the key. Our goal was to delineate the influence of combining two probiotic strains L. acidophilus and L. reuteri on the development of cytokine responses in neonatal gnotobiotic pigs infected with human rotavirus (HRV). We demonstrated that HRV alone, or HRV plus LAB, but not LAB alone, initiated serum cytokine responses, as indicated by significantly higher concentrations of IFN-α, IFN-γ, IL-12, and IL-10 at post-inoculation day (PID) 2 in the HRV only and LAB+HRV+ pigs compared to LAB only and LAB-HRV- pigs. Peak cytokine responses coincided with the peak of HRV replication. LAB further enhanced the Th1 and Th2 cytokine responses to HRV infection as indicated by significantly higher concentrations of IL-12, IFN-γ, IL-4 and IL-10 in the LAB+HRV+ pigs compared to the LAB-HRV+ pigs. The LAB+HRV+ pigs maintained relatively constant concentrations of TGF-β compared to the HRV only group which had a significant increase at PID 2 and decrease at PID 7, suggesting a regulatory role of LAB in maintaining gut homeostasis. At PID 28, cytokine secreting cell (CSC) responses, measured by ELISpot, showed increased Th1 (IL-12, IFN-γ) CSC numbers in the LAB+HRV+ and LAB-HRV+ groups compared to LAB only and LAB-HRV- pigs, with significantly increased IL-12 CSCs in spleen and PBMCs and IFN-γ CSCs in spleen of the LAB+HRV+ group. Thus, HRV infection alone, but not LAB alone was effective in inducing cytokine responses but LAB significantly enhanced both Th1 and Th2 cytokines in HRV-infected pigs. LAB may also help to maintain immunological homeostasis during HRV infection by regulating TGF-β production. PMID:22348907

  18. Response surface methodology to determine optimal cytokine responses in human peripheral blood mononuclear cells after smallpox vaccination

    PubMed Central

    Ryan, Jenna E.; Dhiman, Neelam; Ovsyannikova, Inna G.; Vierkant, Robert A.; Pankratz, V. Shane; Poland, Gregory A.

    2010-01-01

    Feasibility, amount of sample aliquots, processing time and cost are critical considerations for optimizing and conducting assays for large-population based studies. Well designed statistical approaches that quickly identify optimal conditions for a given assay could assist efficient completion of the laboratory assays for such studies. For example, assessment of the profile of secreted cytokines is important in understanding the immune response after vaccination. To characterize the cytokine immune response following smallpox vaccination, PBMC obtained from recently vaccinated subjects were stimulated with varying doses of live or UV-inactivated vaccinia virus and cultured for up to 8 days. In this paper, we describe a novel statistical method to identify optimal operating conditions for length in culture and virus MOI in order to measure a panel of secreted Th1, Th2, and inflammatory cytokines. This statistical method is comprised of two components. It first identifies a subset of the possible time in culture by virus MOI combinations to be studied. It then utilizes response surface analysis techniques to predict the optimal operating conditions for the measurement of each secreted cytokine. This method was applied, and the predicted optimal combinations of length in culture and virus MOI for maximum vaccinia-specific cytokine secretion were identified. The use of the response surface methodology can be applied to the optimization of other laboratory assays; especially when the number of PBMC available limits the testing of all possible combinations of parameters. PMID:19038260

  19. Cytokine and chemokine responses after exposure to ionizing radiation: Implications for the astronauts

    NASA Astrophysics Data System (ADS)

    Laiakis, Evagelia C.; Baulch, Janet E.; Morgan, William F.

    For individuals traveling in space, exposure to space radiation is unavoidable. Since adequate shielding against radiation exposure is not practical, other strategies for protecting the astronauts must be developed. Radiation is also an important therapeutic and diagnostic tool, and evidence from the clinical and experimental settings now shows a firm connection between radiation exposure and changes in cytokine and chemokine levels. These small proteins can be pro- or anti-inflammatory in nature and the balance between those two effects can be altered easily because of exogenous stresses such as radiation. The challenge to identify a common perpetrator, however, lies in the fact that the cytokines that are produced vary based on radiation dose, type of radiation, and the cell types that are exposed. Based on current knowledge, special treatments have successfully been designed by implementing administration of proteins, antibodies, and drugs that counteract some of the harmful effects of radiation. Although these treatments show promising results in animal studies, it has been difficult to transfer those practices to the human situation. Further understanding of the mechanisms by which cytokines are triggered through radiation exposure and how those proteins interact with one another may permit the generation of novel strategies for radiation protection from the damaging effects of radiation. Here, we review evidence for the connection between cytokines and the radiation response and speculate on strategies by which modulating cytokine responses may protect astronauts against the detrimental effects of ionizing radiations.

  20. Interleukin 10 inhibits pro-inflammatory cytokine responses and killing of Burkholderia pseudomallei

    PubMed Central

    Kessler, Bianca; Rinchai, Darawan; Kewcharoenwong, Chidchamai; Nithichanon, Arnone; Biggart, Rachael; Hawrylowicz, Catherine M.; Bancroft, Gregory J.; Lertmemongkolchai, Ganjana

    2017-01-01

    Melioidosis, caused by Burkholderia pseudomallei, is endemic in northeastern Thailand and Northern Australia. Severe septicemic melioidosis is associated with high levels of pro-inflammatory cytokines and is correlated with poor clinical outcomes. IL-10 is an immunoregulatory cytokine, which in other infections can control the expression of pro-inflammatory cytokines, but its role in melioidosis has not been addressed. Here, whole blood of healthy seropositive individuals (n = 75), living in N. E. Thailand was co-cultured with B. pseudomallei and production of IL-10 and IFN-γ detected and the cellular sources identified. CD3− CD14+ monocytes were the main source of IL-10. Neutralization of IL-10 increased IFN-γ, IL-6 and TNF-α production and improved bacteria killing. IFN-γ production and microbicidal activity were impaired in individuals with diabetes mellitus (DM). In contrast, IL-10 production was unimpaired in individuals with DM, resulting in an IL-10 dominant cytokine balance. Neutralization of IL-10 restored the IFN-γ response of individuals with DM to similar levels observed in healthy individuals and improved killing of B. pseudomallei in vitro. These results demonstrate that monocyte derived IL-10 acts to inhibit potentially protective cell mediated immune responses against B. pseudomallei, but may also moderate the pathological effects of excessive cytokine production during sepsis. PMID:28216665

  1. Arenavirus evasion of host anti-viral responses.

    PubMed

    Hayes, Melissa; Salvato, Maria

    2012-10-17

    The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host's response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.

  2. Assessment of Transcriptional Activity of Borrelia burgdorferi and Host Cytokine Genes During Early and Late Infection in a Mouse Model

    PubMed Central

    Feng, Sunlian; Barthold, Stephen W.

    2013-01-01

    Abstract Differential gene expression by Borrelia burgdorferi spirochetes during mammalian infection facilitates their dissemination as well as immune evasion. Modulation of gene transcription in response to host immunity has been documented with the outer surface protein C, but the influence of transcription of other genes is largely unknown. A low-density array (LDA) was developed to study transcriptional activity of 43 B. burgdorferi genes and 19 host genes that may be involved in various host–agent interactions. Gene transcription in heart, joint, and muscle tissue was compared in immunocompetent C3H and immunodeficient C3H-scid mice during early (3 weeks) and late (2 months) B. burgdorferi infection. Among all tissue types, levels of relative transcription of over 80% of B. burgdorferi genes tested were one- to nine-fold less in C3H mice compared to C3H-scid mice. At the later time point, all genes were transcribed in C3H-scid mice, whereas transcription of 16 genes out of 43 tested was not detected in analyzed tissues of C3H mice. Our data suggest that during infection of immunocompetent mice, a majority of B. burgdorferi genes tested are downregulated in response to acquired host immunity. LDA revealed variable patterns of host gene expression in different tissues and at different intervals in infected mice. Higher levels of relative expression for IL-10 during both early and late infection were detected in heart base, and it was unchanged in the tibiotarsal joint. Comparative analysis of B. burgdorferi and host genes transcriptional activity revealed that increased flaB mRNA during early infection was followed by increases of CCL7, CCL8, interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in all assessed tissue types. LDA represents a valuable approach for sensitive and quantitative gene transcription profiling and for understanding Lyme borreliosis. PMID:23930938

  3. TLR9 Activation Dampens the Early Inflammatory Response to Paracoccidioides brasiliensis, Impacting Host Survival

    PubMed Central

    Menino, João Filipe; Saraiva, Margarida; Gomes-Alves, Ana G.; Lobo-Silva, Diogo; Sturme, Mark; Gomes-Rezende, Jéssica; Saraiva, Ana Laura; Goldman, Gustavo H.; Cunha, Cristina; Carvalho, Agostinho; Romani, Luigina; Pedrosa, Jorge; Castro, António Gil; Rodrigues, Fernando

    2013-01-01

    Background Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear. Methodology/Principal findings We used in vitro and in vivo models of infection by P. brasiliensis, comparing wild type and TLR9 deficient (−/−) mice, to assess the contribution of TLR9 on cytokine induction, phagocytosis and outcome of infection. We show that TLR9 recognizes either the yeast form or DNA from P. brasiliensis by stimulating the expression/production of pro-inflammatory cytokines by bone marrow derived macrophages, also increasing their phagocytic ability. We further show that TLR9 plays a protective role early after intravenous infection with P. brasiliensis, as infected TLR9−/− mice died at higher rate during the first 48 hours post infection than wild type mice. Moreover, TLR9−/− mice presented tissue damage and increased expression of several cytokines, such as TNF-α and IL-6. The increased pattern of cytokine expression was also observed during intraperitoneal infection of TLR9−/− mice, with enhanced recruitment of neutrophils. The phenotype of TLR9−/− hosts observed during the early stages of P. brasiliensis infection was reverted upon a transient, 48 hours post-infection, neutrophil depletion. Conclusions/Significance Our results suggest that TLR9 activation plays an early protective role against P. brasiliensis, by avoiding a deregulated type of inflammatory response associated to neutrophils that may lead to tissue damage. Thus

  4. Reservoir Host Immune Responses to Emerging Zoonotic Viruses

    PubMed Central

    Mandl, Judith N.; Ahmed, Rafi; Barreiro, Luis B.; Daszak, Peter; Epstein, Jonathan H.; Virgin, Herbert W.; Feinberg, Mark B.

    2015-01-01

    Zoonotic viruses, such as HIV, Ebola virus, coronaviruses, influenza A viruses, hantaviruses, or henipaviruses, can result in profound pathology in humans. In contrast, populations of the reservoir hosts of zoonotic pathogens often appear to tolerate these infections with little evidence of disease. Why are viruses more dangerous in one species than another? Immunological studies investigating quantitative and qualitative differences in the host-virus equilibrium in animal reservoirs will be key to answering this question, informing new approaches for treating and preventing zoonotic diseases. Integrating an understanding of host immune responses with epidemiological, ecological, and evolutionary insights into viral emergence will shed light on mechanisms that minimize fitness costs associated with viral infection, facilitate transmission to other hosts, and underlie the association of specific reservoir hosts with multiple emerging viruses. Reservoir host studies provide a rich opportunity for elucidating fundamental immunological processes and their underlying genetic basis, in the context of distinct physiological and metabolic constraints that contribute to host resistance and disease tolerance. PMID:25533784

  5. Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design

    PubMed Central

    Brown, Aisling F.; Leech, John M.; Rogers, Thomas R.; McLoughlin, Rachel M.

    2014-01-01

    In apparent contrast to its invasive potential Staphylococcus aureus colonizes the anterior nares of 20–80% of the human population. The relationship between host and microbe appears particularly individualized and colonization status seems somehow predetermined. After decolonization, persistent carriers often become re-colonized with their prior S. aureus strain, whereas non-carriers resist experimental colonization. Efforts to identify factors facilitating colonization have thus far largely focused on the microorganism rather than on the human host. The host responds to S. aureus nasal colonization via local expression of anti-microbial peptides, lipids, and cytokines. Interplay with the co-existing microbiota also influences colonization and immune regulation. Transient or persistent S. aureus colonization induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonization. Intriguingly, colonized patients who develop bacteremia may have a lower S. aureus-attributable mortality than their non-colonized counterparts. This could imply a staphylococcal-specific immune “priming” or immunomodulation occurring as a consequence of colonization and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonization on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonization status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonization and its modulation of host immunity. PMID:24409186

  6. Host-Selective Toxins of Pyrenophora tritici-repentis Induce Common Responses Associated with Host Susceptibility

    PubMed Central

    Pandelova, Iovanna; Figueroa, Melania; Wilhelm, Larry J.; Manning, Viola A.; Mankaney, Aakash N.; Mockler, Todd C.; Ciuffetti, Lynda M.

    2012-01-01

    Pyrenophora tritici-repentis (Ptr), a necrotrophic fungus and the causal agent of tan spot of wheat, produces one or a combination of host-selective toxins (HSTs) necessary for disease development. The two most studied toxins produced by Ptr, Ptr ToxA (ToxA) and Ptr ToxB (ToxB), are proteins that cause necrotic or chlorotic symptoms respectively. Investigation of host responses induced by HSTs provides better insight into the nature of the host susceptibility. Microarray analysis of ToxA has provided evidence that it can elicit responses similar to those associated with defense. In order to evaluate whether there are consistent host responses associated with susceptibility, a similar analysis of ToxB-induced changes in the same sensitive cultivar was conducted. Comparative analysis of ToxA- and ToxB-induced transcriptional changes showed that similar groups of genes encoding WRKY transcription factors, RLKs, PRs, components of the phenylpropanoid and jasmonic acid pathways are activated. ROS accumulation and photosystem dysfunction proved to be common mechanism-of-action for these toxins. Despite similarities in defense responses, transcriptional and biochemical responses as well as symptom development occur more rapidly for ToxA compared to ToxB, which could be explained by differences in perception as well as by differences in activation of a specific process, for example, ethylene biosynthesis in ToxA treatment. Results of this study suggest that perception of HSTs will result in activation of defense responses as part of a susceptible interaction and further supports the hypothesis that necrotrophic fungi exploit defense responses in order to induce cell death. PMID:22792250

  7. Oral inflammation, a role for antimicrobial peptide modulation of cytokine and chemokine responses.

    PubMed

    Brogden, Kim A; Johnson, Georgia K; Vincent, Steven D; Abbasi, Taher; Vali, Shireen

    2013-10-01

    Acute and chronic inflammation commonly occurs throughout the oral cavity. The most common causes are physical damage and microbial infections, and less frequently immune reactions and malignant changes. All of these processes result in the induction of antimicrobial peptides, chemokines and cytokines that lead to cellular infiltrates, a vascular response, tissue destruction and cellular proliferation. A fascinating concept developing in the current literature suggests that antimicrobial peptides modulate the production of chemokines, cytokines and other cellular mediators and that this may have a larger ramification as an underlying mechanism mediating inflammation. Here, we propose that the ability of antimicrobial peptides to induce chemokines and anti-inflammatory or proinflammatory cytokines plays an important role in the early events of oral inflammation and may be a target for the prevention or treatment of oral inflammatory conditions.

  8. Red Blood Cell Supernatant Potentiates LPS-Induced Proinflammatory Cytokine Response From Peripheral Blood Mononuclear Cells

    PubMed Central

    Nydam, Trevor L.; Clarke, Jason H.; Banerjee, Anirban; Silliman, Christopher C.; McCarter, Martin D.

    2009-01-01

    Allogeneic blood transfusion has an immunomodulatory capacity on its recipients through accumulation of immunologically active substances with blood storage, and prestorage leukoreduction reduces many of these mediators. We investigated lipopolysaccharide (LPS)-induced cytokine response of peripheral blood mononuclear cells (PBMCs) exposed to packed red blood cell (PRBC) supernatants from leukoreduced (LR) or non-leukoreduced (NLR) units with variable duration of storage. PRBC units were collected with or without leukoreduction on Day 0 before routine storage. The plasma fraction (supernatant) was isolated from LR and NLR units after 1 day (D1) or 42 days (D42) of storage and exposed to PBMCs versus control media for 24 h, then with LPS for an additional 24 h. Cell supernatants were analyzed for IL-1β, IL-6, IL-8, IL-10, and TNF-α by cytokine bead array. IL-1β, TNF-α, and IL-6 were significantly elevated in PRBC groups versus control. D42 NLR PRBC supernatant significantly increased secretion of IL-1β and IL-6 compared to D1 NLR PRBC supernatant. LR significantly attenuated the cytokine response of IL-1β. Thus, PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs. This response is accentuated with storage duration and partially attenuated with leukoreduction. These findings may partially explain the immune activation seen clinically after blood transfusion. PMID:19441884

  9. Sand fly saliva: effects on host immune response and Leishmania transmission.

    PubMed

    Rohousová, Iva; Volf, Petr

    2006-09-01

    The feeding success of sand flies (Diptera: Phlebotominae) is linked to the vast array of pharmacological substances in their saliva, which interferes with the host haemostasis and immune response. Modification of feeding site plays also an important role in Leishmania transmission. In naive hosts, co-inoculation of saliva and Leishmania parasites increases the chance of successful transmission. Disease exacerbation seems to be associated with enhanced production of type 2 cytokines and selective inhibition of some macrophage functions including the production of NO and H202. On the other hand, hosts repeatedly exposed to sand fly bites develop anti-saliva immune response that results in a protection against Leishmania infection. This led to a new interesting approach to anti-Leishmania vaccine--using salivary components to block parasite transmission. The review is therefore focused on the interactions that run between immunomodulatory molecules in sand fly saliva and host immune response, with the impact on Leishmania infection development. Recent studies revealed that saliva-based vaccine for leishmaniasis might be effective and feasible, however, several questions still require to be solved. The knowledge based on experimental mouse model cannot be fully extrapolated to dogs or humans and due to differences in salivary antigens between sand fly species the protective effect is species-specific. On the other hand, the specificity of salivary antigens enables the use of anti-saliva antibodies for monitoring the exposure of hosts to sand fly bites and might be used as a marker of risks for Leishmania transmission in endemic areas.

  10. Environmental Mold and Mycotoxin Exposures Elicit Specific Cytokine and Chemokine Responses

    PubMed Central

    Rosenblum Lichtenstein, Jamie H.; Hsu, Yi-Hsiang; Gavin, Igor M.; Donaghey, Thomas C.; Molina, Ramon M.; Thompson, Khristy J.; Chi, Chih-Lin; Gillis, Bruce S.; Brain, Joseph D.

    2015-01-01

    Background Molds can cause respiratory symptoms and asthma. We sought to use isolated peripheral blood mononuclear cells (PBMCs) to understand changes in cytokine and chemokine levels in response to mold and mycotoxin exposures and to link these levels with respiratory symptoms in humans. We did this by utilizing an ex vivo assay approach to differentiate mold-exposed patients and unexposed controls. While circulating plasma chemokine and cytokine levels from these two groups might be similar, we hypothesized that by challenging their isolated white blood cells with mold or mold extracts, we would see a differential chemokine and cytokine release. Methods and Findings Peripheral blood mononuclear cells (PBMCs) were isolated from blood from 33 patients with a history of mold exposures and from 17 controls. Cultured PBMCs were incubated with the most prominent Stachybotrys chartarum mycotoxin, satratoxin G, or with aqueous mold extract, ionomycin, or media, each with or without PMA. Additional PBMCs were exposed to spores of Aspergillus niger, Cladosporium herbarum and Penicillium chrysogenum. After 18 hours, cytokines and chemokines released into the culture medium were measured by multiplex assay. Clinical histories, physical examinations and pulmonary function tests were also conducted. After ex vivo PBMC exposures to molds or mycotoxins, the chemokine and cytokine profiles from patients with a history of mold exposure were significantly different from those of unexposed controls. In contrast, biomarker profiles from cells exposed to media alone showed no difference between the patients and controls. Conclusions These findings demonstrate that chronic mold exposures induced changes in inflammatory and immune system responses to specific mold and mycotoxin challenges. These responses can differentiate mold-exposed patients from unexposed controls. This strategy may be a powerful approach to document immune system responsiveness to molds and other inflammation

  11. Host Response Dynamics Following Lethal Infection of Rhesus Macaques With Zaire ebolavirus

    PubMed Central

    Rockx, Barry; Marzi, Andrea; Feldmann, Friederike; Haddock, Elaine; Brining, Douglas; LaCasse, Rachel A.; Gardner, Don; Feldmann, Heinz

    2011-01-01

    To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechanisms underlying disseminated intravascular coagulation in EHF patients. Furthermore, monitoring of expression levels for cytokines/chemokines suggested a mixed anti-inflammatory response syndrome (MARS), which indicates that a catastrophic uncontrolled immunological status contributes to the development of fatal hemorrhagic fever. These results highlight the pathological analogies between EHF and severe sepsis and not only contribute to our understanding of the pathogenic process, but will also help to establish novel postexposure treatment modalities. PMID:21987781

  12. Engineering biomaterials surfaces to modulate the host response.

    PubMed

    Yu, Kai; Mei, Yan; Hadjesfandiari, Narges; Kizhakkedathu, Jayachandran N

    2014-12-01

    Undesirable host response is responsible for the surface induced thrombus generation, activation of the complement system and the inflammatory reactions by the blood-contacting biomaterials. The surface interaction of biomaterials with different blood components is thought to be the critical factor that dictates the host response to biomaterials. Surface engineering can be utilized as a method to enhance the biocompatibility and tailor the biological response to biomaterials. This review provides a brief account of various polymer brush based approaches used for biomaterials surface modification, both passive and bioactive, to make the material surfaces biocompatible and antibacterial. Initially we discuss the utilization of polymer brushes with different structure and chemistry as a novel strategy to design the surface non-fouling that passively prevent the subsequent biological responses. Further we explore the utility of different bioactive agents including peptides, carbohydrates and proteins which can be conjugated the polymer brush to make the surface actively interact with the body and modulate the host response. A number of such avenues have also been explored in this review.

  13. Air pollution-related metals induce differential cytokine responses in bronchial epithelial cells.

    PubMed

    Låg, M; Øvrevik, J; Totlandsdal, A I; Lilleaas, E M; Thormodsæter, A; Holme, J A; Schwarze, P E; Refsnes, M

    2016-10-01

    Different transition metals have been shown to induce inflammatory responses in lung. We have compared eight different metal ions with regard to cytokine responses, cytotoxicity and signalling mechanisms in a human lung epithelial cell model (BEAS-2B). Among the metal ions tested, there were large differences with respect to pro-inflammatory potential. Exposure to Cd(2+), Zn(2+) and As(3+) induced CXCL8 and IL-6 release at concentrations below 100μM, and Mn(2+) and Ni(2+) at concentrations above 200μM. In contrast, VO4(3-), Cu(2+) and Fe(2+) did not induce any significant increase of these cytokines. An expression array of 20 inflammatory relevant genes also showed a marked up-regulation of CXCL10, IL-10, IL-13 and CSF2 by one or more of the metal ions. The most potent metals, Cd(2+), Zn(2+) and As(3+) induced highest levels of oxidative activity, and ROS appeared to be central in their CXCL8 and IL-6 responses. Activation of the MAPK p38 seemed to be a critical mediator. However, the NF-κB pathway appeared predominately to be involved only in Zn(2+)- and As(3+)-induced CXCL8 and IL-6 responses. Thus, the most potent metals Cd(2+), Zn(2+) and As(3+) seemed to induce a similar pattern for the cytokine responses, and with some exceptions, via similar signalling mechanisms.

  14. Host Responses to Intestinal Microbial Antigens in Gluten-Sensitive Mice

    PubMed Central

    Natividad, Jane M.; Huang, Xianxi; Slack, Emma; Jury, Jennifer; Sanz, Yolanda; David, Chella; Denou, Emmanuel; Yang, Pinchang; Murray, Joseph

    2009-01-01

    Background and Aims Excessive uptake of commensal bacterial antigens through a permeable intestinal barrier may influence host responses to specific antigen in a genetically predisposed host. The aim of this study was to investigate whether intestinal barrier dysfunction induced by indomethacin treatment affects the host response to intestinal microbiota in gluten-sensitized HLA-DQ8/HCD4 mice. Methodology/Principal Findings HLA-DQ8/HCD4 mice were sensitized with gluten, and gavaged with indomethacin plus gluten. Intestinal permeability was assessed by Ussing chamber; epithelial cell (EC) ultra-structure by electron microscopy; RNA expression of genes coding for junctional proteins by Q-real-time PCR; immune response by in-vitro antigen-specific T-cell proliferation and cytokine analysis by cytometric bead array; intestinal microbiota by fluorescence in situ hybridization and analysis of systemic antibodies against intestinal microbiota by surface staining of live bacteria with serum followed by FACS analysis. Indomethacin led to a more pronounced increase in intestinal permeability in gluten-sensitized mice. These changes were accompanied by severe EC damage, decreased E-cadherin RNA level, elevated IFN-γ in splenocyte culture supernatant, and production of significant IgM antibody against intestinal microbiota. Conclusion Indomethacin potentiates barrier dysfunction and EC injury induced by gluten, affects systemic IFN-γ production and the host response to intestinal microbiota antigens in HLA-DQ8/HCD4 mice. The results suggest that environmental factors that alter the intestinal barrier may predispose individuals to an increased susceptibility to gluten through a bystander immune activation to intestinal microbiota. PMID:19649259

  15. Characterization of the host inflammatory response following implantation of prolapse mesh in rhesus macaque

    PubMed Central

    Brown, Bryan N.; Mani, Deepa; Nolfi, Ms. Alexis L.; Liang, Rui; Abramowitch, Steve; Moalli, Pamela A.

    2015-01-01

    Objective To determine the predominant cell type (macrophage, T-lymphocyte, B-lymphocyte, mast cell) within the area of implantation of the prototypical polypropylene mesh, Gynemesh PS (Ethicon); and to determine the phenotypic profile (M1 pro-inflammatory, M2 anti-inflammatory) of the macrophage response to three different polypropylene meshes: Gynemesh PS (Ethicon), and two lower weight, higher porosity meshes, UltraPro (Ethicon) and Restorelle (Coloplast). Study Design Sacrocolpopexy was performed following hysterectomy in rhesus macaques. Sham-operated animals served as controls. At 12 weeks post-surgery, the vagina-mesh complex was excised and the host inflammatory response was evaluated. Hematoxylin and eosin was used to perform routine histomorphologic evaluation. Identification of leukocyte (CD45+) subsets was performed by immunolabeling for CD68 (macrophage), CD3 (T-lymphocyte), CD20 (B-lymphocyte), and CD117 (mast cell). M1 and M2 macrophage subsets were identified using immunolabeling (CD86+ and CD206+, respectively), and further evaluation was performed using ELISA for two M1 (TNF-α and IL-12) and two M2 (IL-4 and IL-10) cytokines. Results Histomorphologic evaluation showed a dense cellular response surrounding each mesh fiber. CD45+ leukocytes accounted for 21.4±5.4% of total cells within the peri-mesh area captured in a 20× field, with macrophages as the predominant luekocyte subset (10.5±3.9% of total cells) followed by T-lymphocytes (7.3±1.7%), B-lymphocytes (3.0±1.2%), and mast cells (0.2±0.2%). The response was observed to be more diffuse with increasing distance from the fiber surface. Few leukocytes of any type were observed in sham-operated animals. Immunolabeling revealed polarization of the macrophage response towards the M1 phenotype in all mesh groups. However, the ratio of M2:M1 macrophages was increased in the fiber area in UltraPro (P=0.033) and Restorelle (P=0.016) compared to Gynemesh PS. In addition, a shift towards increased

  16. Coxiella burnetii Infects Primary Bovine Macrophages and Limits Their Host Cell Response

    PubMed Central

    Sobotta, Katharina; Hillarius, Kirstin; Mager, Marvin; Kerner, Katharina; Heydel, Carsten

    2016-01-01

    Although domestic ruminants have long been recognized as the main source of human Q fever, little is known about the lifestyle that the obligate intracellular Gram-negative bacterium Coxiella burnetii adopts in its animal host. Because macrophages are considered natural target cells of the pathogen, we established primary bovine monocyte-derived macrophages (MDM) as an in vitro infection model to study reservoir host-pathogen interactions at the cellular level. In addition, bovine alveolar macrophages were included to take cell type peculiarities at a host entry site into account. Cell cultures were inoculated with the virulent strain Nine Mile I (NMI; phase I) or the avirulent strain Nine Mile II (NMII; phase II). Macrophages from both sources internalized NMI and NMII. MDM were particularly permissive for NMI internalization, but NMI and NMII replicated with similar kinetics in these cells. MDM responded to inoculation with a general upregulation of Th1-related cytokines such as interleukin-1β (IL-1β), IL-12, and tumor necrosis factor alpha (TNF-α) early on (3 h postinfection). However, inflammatory responses rapidly declined when C. burnetii replication started. C. burnetii infection inhibited translation and release of IL-1β and vastly failed to stimulate increased expression of activation markers, such as CD40, CD80, CD86, and major histocompatibility complex (MHC) molecules. Such capability of limiting proinflammatory responses may help Coxiella to protect itself from clearance by the host immune system. The findings provide the first detailed insight into C. burnetii-macrophage interactions in ruminants and may serve as a basis for assessing the virulence and the host adaptation of C. burnetii strains. PMID:27021246

  17. Coxiella burnetii Infects Primary Bovine Macrophages and Limits Their Host Cell Response.

    PubMed

    Sobotta, Katharina; Hillarius, Kirstin; Mager, Marvin; Kerner, Katharina; Heydel, Carsten; Menge, Christian

    2016-06-01

    Although domestic ruminants have long been recognized as the main source of human Q fever, little is known about the lifestyle that the obligate intracellular Gram-negative bacterium Coxiella burnetii adopts in its animal host. Because macrophages are considered natural target cells of the pathogen, we established primary bovine monocyte-derived macrophages (MDM) as an in vitro infection model to study reservoir host-pathogen interactions at the cellular level. In addition, bovine alveolar macrophages were included to take cell type peculiarities at a host entry site into account. Cell cultures were inoculated with the virulent strain Nine Mile I (NMI; phase I) or the avirulent strain Nine Mile II (NMII; phase II). Macrophages from both sources internalized NMI and NMII. MDM were particularly permissive for NMI internalization, but NMI and NMII replicated with similar kinetics in these cells. MDM responded to inoculation with a general upregulation of Th1-related cytokines such as interleukin-1β (IL-1β), IL-12, and tumor necrosis factor alpha (TNF-α) early on (3 h postinfection). However, inflammatory responses rapidly declined when C. burnetii replication started. C. burnetii infection inhibited translation and release of IL-1β and vastly failed to stimulate increased expression of activation markers, such as CD40, CD80, CD86, and major histocompatibility complex (MHC) molecules. Such capability of limiting proinflammatory responses may help Coxiella to protect itself from clearance by the host immune system. The findings provide the first detailed insight into C. burnetii-macrophage interactions in ruminants and may serve as a basis for assessing the virulence and the host adaptation of C. burnetii strains.

  18. Characterization of host immune responses in Ebola virus infections.

    PubMed

    Wong, Gary; Kobinger, Gary P; Qiu, Xiangguo

    2014-06-01

    Ebola causes highly lethal hemorrhagic fever in humans with no licensed countermeasures. Its virulence can be attributed to several immunoevasion mechanisms: an early inhibition of innate immunity started by the downregulation of type I interferon, epitope masking and subversion of the adaptive humoural immunity by secreting a truncated form of the viral glycoprotein. Deficiencies in specific and non-specific antiviral responses result in unrestricted viral replication and dissemination in the host, causing death typically within 10 days after the appearance of symptoms. This review summarizes the host immune response to Ebola infection, and highlights the short- and long-term immune responses crucial for protection, which holds implications for the design of future vaccines and therapeutics.

  19. Spatiotemporal phosphoprotein distribution and associated cytokine response of a traumatic injury.

    PubMed

    Han, Alice A; Currie, Holly N; Loos, Matthew S; Vrana, Julie A; Fabyanic, Emily B; Prediger, Maren S; Boyd, Jonathan W

    2016-03-01

    Molecular mechanisms of wound healing have been extensively characterized, providing a better understanding of the processes involved in wound repair and offering advances in treatment methods. Both spatial and temporal investigations of injury biomarkers have helped to pinpoint significant time points and locations during the recovery process, which may be vital in managing the injury and making the appropriate diagnosis. This study addresses spatial and temporal differences of phosphoproteins found in skeletal muscle tissue following a traumatic femur fracture, which were further compared to co-localized cytokine responses. In particular, several proteins (Akt, ERK, c-Jun, CREB, JNK, MEK1, and p38) and post-translational phosphorylations (p-Akt, p-c-Jun, p-CREB, p-ERK1/2, p-MEK1, p-p38, p-GSK3α/β, p-HSP27, p-p70S6K, and p-STAT3) associated with inflammation, new tissue formation, and remodeling were found to exhibit significant spatial and temporal differences in response to the traumatic injury. Quadratic discriminant analysis of all measured responses, including cytokine concentrations from previously published findings, was used to classify temporal and spatial observations at high predictive rates, further confirming that distinct spatiotemporal distributions for total protein, phosphorylation signaling, and cytokine (IL-1α, IL-1ß, IL2, IL6, TNF-α, and MIP-1α) responses exist. Finally, phosphoprotein measurements were found to be significantly correlated to cytokine concentrations, suggesting coordinated intracellular and extracellular activity during crucial periods of repair. This study represents a first attempt to monitor and assess integrated changes in extracellular and intracellular signaling in response to a traumatic injury in muscle tissues, which may provide a framework for future research to improve both our understanding of wounds and their treatment options.

  20. Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines.

    PubMed

    Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Yu, Yang; Johnson, Alan Kim; Felder, Robert B

    2013-07-01

    Proinflammatory cytokines play an important role in regulating autonomic and cardiovascular function in hypertension and heart failure. Peripherally administered proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), act on the brain to increase blood pressure, heart rate, and sympathetic nerve activity. These molecules are too large to penetrate the blood-brain barrier, and so the mechanisms by which they elicit these responses remain unknown. We tested the hypothesis that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood-brain barrier, plays a major role in mediating the sympathetic and hemodynamic responses to circulating proinflammatory cytokines. Intracarotid artery injection of TNF-α (200 ng) or IL-1β (200 ng) dramatically increased mean blood pressure, heart rate, and renal sympathetic nerve activity in rats with sham lesions of the SFO (SFO-s). These excitatory responses to intracarotid artery TNF-α and IL-1β were significantly attenuated in SFO-lesioned (SFO-x) rats. Similarly, the increases in mean blood pressure, heart rate, and renal sympathetic nerve activity in response to intravenous injections of TNF-α (500 ng) or IL-1β (500 ng) in SFO-s rats were significantly reduced in the SFO-x rats. Immunofluorescent staining revealed a dense distribution of the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, in the SFO. These data suggest that SFO is a predominant site in the brain at which circulating proinflammatory cytokines act to elicit cardiovascular and sympathetic responses.

  1. Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients' Response to Immunotherapy.

    PubMed

    Fischbacher, Dorothea; Merle, Marion; Liepert, Anja; Grabrucker, Christine; Kroell, Tanja; Kremser, Andreas; Dreyßig, Julia; Freudenreich, Markus; Schuster, Friedhelm; Borkhardt, Arndt; Kraemer, Doris; Koehne, Claus-Henning; Kolb, Hans-Jochem; Schmid, Christoph; Schmetzer, Helga Maria

    To enlighten interactions between autologous, allogeneic or T-cells from patients after stem cell transplantation with leukaemia-derived-dendritic-cells containing dendritic cells or blast containing mononuclear cells (n = 21, respectively), we determined cytokine-concentrations (interleukin 2, 4, 6, 10, tumor-necrosis-factor-α, interferon-γ) in supernatants of mixed-lymphocyte-culture and in serum (n = 16) of 20 patients with acute myeloid leukaemia and three patients with myelodysplastic syndromes by cytometric-bead-assay. We correlated our data with lytic capabilities of stimulated T-cells in a fluorolysis-assay and clinical data: Dendritic-cell-/mononuclear-cell-stimulation of T-cells resulted in increased cytokine-levels in culture-medium compared to serum. There were no significant differences between cytokine-patterns of cases with/without lytic T-cell-activity, response to immunotherapy (stem cell transplantation/donor-lymphocyte-infusion) or graft-versus-host-disease. However, some predictive cytokine-cut-off-values for antileukaemic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease could be defined. Cytokine-profiles alone, without functional assays, are no useful tool to predict antileukaemic T-cell-function, although they can indicate lytic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease.

  2. Hematopoietic cytokines.

    PubMed

    Metcalf, Donald

    2008-01-15

    The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.

  3. Host response to Clostridium difficile infection: Diagnostics and detection.

    PubMed

    Usacheva, Elena A; Jin, Jian-P; Peterson, Lance R

    2016-12-01

    Clostridium difficile infection (CDI) is a significant healthcare concern worldwide, and C. difficile is recognised as the most frequent aetiological agent of infectious healthcare-associated diarrhoea in hospitalised adult patients. The clinical manifestation of CDI varies from self-limited diarrhoea to life-threatening colitis. Such a broad disease spectrum can be explained by the impact of host factors. Currently, a complex CDI aetiology is widely accepted, acknowledging the interaction between bacteria and the host. C. difficile strains producing clostridial toxins A and B are considered toxigenic and can cause disease; those not producing the toxins are non-pathogenic. A person colonised with a toxigenic strain will not necessarily develop CDI. It is imperative to recognise patients with active disease from those only colonised with this pathogen and to implement appropriate treatment. This can be achieved by diagnostics that rely on host factors specific to CDI. This review will focus on major aspects of CDI pathogenesis and molecular mechanisms, describing host factors in disease progression and assessment of the host response in order to facilitate the development of CDI-specific diagnostics.

  4. Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry.

    PubMed

    Quan, Lei; Gong, Zhihong; Yao, Song; Bandera, Elisa V; Zirpoli, Gary; Hwang, Helena; Roberts, Michelle; Ciupak, Gregory; Davis, Warren; Sucheston, Lara; Pawlish, Karen; Bovbjerg, Dana H; Jandorf, Lina; Cabasag, Citadel; Coignet, Jean-Gabriel; Ambrosone, Christine B; Hong, Chi-Chen

    2014-03-15

    Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status.

  5. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa

    PubMed Central

    Redd, Andrew D.; Dabitao, Djeneba; Bream, Jay H.; Charvat, Blake; Laeyendecker, Oliver; Kiwanuka, Noah; Lutalo, Tom; Kigozi, Godfrey; Tobian, Aaron A. R.; Gamiel, Jordyn; Neal, Jessica D.; Oliver, Amy E.; Margolick, Joseph B.; Sewankambo, Nelson; Reynolds, Steven J.; Wawer, Maria J.; Serwadda, David; Gray, Ronald H.; Quinn, Thomas C.

    2009-01-01

    Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon's role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa. PMID:19357303

  6. Host responses to Plasmodium yoelii hepatic stages: a paradigm in host-parasite interaction.

    PubMed

    Lau, A O; Sacci, J B; Azad, A F

    2001-02-01

    The liver stage of malaria, caused by the genus Plasmodium, is clinically silent, but immunologically significant. Ample evidence exists for an effective CD8(+) T cell response to this stage as well as the involvement of gammadeltaT cells and NK1.1(int) cells in immunized animal models. In contrast, there is little information concerning responses in a naive host. Here we report that several host gene expressions in the liver, spleen, and kidney of BALB/c mice are altered during the liver stage of Plasmodium yoelii infection. Really interesting new gene 3 (Ring3), semaphorin subclass 4 member G, glutamylcysteine synthetase, and p45 NF erythroid 2 were all up-regulated 24 h after infection with P. yoelii. Semaphorin subclass 4 member G expression was elevated in the kidney, whereas Ring3 was elevated in both spleen and kidney. The expression of TNF-alpha (TNF-alpha and IFN-gamma) were down-regulated in all three tissues tested except in infected spleen where IFN-gamma was elevated. P. yoelii-related host gene changes were compared with those in Toxoplasma gondii-infected livers. Ring3 expression increased 5-fold over control values, whereas expression of the other transcripts remained unchanged. TNF-alpha and IFN-gamma expressions were increased in the Toxoplasma-infected livers. The uniform increase of Ring3 expression in both Plasmodium- and Toxoplasma-infected livers suggests an innate immune response against parasitic infections, whereas the other gene expression changes are consistent with Plasmodium parasite-specific responses. Taken together, these changes suggest the immune responses to P. yoelii infection are both parasite and organ specific.

  7. A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells.

    PubMed

    Carson, W E; Yu, H; Dierksheide, J; Pfeffer, K; Bouchard, P; Clark, R; Durbin, J; Baldwin, A S; Peschon, J; Johnson, P R; Ku, G; Baumann, H; Caligiuri, M A

    1999-04-15

    The mechanism of cytokine-induced shock remains poorly understood. The combination of IL-2 and IL-12 has synergistic antitumor activity in vivo, yet has been associated with significant toxicity. We examined the effects of IL-2 plus IL-12 in a murine model and found that the daily, simultaneous administration of IL-2 and IL-12 resulted in shock and 100% mortality within 4 to 12 days depending on the strain employed. Mice treated with IL-2 plus IL-12 exhibited NK cell apoptosis, pulmonary edema, degenerative lesions of the gastrointestinal tract, and elevated serum levels of proinflammatory cytokines and acute phase reactants. The actions of TNF-alpha, IFN-gamma, macrophage-inflammatory protein-1alpha, IL-1, IL-1-converting enzyme, Fas, perforin, inducible nitric oxide synthase, and STAT1 did not contribute to the observed toxicity, nor did B or T cells. However, toxicity and death from treatment with IL-2 plus IL-12 could be completely abrogated by elimination of NK cells. These results suggest that the fatal systemic inflammatory response induced by this cytokine treatment is critically dependent upon NK cells, but does not appear to be mediated by the known effector molecules of this cellular compartment. These data may provide insight into the pathogenesis of cytokine-induced shock in humans.

  8. Escaping Deleterious Immune Response in Their Hosts: Lessons from Trypanosomatids

    PubMed Central

    Geiger, Anne; Bossard, Géraldine; Sereno, Denis; Pissarra, Joana; Lemesre, Jean-Loup; Vincendeau, Philippe; Holzmuller, Philippe

    2016-01-01

    The Trypanosomatidae family includes the genera Trypanosoma and Leishmania, protozoan parasites displaying complex digenetic life cycles requiring a vertebrate host and an insect vector. Trypanosoma brucei gambiense, Trypanosoma cruzi, and Leishmania spp. are important human pathogens causing human African trypanosomiasis (HAT or sleeping sickness), Chagas’ disease, and various clinical forms of Leishmaniasis, respectively. They are transmitted to humans by tsetse flies, triatomine bugs, or sandflies, and affect millions of people worldwide. In humans, extracellular African trypanosomes (T. brucei) evade the hosts’ immune defenses, allowing their transmission to the next host, via the tsetse vector. By contrast, T. cruzi and Leishmania sp. have developed a complex intracellular lifestyle, also preventing several mechanisms to circumvent the host’s immune response. This review seeks to set out the immune evasion strategies developed by the different trypanosomatids resulting from parasite–host interactions and will focus on: clinical and epidemiological importance of diseases; life cycles: parasites–hosts–vectors; innate immunity: key steps for trypanosomatids in invading hosts; deregulation of antigen-presenting cells; disruption of efficient specific immunity; and the immune responses used for parasite proliferation. PMID:27303406

  9. Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway.

    PubMed

    Chandrasekar, Bysani; Melby, Peter C; Sarau, Henry M; Raveendran, Muthuswamy; Perla, Rao P; Marelli-Berg, Federica M; Dulin, Nickolai O; Singh, Ishwar S

    2003-02-14

    It is well established that cytokines can induce the production of chemokines, but the role of chemokines in the regulation of cytokine expression has not been fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha promoter activity, and up-regulated mRNA expression. Increased transcription and mRNA stability both contributed to cytokine expression. LIX-mediated cytokine gene transcription was inhibited by interleukin-10. Transient overexpression of kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB activation in rat CDEC. Inhibition of G(i) protein-coupled signal transduction, poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and abrogated its activation in mouse CDEC that express only CXCR2. These results indicate that LIX activates NF-kappaB and induces kappaB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to attracting and activating neutrophils, the ELR(+) CXC chemokines amplify the inflammatory cascade, stimulating local production of cytokines that have negative inotropic and proapoptotic effects.

  10. CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization.

    PubMed

    Livingston, Kimberly A; Jiang, Xiaowen; Stephensen, Charles B

    2013-04-30

    Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10(+) cells. Eight healthy subjects were given a TT booster vaccination. Blood was drawn before, 3, 7, 14, and 28days after vaccination and peripheral blood mononuclear cells (PBMC) were cultured for 7days with TT, negative control (diluent), and a positive control (Staphylococcus enterotoxin B [SEB]). Activation markers (CD25 and CD69) were measured after 44h (n=8), cytokines in supernatant after 3 and 7days, and intracellular cytokine staining (ICS) of proliferated cells (identified by dye dilution) after 7days (n=6). Vaccination increased TT-specific expression of CD25 and CD69 on CD3(+)CD4(+) lymphocytes, and TT-specific proliferation at 7, 14 and 28days post vaccination. Vaccination induced TT-specific Th1 (IFN-γ, TNF-α, and IL-2) Th2 (IL-13, IL-5, and IL-4), Th17 (IL-17A) and IL-10(+) cells as measured by ICS. TT-specific Th1 cells were the most abundant (12-15% of all TT-specific CD4(+) T-cells) while IL10(+) (1.8%) Th17 (1.1%) and Th2 cells (0.2-0.6%) were less abundant. TT-specific cytokine concentrations in PBMC supernatants followed the same pattern where a TT-specific IL-9 response was also seen. In conclusion, TT booster vaccination induced a broad T-helper cell response. This method of evaluating cytokine phenotypes may be useful in examining the impact of nutrition and environmental conditions on the plasticity of T-helper cell memory responses.

  11. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1993-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to further explore the effects of space flight on cytokines and cytokine-directed immunological function.

  12. Host Response to Nontuberculous Mycobacterial Infections of Current Clinical Importance

    PubMed Central

    Orme, Ian M.

    2014-01-01

    The nontuberculous mycobacteria are a large group of acid-fast bacteria that are very widely distributed in the environment. While Mycobacterium avium was once regarded as innocuous, its high frequency as a cause of disseminated disease in HIV-positive individuals illustrated its potential as a pathogen. Much more recently, there is growing evidence that the incidence of M. avium and related nontuberculous species is increasing in immunocompetent individuals. The same has been observed for M. abscessus infections, which are very difficult to treat; accordingly, this review focuses primarily on these two important pathogens. Like the host response to M. tuberculosis infections, the host response to these infections is of the TH1 type but there are some subtle and as-yet-unexplained differences. PMID:24914222

  13. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function

    PubMed Central

    Reunanen, Justus; Meijerink, Marjolein; Pietilä, Taija E.; Kainulainen, Veera; Klievink, Judith; Huuskonen, Laura; Aalvink, Steven; Skurnik, Mikael; Boeren, Sjef; Satokari, Reetta; Mercenier, Annick; Palva, Airi; Smidt, Hauke; de Vos, Willem M.; Belzer, Clara

    2017-01-01

    Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc_1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc_1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function. PMID:28249045

  14. Intestinal cytokine response after gut ischemia: role of gut barrier failure.

    PubMed Central

    Grotz, M R; Deitch, E A; Ding, J; Xu, D; Huang, Q; Regel, G

    1999-01-01

    OBJECTIVE: To investigate the effect of intestinal ischemia with and without a reperfusion injury on intestinal cytokine production and gut permeability. SUMMARY BACKGROUND DATA: In humans and in animal models, the gut has been implicated as a cytokine-producing organ after ischemia/reperfusion (I/R)-type injuries. Because of the limitations of in vivo models, it has been difficult to demonstrate directly that the gut releases cytokines after an I/R injury or whether there is a relation between the magnitude of the ischemic process and the cytokine response. METHODS: Ileal mucosal membranes from rats subjected to sham or 45 or 75 min of superior mesenteric occlusion (SMAO) or 45 minutes of SMAO and 30 minutes of reperfusion (SMAO 45/30) were mounted in the Ussing chamber system. Levels of tumor necrosis factor-alpha and interleukin-6 were serially measured in the mucosal and serosal reservoirs of the Ussing system, as was mucosal permeability as reflected by the passage of bacteria or phenol red across the ileal membrane. In a second group of experiments, Escherichia coli C25 was added to the mucosal reservoir to determine if the cytokine response would be increased. RESULTS: Mucosal and serosal levels of tumor necrosis factor-alpha were equally increased after SMAO, with the highest levels in the 75-minute SMAO group. The highest levels of interleukin-6 were found in rats subjected to 75 minutes of SMAO or SMAO 45/30; the serosal levels of interleukin-6 were four to sixfold higher than the mucosal levels. The addition of E. coli C25 resulted in a significant increase in the amount of interleukin-6 or tumor necrosis factor-alpha recovered from the mucosal reservoir. Increased ileal membrane permeability was observed only in rats subjected to 75 minutes of SMAO or SMAO 45/30. CONCLUSION: These results directly document that the levels of tumor necrosis factor-alpha and interleukin-6 released from the gut increase after an ischemic or I/R injury, such as SMAO, and

  15. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon.

    PubMed

    Totura, Allison L; Baric, Ralph S

    2012-06-01

    SARS-CoV is a pathogenic coronavirus that emerged from a zoonotic reservoir, leading to global dissemination of the virus. The association SARS-CoV with aberrant cytokine, chemokine, and Interferon Stimulated Gene (ISG) responses in patients provided evidence that SARS-CoV pathogenesis is at least partially controlled by innate immune signaling. Utilizing models for SARS-CoV infection, key components of innate immune signaling pathways have been identified as protective factors against SARS-CoV disease, including STAT1 and MyD88. Gene transcription signatures unique to SARS-CoV disease states have been identified, but host factors that regulate exacerbated disease phenotypes still remain largely undetermined. SARS-CoV encodes several proteins that modulate innate immune signaling through the antagonism of the induction of Interferon and by avoidance of ISG effector functions.

  16. Cytokine, antibody and proliferative cellular responses elicited by Taenia solium calreticulin upon experimental infection in hamsters.

    PubMed

    Mendlovic, Fela; Cruz-Rivera, Mayra; Ávila, Guillermina; Vaughan, Gilberto; Flisser, Ana

    2015-01-01

    Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT) on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus). Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA) were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN) cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis.

  17. Cytokine, Antibody and Proliferative Cellular Responses Elicited by Taenia solium Calreticulin upon Experimental Infection in Hamsters

    PubMed Central

    Mendlovic, Fela; Cruz-Rivera, Mayra; Ávila, Guillermina; Vaughan, Gilberto; Flisser, Ana

    2015-01-01

    Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT) on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus). Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA) were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN) cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis. PMID:25811778

  18. Respiratory syncytial virus--viral biology and the host response.

    PubMed

    Hacking, D; Hull, J

    2002-07-01

    Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. We have an incomplete understanding of the reasons why some infants are more severely affected by RSV than others. There is no effective antiviral treatment for the infection. Advances in our understanding of the biology of RSV, particularly in relation to the attachment protein G and the fusion protein F, have revealed potential targets for new antiviral therapies and vaccine development. In response to RSV infection an intense inflammatory response is triggered, mediated initially by the infected airway epithelial cells. Cell mediated responses are important in controlling the extent of infection and in viral clearance. Humoral responses are important in protection. There is early evidence that genetic variation of the host response can influence the outcome of RSV-induced bronchiolitis.

  19. Host response to Brucella infection: review and future perspective.

    PubMed

    Elfaki, Mohamed G; Alaidan, Alwaleed Abdullah; Al-Hokail, Abdullah Abdulrahman

    2015-07-30

    Brucellosis is a zoonotic and contagious infectious disease caused by infection with Brucella species. The infecting brucellae are capable of causing a devastating multi-organ disease in humans with serious health complications. The pathogenesis of Brucella infection is influenced largely by host factors, Brucella species/strain, and the ability of invading brucellae to survive and replicate within mononuclear phagocytic cells, preferentially macrophages (Mf). Consequently, the course of human infection may appear as an acute fatal or progress into chronic debilitating infection with periodical episodes that leads to bacteremia and death. The existence of brucellae inside Mf represents one of the strategies used by Brucella to evade the host immune response and is responsible for treatment failure in certain human populations treated with anti-Brucella drugs. Moreover, the persistence of brucellae inside Mf complicates the diagnosis and may affect the host cell signaling pathways with consequent alterations in both innate and adaptive immune responses. Therefore, there is an urgent need to pursue the development of novel drugs and/or vaccine targets against human brucellosis using high throughput technologies in genomics, proteomics, and immunology.

  20. Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate

    SciTech Connect

    Pruett, Stephen B. . E-mail: spruet@LSUHSC.edu; Fan, Ruping; Zheng, Qiang

    2006-06-01

    Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S. We recently reported that it alters the induction of cytokine production mediated though Toll-like receptor (TLR) 4 at relevant dosages in mice. Its chemical properties and evidence from the literature suggest thee potential mechanisms of action for this compound. It could either act as a free radical scavenger (by means of its free S{sup -}group) or promote oxidation by breaking down to form methylisothiocyanate, which can deplete glutathione. It is a potent copper chelator and may affect the availability of copper to a number of copper-dependent enzymes (including some signaling molecules). SMD induces a classical neuroendocrine stress response characterized by elevated serum corticosterone concentrations, which could affect cytokine production. Although each of these mechanisms could potentially contribute to altered cytokine responses, direct evidence is lacking. The present study was conducted to obtain such evidence. The role of redox balance was investigated by pretreating mice with N-acetyl cysteine (NAC), which increases cellular glutathione concentrations, before administration of SMD. NAC exacerbated the SMD-induced suppression of IL-12 and the SMD-induced enhancement of IL-10 in the serum. The role of copper chelation was investigated by comparing the effects of SMD with an equimolar dose to SMD that was administered in the form of a copper chelation complex. Addition of copper significantly decreased the action of SMD on IL-12 production but not on IL-10 production. The role of the stress response was investigated by pretreating mice with antagonists of corticosterone and catecholamines. This treatment partially prevented the action of SMD on IL-10 and IL-12 in the peritoneal fluid. The results suggest that all of the proposed mechanisms have some role in the alteration of cytokine production by SMD.

  1. Echinacea purpurea (L.) Moench modulates human T-cell cytokine response.

    PubMed

    Fonseca, Fabiana N; Papanicolaou, Genovefa; Lin, Hong; Lau, Clara B S; Kennelly, Edward J; Cassileth, Barrie R; Cunningham-Rundles, Susanna

    2014-03-01

    The study objective was to evaluate the composition of a neutral and weakly acidic water-soluble extract from Echinacea purpurea (L.) Moench (EchNWA) previously shown to modify murine influenza infection, and to assess immunomodulatory effects on human T-cells. EchNWA extract from fresh aerial parts was extracted with water, ethanolic precipitation, and size-exclusion chromatography. The chemical profile of EchNWA was characterized by chromatography (size-exclusion, HPLC, GC-MS), and small molecule fingerprint analysis performed by HPLC-PDA. Jurkat T-cells at high and low cell density were pretreated or not with doses of EchNWA, followed by activation with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I). Interleukin-2 (IL-2) and interferon gamma (IFNg) cytokine secretions were measured by multi-cytokine luminex technology. Results showed that EchNWA contains 80% polysaccharides, predominantly a 10kDa entity; phenolic compounds, cynarin, cichoric and caftaric acids, but no detectable alkylamides. Cytokine production required stimulation and was lower after PMA+I activation in high-density compared to low-density conditions. EchNWA mediated a strong dose-dependent enhancement of high-density T-cell production of IL-2 and IFNg response to PMA+I. EchNWA alone did not stimulate T-cells. EchNWA enhanced mean fluorescence intensity of IL-2 in Jurkat T-cells activated by PMA+1 or ionomycin alone. Conversely EchNWA mediated modest but significant suppression of IFNg response and reduced the percentage of CD25+ T-cells under low-density conditions. Conclusions are that EchNWA polysaccharides, but not phenolic compounds have dose-related adjuvant effects on human T-cell cytokine responses characterized by enhancing and suppressive effects that are regulated by T-cell density.

  2. Biomaterials and host versus graft response: A short review

    PubMed Central

    Velnar, Tomaz; Bunc, Gorazd; Klobucar, Robert; Gradisnik, Lidija

    2016-01-01

    Biomaterials and biotechnology are increasing becoming an important area in modern medicine. The main aim in this area is the development of materials, which are biocompatible to normal tissue. Tissue-implant interactions with molecular, biological and cellular characteristics at the implant-tissue interface are important for the use and development of implants. Implantation may cause an inflammatory and immune response in tissue, foreign body reaction, systemic toxicity and imminent infection. Tissue-implant interactions determine the implant life-period. The aims of the study are to consider the biological response to implants. Biomaterials and host reactions to implants and their mechanisms are also briefly discussed. PMID:26894284

  3. Early cytokine and antibody responses against Coxiella burnetii in aerosol infection of BALB/c mice

    PubMed Central

    Schoffelen, Teske; Self, Joshua S.; Fitzpatrick, Kelly A.; Netea, Mihai G.; van Deuren, Marcel; Joosten, Leo A. B.; Kersh, Gilbert J.

    2016-01-01

    Coxiella burnetii, a Gram-negative intracellular bacterium, can give rise to Q fever in humans and is transmitted mainly by inhalation of infected aerosols from animal reservoirs. Serology is commonly used to diagnose Q fever, but the early cellular immune response –i.e. C. burnetii-specific interferon(IFN)-γ production in response to antigen challenge– might be an additional diagnostic. Detection of IFN-γ responses has been used to identify past and chronic Q fever infections, but the IFN-γ response in acute Q fever has not been described. By challenging immunocompetent BALB/c mice with aerosols containing phase I C. burnetii, the timing and extent of IFN-γ recall responses was evaluated in an acute C. burnetii infection. Other cytokines were also measured in an effort to identify other potential diagnostic markers. The data show that after initial expansion of bacteria first in lungs and then in other tissues, the infection was cleared from day 10 onwards as reflected by the decreasing number of bacteria. The antigen-induced IFN-γ production by splenocytes coincided with emergence of IgM phase II-antibodies at day 10 post-infection, and preceded appearance of IgG-antibodies. This was accompanied by the production of pro-inflammatory cytokines including IL-6, KC and IP-10, followed by MCP-1, but not by IL-1β and TNF-α, and only very low production of the anti-inflammatory cytokine IL-10. These data suggest that analysis of antigen-specific IFN-γ responses could be a useful tool for diagnosis of acute Q-fever. Moreover, the current model of C.burnetii infection could be used to give new insights into immunological factors that predispose to development of persistent infection. PMID:25618420

  4. Distinct Th1- and Th2-Type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands.

    PubMed

    Malhotra, Indu; Mungai, Peter; Muchiri, Eric; Ouma, John; Sharma, Shobhona; Kazura, James W; King, Christopher L

    2005-06-01

    Prenatal immunity to Plasmodium falciparum merozoite proteins involved in erythrocyte invasion may contribute to the partial protection against malaria that is acquired during infancy in areas of stable malaria transmission. We examined newborn and maternal cytokine and antibody responses to merozoite surface protein-1 (MSP-1), ribosomal phosphoprotein P0 (PfP0), and region II of erythrocyte binding antigen-175 (EBA-175) in infant-mother pairs in Kenya. Overall, 82 of 167 (50%), 106 of 176 (60%), and 38 of 84 (45%) cord blood lymphocytes (CBL) from newborns produced one or more cytokines in response to MSP-1, PfP0, and EBA-175, respectively. Newborns of primigravid and/or malaria-infected women were more likely to have antigen-responsive CBL than were newborns of multigravid and/or uninfected women at delivery. Newborn cytokine responses did not match those of their mothers and fell into three distinct categories, Th1 (21 of 55 CBL donors produced only gamma interferon and/or interleukin 2 [IL-2]), Th2 (21 of 55 produced only IL-5 and/or IL-13), and mixed Th1/Th2 (13 of 55). Newborns produced more IL-10 than adults. High and low levels of cord blood IL-12 p70 production induced by anti-CD40 activation were associated with malaria-specific Th1 and Th2 responses, respectively. Antigen-responsive CBL in some newborns were detected only after depletion of IL-10-secreting CD8 cells with enrichment for CD4 cells. These data indicate that prenatal sensitization to blood-stage Plasmodium falciparum occurs frequently in areas where malaria is holoendemic. Modulation of this immunity, possibly by maternal parity and malaria, may affect the acquisition of protective immunity against malaria during infancy.

  5. Enhanced immune response of MAIT cells in tuberculous pleural effusions depends on cytokine signaling

    PubMed Central

    Jiang, Jing; Chen, Xinchun; An, Hongjuan; Yang, Bingfen; Zhang, Fuping; Cheng, Xiaoxing

    2016-01-01

    The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1β, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3+CD4+, and most IL-12p40-producing cells (91.39%) were CD14+ cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells. PMID:27586092

  6. Enhanced immune response of MAIT cells in tuberculous pleural effusions depends on cytokine signaling.

    PubMed

    Jiang, Jing; Chen, Xinchun; An, Hongjuan; Yang, Bingfen; Zhang, Fuping; Cheng, Xiaoxing

    2016-09-02

    The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1β, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3(+)CD4(+), and most IL-12p40-producing cells (91.39%) were CD14(+) cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells.

  7. Colostrum proinflammatory cytokines as biomarkers of bovine immune response to bovine tuberculosis (bTB).

    PubMed

    Sánchez-Soto, Eduardo; Ponce-Ramos, Rosa; Hernández-Gutiérrez, Rodolfo; Gutiérrez-Ortega, Abel; Álvarez, Angel H; Martínez-Velázquez, Moisés; Absalón, Angel E; Ortiz-Lazareno, Pablo; Limón-Flores, Alberto; Estrada-Chávez, Ciro; Herrera-Rodríguez, Sara E

    2017-02-01

    Bovine colostrum contains compounds, which provide passive immune protection from mother to newborn calves. Little is known about cytokine levels and their role in bovine colostrum. Moreover, the capacity of bovine colostrum cells to mount specific immune responses after natural exposure to bovine tuberculosis (bTB) antigens in dairy herds has not been studied, thus far. The purpose of this study was to identify biomarkers for bTB infection measurable in bovine colostrum. The present study reveals that isolated-immune colostrum cells can mount a specific immune response against bTB antigens, by measuring the novo IFN-γ release in cell culture. We found that IFN-γ levels in the responders (Bov(+)) to bTB antigen were higher than in non-responders (Bov(-)). On the other hand, proinflammatory cytokines contained in colostrum's whey were tested in Tuberculin Skin Test (TST) reactor (TST(+)) and non-reactor (TST(-)) animals to assess their potential role as biomarker. We observed that IFN-γ levels were lower or undetectable, as opposed to IL4 levels were measurable, the TNF-α level was higher in TST(-) than TST(+), while IL-6 levels showed the opposite reaction and with no statistical significance. Moreover, IL-1α mRNA expression levels were higher in colostrum mononuclear cells (CMC) in Bov(+) cattle. Collectively, these data suggest that the differential expression of pro and anti-inflammatory cytokines could have relevant value to diagnose bTB in cattle.

  8. Modulation of the cytokine response in human monocytes by mycobacterium leprae phenolic glycolipid-1.

    PubMed

    Manca, Claudia; Peixoto, Blas; Malaga, Wladimir; Guilhot, Christophe; Kaplan, Gilla

    2012-01-01

    Leprosy is a chronic but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae. M. leprae cell wall is characterized by a unique phenolic glycolipid-1 (PGL-1) reported to have several immune functions. We have examined the role of PGL-1 in the modulation of monocyte cytokine/chemokine production in naive human monocytes. PGL-1 in its purified form or expressed in a recombinant Mycobacterium bovis Bacillus Colmette-Guérin (BCG) background (rBCG-PGL-1) was tested. We found that PGL-1 selectively modulated the induction of specific monocyte cytokines and chemokines and, when used as prestimulus, exerted priming and/or inhibitory effects on the induction of selected cytokines/chemokines in response to a second stimulus. Taken together, the results of this study support a modulatory role for PGL-1 in the innate immune response to M. leprae. Thus, PGL-1 may play an important role in the development of the anergic clinical forms of disease and in tissue damage seen in lepromatous patients and during the reactional states of leprosy.

  9. Intestinal cytokine response of commercial source broiler chicks to Salmonella typhimurium infection.

    PubMed

    Fasina, Y O; Holt, P S; Moran, E T; Moore, R W; Conner, D E; McKee, S R

    2008-07-01

    Development of molecular-based immunotherapeutic strategies for controlling Salmonella Typhimurium (ST) infection in poultry requires a better understanding of intestinal and cecal cytokine responses. Accordingly, an experiment was conducted to measure changes in intestinal cytokine expression when commercial source broiler chickens were challenged with a nalidixic acid-resistant ST. Ross broiler chicks were nonchallenged with ST (control treatment) or challenged by orally giving 7.8 x 10(6) cfu at 4 d of age (STC treatment). Each treatment consisted of 4 replicate pens with 14 chicks per pen. Expression levels of proinflammatory cytokines, interferon-gamma, and antiinflammatory interleukin (IL)-10 were determined at 5 and 10 d postchallenge (PC). Intestinal flushes were also collected from each treatment at 7 d PC to estimate IgA and IgG. Results showed an upregulation in IL-1beta mRNA in STC chicks at 5 d PC. By 10 d PC, the expression of IL-1beta was further increased and accompanied by an upregulation of IL-6 and interferon-gamma mRNA, whereas IL-10 mRNA expression decreased. It was concluded that ST induced an intestinal mucosal inflammatory response in commercial source broiler chicks less than 2 wk of age.

  10. Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications.

    PubMed

    Candore, Giuseppina; Bulati, Matteo; Caruso, Calogero; Castiglia, Laura; Colonna-Romano, Giuseppina; Di Bona, Danilo; Duro, Giovanni; Lio, Domenico; Matranga, Domenica; Pellicanò, Mariavaleria; Rizzo, Claudia; Scapagnini, Giovanni; Vasto, Sonya

    2010-01-01

    Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot topics concerning AD pathophysiology that have an important impact on therapeutic perspectives. Hence, we have focused our attention on inflammation, cytokines, immune response, apolipoprotein E (APOE), cholesterol, oxidative stress, as well as exploring the related therapeutic possibilities, i.e., nonsteroidal antiinflammatory drugs, cytokine blocking antibodies, immunotherapy, diet, and curcumin.

  11. Infection of Burkholderia cepacia Induces Homeostatic Responses in the Host for Their Prolonged Survival: The Microarray Perspective

    PubMed Central

    Mariappan, Vanitha; Vellasamy, Kumutha Malar; Thimma, Jaikumar; Hashim, Onn Haji; Vadivelu, Jamuna

    2013-01-01

    Burkholderia cepacia is an opportunistic human pathogen associated with life-threatening pulmonary infections in immunocompromised individuals. Pathogenesis of B. cepacia infection involves adherence, colonisation, invasion, survival and persistence in the host. In addition, B. cepacia are also known to secrete factors, which are associated with virulence in the pathogenesis of the infection. In this study, the host factor that may be the cause of the infection was elucidated in human epithelial cell line, A549, that was exposed to live B. cepacia (mid-log phase) and its secretory proteins (mid-log and early-stationary phases) using the Illumina Human Ref-8 microarray platform. The non-infection A549 cells were used as a control. Expression of the host genes that are related to apoptosis, inflammation and cell cycle as well as metabolic pathways were differentially regulated during the infection. Apoptosis of the host cells and secretion of pro-inflammatory cytokines were found to be inhibited by both live B. cepacia and its secretory proteins. In contrast, the host cell cycle and metabolic processes, particularly glycolysis/glycogenesis and fatty acid metabolism were transcriptionally up-regulated during the infection. Our microarray analysis provided preliminary insights into mechanisms of B. cepacia pathogenesis. The understanding of host response to an infection would provide novel therapeutic targets both for enhancing the host’s defences and repressing detrimental responses induced by the invading pathogen. PMID:24116227

  12. Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure.

    PubMed

    Doremus-Fitzwater, Tamara L; Gano, Anny; Paniccia, Jacqueline E; Deak, Terrence

    2015-09-01

    Alcohol induces widespread changes in cytokine expression, with recent data from our laboratory having demonstrated that, during acute ethanol intoxication, adult rats exhibit consistent increases in interleukin (IL)-6 mRNA expression in several brain regions, while showing reductions in IL-1 and TNFα expression. Given evidence indicating that adolescence may be an ontogenetic period in which some neuroimmune processes and cells may not yet have fully matured, the purpose of the current experiments was to examine potential age differences in the central cytokine response of adolescent (P31-33days of age) and adult (69-71days of age) rats to either an acute immune (lipopolysaccharide; LPS) or non-immune challenge (ethanol). In Experiment 1, male Sprague-Dawley rats were given an intraperitoneal (i.p.) injection of either sterile saline, LPS (250μg/kg), or ethanol (4-g/kg), and then trunk blood and brain tissue were collected 3h later for measurement of blood ethanol concentrations (BECs), plasma endotoxin, and central mRNA expression of several immune-related gene targets. In Experiment 2, the response to intragastrically (i.g.) administered ethanol was examined and compared to animals given tap water (i.g.). Results showed that LPS stimulated robust increases in expression of IL-1, IL-6, TNFα, and IκBα in the hippocampus, PVN, and amygdala, and that these increases were generally less pronounced in adolescents relative to adults. Following an i.p. ethanol challenge, IL-6 and IκBα expression was significantly increased in both ages in the PVN and amygdala, and adults exhibited even greater increases in IκBα than adolescents. I.g. administration of ethanol also increased IL-6 and IκBα expression in all three brain regions, with hippocampal IL-6 elevated even more so in adults compared to adolescents. Furthermore, assessment of plasma endotoxin concentrations revealed (i) whereas robust increases in plasma endotoxin were observed in adults injected with LPS

  13. Immunohistochemical study and mRNA cytokine profile of the local immune response in cattle naturally infected with Calicophoron daubneyi.

    PubMed

    Fuertes, Miguel; Manga-González, Yolanda; Benavides, Julio; González-Lanza, M Camino; Giráldez, Francisco Javier; Mezo, Mercedes; González-Warleta, Marta; Fernández, Miguel; Regidor-Cerrillo, Javier; Castaño, Pablo; Royo, Marcos; Ortega-Mora, Luis M; Pérez, Valentín; Ferreras, M Carmen

    2015-11-30

    In order to recognize the local immune response of the definitive host to Calicophoron daubneyi natural infection, an immunohistochemical study was carried out in the reticulum and rumen in 49 naturally infected cattle. The role of cytokines (IL-4 and IL-10 interleukins and IFN-γ) in the activation of specific defence mechanisms was evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assays to study cytokine mRNA expression. In all infected animals, CD3+ T lymphocytes seemed to be the main element of the inflammatory infiltrate in the reticular and ruminal lamina propria at the point of the parasite adhesion. Intraepithelial globule leukocytes also showed immunolabelling for CD3. Most CD3+ cells also expressed CD4 (T cell helper) antigen although sporadic CD8+-cytotoxic lymphocytes were observed. Local expression of IFN-γ was observed in damaged papillae at the site of parasite attachment and in scattered cells in the lamina propria. B cells (CD79αcy+, CD45+ and IgG+) were found constantly in relation to lymphoid aggregates. MAC387 was expressed in squamous epithelium and in macrophages of the lamina propria of affected papillae. Macrophages in this location also stained positively for CD163 and CD68. Intraepithelial Langerhans cells and macrophages located in the lamina propria showed immunopositivity for MHCII in the affected areas. RT-qPCR analysis confirmed a statistical significant increase of IFN-γ, and IL-10 expression (p<0.01) in the rumen associated with the presence of flukes. These findings suggest a predominant Th1 polarized local immune response with the probable involvement of Th regulatory cells in cattle C. daubneyi natural infection.

  14. Legionella suppresses the host unfolded protein response via multiple mechanisms

    PubMed Central

    Treacy-Abarca, Sean; Mukherjee, Shaeri

    2015-01-01

    The intracellular pathogen, Legionella pneumophila, secretes ∼300 effector proteins to modulate the host environment. Given the intimate interaction between L. pneumophila and the endoplasmic reticulum, we investigated the role of the host unfolded protein response (UPR) during L. pneumophila infection. Interestingly, we show that the host identifies L. pneumophila infection as a form of endoplasmic reticulum stress and the sensor pATF6 is processed to generate pATF6(N), a transcriptional activator of downstream UPR genes. However, L. pneumophila is able to suppress the UPR and block the translation of prototypical UPR genes, BiP and CHOP. Furthermore, biochemical studies reveal that L. pneumophila uses two effectors (Lgt1 and Lgt2) to inhibit the splicing of XBP1u mRNA to spliced XBP1 (XBP1s), an UPR response regulator. Thus, we demonstrate that L. pneumophila is able to inhibit the UPR by multiple mechanisms including blocking XBP1u splicing and causing translational repression. This observation highlights the utility of L. pneumophila as a powerful tool for studying a critical protein homeostasis regulator. PMID:26219498

  15. Host Cell Responses to Persistent Mycoplasmas - Different Stages in Infection of HeLa Cells with Mycoplasma hominis

    PubMed Central

    Hopfe, Miriam; Deenen, René; Degrandi, Daniel; Köhrer, Karl; Henrich, Birgit

    2013-01-01

    Mycoplasma hominis is a facultative human pathogen primarily associated with bacterial vaginosis and pelvic inflammatory disease, but it is also able to spread to other sites, leading to arthritis or, in neonates, meningitis. With a minimal set of 537 annotated genes, M. hominis is the second smallest self-replicating mycoplasma and thus an ideal model organism for studying the effects of an infectious agent on its host more closely. M. hominis adherence, colonisation and invasion of HeLa cells were characterised in a time-course study using scanning electron microscopy, confocal microscopy and microarray-based analysis of the HeLa cell transcriptome. At 4 h post infection, cytoadherence of M. hominis to the HeLa cell surface was accompanied by differential regulation of 723 host genes (>2 fold change in expression). Genes associated with immune responses and signal transduction pathways were mainly affected and components involved in cell-cycle regulation, growth and death were highly upregulated. At 48 h post infection, when mycoplasma invasion started, 1588 host genes were differentially expressed and expression of genes for lysosome-specific proteins associated with bacterial lysis was detected. In a chronically infected HeLa cell line (2 weeks), the proportion of intracellular mycoplasmas reached a maximum of 10% and M. hominis-filled protrusions of the host cell membrane were seen by confocal microscopy, suggesting exocytotic dissemination. Of the 1972 regulated host genes, components of the ECM-receptor interaction pathway and phagosome-related integrins were markedly increased. The immune response was quite different to that at the beginning of infection, with a prominent induction of IL1B gene expression, affecting pathways of MAPK signalling, and genes connected with cytokine-cytokine interactions and apoptosis. These data show for the first time the complex, time-dependent reaction of the host directed at mycoplasmal clearance and the counter measures of

  16. Cruzipain, a major Trypanosoma cruzi antigen, conditions the host immune response in favor of parasite.

    PubMed

    Giordanengo, Laura; Guiñazú, Natalia; Stempin, Cinthia; Fretes, Ricardo; Cerbán, Fabio; Gea, Susana

    2002-04-01

    We recently demonstrated that humoral immune response to cruzipain, a major antigen of Trypanosoma cruzi parasite, is implicated in the pathogenesis of experimental Chagas' disease. In the present study, the spleen cell phenotype and the cytokine profile induced by cruzipain in immunized mice were analyzed. The results showed that cruzipain increases the number of spleen cells with large size and granularity. Splenocyte populations with CD19(+), Mac-1(+), Gr-1(+) and CD11c(+) positive surface markers significantly increased in immune mice compared to controls ones. Histological study revealed the presence of high number of megacariocyte and granulocyte-macrophage progenitors, indicating extramedullary hemopoiesis in spleens of immune mice. The finding of high levels of IL-4, IL5 and IL-10 and low levels of IFN-gamma and IL-12 in supernatants of immune cells stimulated with cruzipain indicates a preferential activation of T2 type cells in immune animals. To investigate the role of innate immunity cells, the classical and alternative metabolic pathways of spleen macrophages from immune mice stimulated by cruzipain were also studied. The results showed an increase of urea associated with a decrease of nitrite levels, suggesting that cruzipain up-regulates the arginase way. Therefore, cruzipain leads to T2 type cytokine profile which may enhance the arginase via in the macrophages promoting a susceptible mechanism to infection. Thus, we postulate that during T. cruzi infection, cruzipain could be used by the parasite to spread inside the host.

  17. Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae

    PubMed Central

    Turner, Kelli L.; Cahill, Bethaney K.; Dilello, Sarah K.; Gutel, Dedra; Brunson, Debra N.; Albertí, Sebastián

    2015-01-01

    Antibiotic-resistant strains of Klebsiella pneumoniae often exhibit porin loss. In this study, we investigated how porin loss impacted the composition of secreted outer membrane vesicles as well as their ability to trigger proinflammatory cytokine secretion by macrophages. We hypothesize that porin loss associated with antibiotic resistance will directly impact both the composition of outer membrane vesicles and their interactions with phagocytic cells. Using clonally related clinical isolates of extended-spectrum beta-lactamase (ESBL)-positive Klebsiella pneumoniae with different patterns of porin expression, we demonstrated that altered expression of OmpK35 and OmpK36 results in broad alterations to the protein profile of secreted vesicles. Additionally, the level of OmpA incorporation was elevated in strains lacking a single porin. Porin loss significantly impacted macrophage inflammatory responses to purified vesicles. Outer membrane vesicles lacking both OmpK35 and OmpK36 elicited significantly lower levels of proinflammatory cytokine secretion than vesicles from strains expressing one or both porins. These data demonstrate that antibiotic resistance-associated porin loss has a broad and significant effect on both the composition of outer membrane vesicles and their interactions with phagocytic cells, which may impact bacterial survival and inflammatory reactions in the host. PMID:26666932

  18. Genetic dissection of host immune response in pneumonia development and progression

    PubMed Central

    Smelaya, Tamara V.; Belopolskaya, Olesya B.; Smirnova, Svetlana V.; Kuzovlev, Artem N.; Moroz, Viktor V.; Golubev, Arkadiy M.; Pabalan, Noel A.; Salnikova, Lyubov E.

    2016-01-01

    The role of host genetic variation in pneumonia development and outcome is poorly understood. We studied common polymorphisms in the genes of proinflammatory cytokines (IL6 rs1800795, IL8 rs4073, IL1B rs16944), anti-inflammatory cytokines (IL10 rs1800896, IL4 rs2243250, IL13 rs20541) and toll-like receptors (TLR2 rs5743708 and rs4696480, TLR4 rs4986791, TLR9 rs352139, rs5743836 and rs187084) in patients with community-acquired pneumonia (CAP) (390 cases, 203 controls) and nosocomial pneumonia (355 cases, 216 controls). Experimental data were included in a series of 11 meta-analyses and eight subset analyses related to pneumonia susceptibility and outcome. TLR2 rs5743708 minor genotype appeared to be associated with CAP/Legionnaires’ disease/pneumococcal disease. In CAP patients, the IL6 rs1800795-C allele was associated with severe sepsis/septic shock/severe systemic inflammatory response, while the IL10 rs1800896-A allele protected against the development of these critical conditions. To contribute to deciphering of the above results, we performed an in silico analysis and a qualitative synthesis of literature data addressing basal and stimulated genotype-specific expression level. This data together with database information on transcription factors’ affinity changes caused by SNPs in putative promoter regions, the results of linkage disequilibrium analysis along with SNPs functional annotations supported assumptions about the complexity underlying the revealed associations. PMID:27725770

  19. Differential Host Response, Rather Than Early Viral Replication Efficiency, Correlates with Pathogenicity Caused by Influenza Viruses

    PubMed Central

    Askovich, Peter S.; Sanders, Catherine J.; Rosenberger, Carrie M.; Diercks, Alan H.; Dash, Pradyot; Navarro, Garnet; Vogel, Peter; Doherty, Peter C.; Thomas, Paul G.; Aderem, Alan

    2013-01-01

    Influenza viruses exhibit large, strain-dependent differences in pathogenicity in mammalian hosts. Although the characteristics of severe disease, including uncontrolled viral replication, infection of the lower airway, and highly inflammatory cytokine responses have been extensively documented, the specific virulence mechanisms that distinguish highly pathogenic strains remain elusive. In this study, we focused on the early events in influenza infection, measuring the growth rate of three strains of varying pathogenicity in the mouse airway epithelium and simultaneously examining the global host transcriptional response over the first 24 hours. Although all strains replicated equally rapidly over the first viral life-cycle, their growth rates in both lung and tracheal tissue strongly diverged at later times, resulting in nearly 10-fold differences in viral load by 24 hours following infection. We identified separate networks of genes in both the lung and tracheal tissues whose rapid up-regulation at early time points by specific strains correlated with a reduced viral replication rate of those strains. The set of early-induced genes in the lung that led to viral growth restriction is enriched for both NF-κB binding site motifs and members of the TREM1 and IL-17 signaling pathways, suggesting that rapid, NF-κB –mediated activation of these pathways may contribute to control of viral replication. Because influenza infection extending into the lung generally results in severe disease, early activation of these pathways may be one factor distinguishing high- and low-pathogenicity strains. PMID:24073225

  20. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.

    PubMed

    Gądek-Michalska, Anna; Tadeusz, Joanna; Rachwalska, Paulina; Bugajski, Jan

    2013-01-01

    Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression. This hyperactivity is caused by diminished feedback inhibition of glucocorticoid (GC)-induced reduction of HPA axis signaling and increased corticotrophin-releasing hormone (CRH) secretion from the hypothalamic paraventricular nucleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorticoid receptor (GR) levels were significantly changed in the prefrontal cortex (PFC) and hippocampus, both structures known to be deeply involved in the pathogenesis of depression. Cytokines secreted by both immune and non-immune cells can markedly affect neurotransmission within regulatory brain circuits related to the expression of emotions; cytokines may also induce hormonal changes similar to those observed following exposure to stress. Proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are implicated in the etiologies of clinical depression and anxiety disorders. Prolonged stress responses and cytokines impair neuronal plasticity and stimulation of neurotransmission. Exposure to acute stress and IL-1β markedly increased IL-1β levels in the PFC, hippocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1β. Inflammatory responses in the brain contribute to cellular damage associated with neuropsychiatric diseases related to stress. Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors. Induced CRH release involves IL-1, IL-6 and TNF-α, for stimulation adrenocorticotropic hormone (ACTH) release from the anterior

  1. Relationship of basal heart rate variability to in vivo cytokine responses after endotoxin exposure.

    PubMed

    Jan, Badar U; Coyle, Susette M; Macor, Marie A; Reddell, Michael; Calvano, Steve E; Lowry, Stephen F

    2010-04-01

    Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the severity injury and responses to infectious challenge among critically ill patients. In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-alpha production. We sought to define the influence of gender on HRV responses to in vivo endotoxin challenge in healthy humans and to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses. Young (<30 years of age), healthy subjects (n = 30) received endotoxin (2 ng/kg), and HRV and blood samples were obtained serially thereafter. Plasma cytokines were measured by enzyme-linked immunosorbent assay, and HRV parameters were determined by analysis of serial 5-min epochs of heart rate monitoring. In addition, calculation of multiscale entropy deriving from cardiac monitoring data was performed. The influence of factors such as gender, body mass index, and resting heart rate on HRV after endotoxin exposure was assessed. We found that gender, body mass index, or resting heart rate did not significantly alter the HRV response after endotoxin exposure. Using entropy analysis, we observed that females had significantly higher entropy values at 24 h after endotoxin exposure. Using a serially sampling protocol for cytokine determination, we found a significant correlation of several baseline HRV parameters (percentage of interval differences of successive interbeat intervals more than 50 ms, r = 0.42, P < 0.05; high-frequency variability, r = 0.4, P < 0.05; and low-frequency/high-frequency ratio, r = -0.43, P < 0.05) on TNF-alpha release after endotoxin exposure.

  2. Effects of prior acute exercise on circulating cytokine concentration responses to a high-fat meal.

    PubMed

    Brandauer, Josef; Landers-Ramos, Rian Q; Jenkins, Nathan T; Spangenburg, Espen E; Hagberg, James M; Prior, Steven J

    2013-08-01

    High-fat meal consumption alters the circulating cytokine profile and contributes to cardiometabolic diseases. A prior bout of exercise can ameliorate the triglyceride response to a high-fat meal, but the interactive effects of exercise and high-fat meals on cytokines that mediate cardiometabolic risk are not fully understood. We investigated the effects of prior exercise on the responses of circulating tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, leptin, retinol-binding protein 4 (RBP4), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) to a high-fat meal. Ten healthy men were studied before and 4 h after ingestion of a high-fat meal either with or without ∼50 min of endurance exercise at 70% of VO2 max on the preceding day. In response to the high-fat meal, lower leptin and higher VEGF, bFGF, IL-6, and IL-8 concentrations were evident (P < 0.05 for all). There was no effect of the high-fat meal on PlGF, TNF-α, or RBP4 concentrations. We found lower leptin concentrations with prior exercise (P < 0.05) and interactive effects of prior exercise and the high-fat meal on sFlt-1 (P < 0.05). The high-fat meal increased IL-6 by 59% without prior exercise and 218% with prior exercise (P < 0.05). In conclusion, a prior bout of endurance exercise does not affect all high-fat meal-induced changes in circulating cytokines, but does affect fasting or postprandial concentrations of IL-6, leptin, and sFlt-1. These data may reflect a salutary effect of prior exercise on metabolic responses to a high-fat meal.

  3. Effect of immunostimulatory oligodeoxynucleotides on host responses and the establishment of Brugia pahangi in Mongolian gerbils (Meriones unguiculatus).

    PubMed

    Chirgwin, Sharon R; Nowling, Jena M; Coleman, Sharon U; Klei, Thomas R

    2003-06-01

    Infection of humans with filarial parasites has long been associated with the maintenance of a dominant Th2-type host immune response. This is reflected by increases in interleukin (IL)-4- and IL-5-producing T cells, elevated immunoglobulin (Ig)E and IgG4 levels, and a pronounced eosinophilia. The Mongolian gerbil (Meriones unguiculatus) is permissive for the filarial nematodes Brugia malayi and B. pahangi. As in humans, persistent microfilaremic infections of gerbils with Brugia spp. results in increases in Th2 cytokines such as IL-4 and IL-5. The association of dominant Th2 cytokine profiles with the maintenance of infection suggests that the introduction of Brugia spp. into a strongly Th1-biased environment may adversely affect parasite establishment. Indeed, studies conducted in mice with B. malayi suggest that depleting Th1 effectors such as interferon (IFN)-gamma and nitric oxide results in increased worm recoveries. In the present studies, the Mongolian gerbil was used as a model to investigate the effect of a dominant Th1 cytokine environment on the establishment of B. pahangi. Intraperitoneal (i.p.) administration of immunostimulatory oligodeoxynucleotide (IS ODN) induced the production of IFN-gamma in the peritoneal exudate cells and spleen of gerbils. The presence of IFN-gamma at the time of B. pahangi infection did result in an altered host immune response to B. pahangi. Gerbils that received IS ODN before i.p. B. pahangi infections showed lower levels of the Th2-type cytokines IL-4 and IL-5, compared with animals that received B. pahangi alone (0 + Bp). This alteration in cytokine profile, however, did not alter the establishment or development of B. pahangi in the peritoneal cavity. Furthermore, there was no difference in the granulomatous response of gerbils to soluble adult B. pahangi antigen bound to beads embolized in their lungs, regardless of treatment group, suggesting that IL-4 and IL-5 are not essential contributors to the systemic host

  4. Examination of epithelial tissue cytokine response to natural peste des petits ruminants virus (PPRV) infection in sheep and goats by immunohistochemistry.

    PubMed

    Atmaca, H T; Kul, O

    2012-01-01

    In this study, we aimed to evaluate expression of IL-4, IL-10, TNF-α, IFN-γ and iNOS in lingual, buccal mucosa and lung epithelial tissue using immunoperoxidase technique and to compare with the tissues of control animals. The tissues used in the study were collected from 17 PPRV-affected and 5 healthy sheep and goats. In PPRV positive animals, the lungs, lingual and buccal mucosa had significantly higher iNOS, IFN-γ and TNF-α expressions compared to control group animals. There was no significant difference between PPRV positive and control groups for IL-4 and IL-10 expressions of epithelial tissues. In conclusion, the epithelial tissues infected by PPRV showed significant iNOS, IFN-γ and TNF-α expressions and they might play an important role in the initiation and regulation of cytokine response, as they take place in the first host barrier to be in contact with PPRV. It is suggested that the more epithelial damage produced by PPRV the more cytokine response may result in the infected epithelial cells. The first demonstration of iNOS expression and epithelial cytokine response to PPRV in natural cases is important because it may contribute to an early initiation of systemic immunity against PPRV infection, in addition to direct elimination of the virus during the initial epithelial phase of the infection.

  5. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.

    PubMed

    Abimannan, Thiruvaimozhi; Peroumal, Doureradjou; Parida, Jyoti R; Barik, Prakash K; Padhan, Prasanta; Devadas, Satish

    2016-10-01

    Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4(+) T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4(+) T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4(+) T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A(+) (Th17), IFN(-)γ(+) (Th1) and IL-17A(+)/IFN(-)γ(+) (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.

  6. SURFACE CHEMISTRY INFLUENCE IMPLANT MEDIATED HOST TISSUE RESPONSES

    PubMed Central

    Kamath, Shwetha; Bhattacharyya, Dhiman; Padukudru, Chandana; Timmons, Richard B.; Tang, Liping

    2011-01-01

    Implant-mediated fibrotic reactions are detrimental to the performance of encapsulated cells, implanted drug release devices and sensors. To improve the implant function and longevity, research has emphasized altering cellular responses. Although material surface functional groups have been shown to be potent in affecting cellular activity in vitro and short term in vivo responses, these groups appear to have little influence on long-term in vivo fibrotic reactions, possibly as a result of insufficient interactions between recruited host cells and functional groups on the implants. To maximize the influence of functionality on cells, and to mimic drug release microspheres, functionalized micron-sized particles were created and tested for their ability in modulating tissue responses to biomaterial implants. In this work, the surfaces of polypropylene particles were controllably coated with four different functional groups, specifically –OH, -NH2, -CFx and –COOH, using a radio frequency glow discharge plasma polymerization technique. The effect of these surface functionalities on host tissue responses were then evaluated using a mice subcutaneous implantation model. Major differences were observed in contrasting tissue response to the different chemistries. Surfaces with –OH and –NH2 surface groups induced the thickest fibrous capsule accompanied with the greatest cellular infiltration into the implants. In contrast, surfaces with –CFx and –COOH exhibited the least inflammatory/fibrotic responses and cellular infiltrations. The present results clearly demonstrate that, by increasing the available functionalized surface area and spatial distribution, the effect of surface chemistry on tissue reactivity can be substantially enhanced. PMID:18022841

  7. Fibrinogen adsorption and host tissue responses to plasma functionalized surfaces.

    PubMed

    Tang, L; Wu, Y; Timmons, R B

    1998-10-01

    The physical and chemical characteristics of material surfaces are thought to play important roles in biomaterial-mediated tissue responses. To understand the importance of discrete biomaterial chemical characteristics in modifying host tissue responses, we constructed surfaces bearing different functional groups using radio frequency glow discharge plasma polymerization. Surfaces evaluated included those having high concentrations of -OH, -NH2, -CF3, and siloxyl groups. These surfaces and polyethylene terephthalate controls were used to assess the importance of particular physicochemical characteristics in surface:protein:cell interactions both in vitro and in vivo. The results obtained show that surface functionalities do significantly affect both the adsorption and "denaturation" of adsorbed fibrinogen (which is an important mediator of inflammatory responses to biomaterial implants). In addition, these surfaces provoke different degrees of acute inflammatory responses. Interestingly, the amounts of "denatured" fibrinogen that spontaneously accumulate on the individual surfaces correlate closely with the extent of biomaterial-mediated inflammation. These results suggest that surfaces that tend to "irreversibly" bind fibrinogen prompt greater acute inflammatory responses. Unexpectedly, all test surfaces except those bearing a siloxyl group engender relatively similar biomaterial-mediated fibrotic responses. Thus surface functionalities alone may not be sufficient to affect subsequent fibrotic responses.

  8. Stimulation of the host immune response by photodynamic therapy (PDT)

    NASA Astrophysics Data System (ADS)

    Gollnick, Sandra O.; Kabingu, Edith; Kousis, Philaretos C.; Henderson, Barbara W.

    2004-07-01

    The tumor response to photodynamic therapy (PDT) involves a complex interplay between direct cytotoxicity to the tumor cells and secondary damage as a result of the effects of PDT on the vasculature and stimulation of the host inflammatory response. Pre-clinical and clinical studies have suggested that the combination of direct and indirect effects of PDT culminate in an activation of host anti-tumor immune responses. We have begun to examine the direct effects of PDT on tumor immunogenicity and have made the novel discovery that PDT treatment of tumor cells in vitro enhances tumor cell immunogenicity. We have further demonstrated that the increase in tumor cell immunogenicity by PDT can be correlated with the ability of PDT-generated tumor cell lysates to stimulate dendritic cell maturation and activation. The mechanisms by which PDT is able to enhance tumor cell immunogenicity and stimulate dendritic cell maturation and activation is unclear, however our finding suggest that alterations in tumor immunogenicity correlate with enhanced release of dendritic cell stimulating factors such as heat shock proteins.

  9. Winter day lengths enhance T lymphocyte phenotypes, inhibit cytokine responses, and attenuate behavioral symptoms of infection in laboratory rats.

    PubMed

    Prendergast, Brian J; Kampf-Lassin, August; Yee, Jason R; Galang, Jerome; McMaster, Nicholas; Kay, Leslie M

    2007-11-01

    Annual variations in day length (photoperiod) trigger changes in the immune and reproductive system of seasonally-breeding animals. The purpose of this study was to determine whether photoperiodic changes in immunity depend on concurrent photoperiodic responses in the reproductive system, or whether immunological responses to photoperiod occur independent of reproductive responses. Here we report photoperiodic changes in enumerative, functional, and behavioral aspects of the immune system, and in immunomodulatory glucocorticoid secretion, in reproductively non-photoperiodic Wistar rats. T-cell numbers (CD3+, CD8+, CD8+CD25+, CD4+CD25+) were higher in the blood of rats housed in short as opposed to long-day lengths for 10 weeks. Following a simulated bacterial infection (Escherichia coli LPS; 125 microg/kg) the severity of several acute-phase sickness behaviors (anorexia, cachexia, neophobia, and social withdrawal) were attenuated in short days. LPS-stimulated IL-1beta and IL-6 production were comparable between photoperiods, but plasma TNFalpha was higher in long-day relative to short-day rats. In addition, corticosterone concentrations were higher in short-day relative to long-day rats. The data are consistent with the hypothesis that photoperiodic regulation of the immune system can occur entirely independently of photoperiodic regulation of the reproductive system. In the absence of concurrent reproductive responses, short days increase the numbers of leukocytes capable of immunosurveillance and inhibition of inflammatory responses, increase proinflammatory cytokine production, increase immunomodulatory glucocorticoid secretion, and ultimately attenuate behavioral responses to infection. Seasonal changes in the host immune system, endocrine system, and behavior may contribute to the seasonal variability in disease outcomes, even in reproductively non-photoperiodic mammals.

  10. Differential cytokine response in interstitial fluid in skin and serum during experimental inflammation in rats

    PubMed Central

    Nedrebø, Torbjørn; Reed, Rolf K; Jonsson, Roland; Berg, Ansgar; Wiig, Helge

    2004-01-01

    Tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are important mediators produced during inflammation. We hypothesized that the pro-inflammatory cytokine response in the interstitial fluid (IF) is different from that in serum, and we aimed at quantifying the amount of TNF-α and IL-1β in the IF. By centrifugation of rat skin at < 424 g pure IF is extracted. Using ELISA such fluid was analysed for cytokines in back and/or paw skin of pentobarbital-anaesthetized rats, after either induction of endotoxaemia or ischaemia–reperfusion (I/R) injury. During endotoxaemia, TNF-α increased in the IF from 0 in control to 640 ± 100 pg ml−1 (mean ±s.e.m.) after 90 min, with the serum concentration being 5–10 times higher at all time points. The response pattern of IL-1β after lipopolysaccharide (LPS) challenge differed greatly from that of TNF-α with a large increase in IF from 390 ± 90 to 28 000 ± 1500 pg ml−1 after 210 min, and a significantly smaller increase in serum (600 ± 45 pg ml−1). During reperfusion of the hind paw after 2 h of ischaemia, there was a gradual increase of TNF-α in both IF of the paw skin and serum after 3 min of reperfusion. Both declined after 20 min. The pattern for IL-1β differed, increasing significantly less in serum (25 ± 15 pg ml−1 after 20 min of reperfusion) than in the IF (1100 ± 200 pg ml−1). Immunostaining of the inflamed tissues showed increased expression of the two cytokines in cells of both epidermis and dermis compared to controls. Subdermal injections of TNF-α and IL-1β at the same concentrations found in IF after LPS infusion affected interstitial fluid pressure significantly. Local TNF-α production dominates after I/R injury, whereas in endotoxaemia systemic production predominates. For IL-1β local production dominates in both conditions. Thus, there is a differential pattern of cytokine production and the current method allows the study of the role of cytokines in IF during different

  11. Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis

    PubMed Central

    2010-01-01

    Background Infestation of ovine skin with the ectoparasitic mite Psoroptes ovis results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the in vivo skin response to infestation with P. ovis to gain a clearer understanding of the mechanisms and signalling pathways involved. Results Infestation with P. ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (IL1A, IL1B, IL6, IL8 and TNF) and factors involved in immune cell activation and recruitment (SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 and CXCL2). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response. Conclusions This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to P. ovis, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to P. ovis, including the

  12. Host DNA damage response facilitates African swine fever virus infection.

    PubMed

    Simões, Margarida; Martins, Carlos; Ferreira, Fernando

    2013-07-26

    Studies with different viral infection models on virus interactions with the host cell nucleus have opened new perspectives on our understanding of the molecular basis of these interactions in African swine fever virus (ASFV) infection. The present study aims to characterize the host DNA damage response (DDR) occurring upon in vitro infection with the ASFV-Ba71V isolate. We evaluated protein levels during ASFV time-course infection, of several signalling cascade factors belonging to DDR pathways involved in double strand break repair - Ataxia Telangiectasia Mutated (ATM), ATM-Rad 3 related (ATR) and DNA dependent protein kinase catalytic subunit (DNA-PKcs). DDR inhibitory trials using caffeine and wortmannin and ATR inducible-expression cell lines were used to confirm specific pathway activation during viral infection. Our results show that ASFV specifically elicits ATR-mediated pathway activation from the early phase of infection with increased levels of H2AX, RPA32, p53, ATR and Chk1 phosphorylated forms. Viral p72 synthesis was abrogated by ATR kinase inhibitors and also in ATR-kd cells. Furthermore, a reduction of viral progeny was identified in these cells when compared to the outcome of infection in ATR-wt. Overall, our results strongly suggest that the ATR pathway plays an essential role for successful ASFV infection of host cells.

  13. Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation To Resist Host Immunity

    PubMed Central

    Leistikow, Rachel L.; Kirksey, Meghan A.; Voskuil, Martin I.; McKinney, John D.

    2013-01-01

    Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A ΔpstA1 mutant was fully virulent in IFN-γ−/− mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that ΔpstA1 bacteria are sensitized to an IFN-γ-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that ΔpstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of ΔpstA1 bacteria in NOS2−/− mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response. PMID:23132496

  14. Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection.

    PubMed

    Feruglio, S L; Tonby, K; Kvale, D; Dyrhol-Riise, A M

    2015-03-01

    Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-α] and degranulation (CD107a) as well as subsets of CD4(+) T regulatory cells (Tregs ) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb-specific total IFN-γ and single IFN-γ-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2(+) cells increased over time for both CD4(+) and CD8(+) T cells. The Treg subsets CD25(high) CD127(low) , CD25(high) CD147(++) and CD25(high) CD127(low) CD161(+) expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25(high) CD127(low) CD39(+) Tregs remained unchanged. The fraction of CD25(high) CD127(low) Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4(+) and CD8(+) T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further.

  15. The balance between pro- and anti-inflammatory cytokines in the immune responses to BCG and DTwP vaccines.

    PubMed

    Druszczynska, Magdalena; Kowalewicz-Kulbat, Magdalena; Maszewska, Agnieszka; Rudnicka, Karolina; Szpakowski, Piotr; Wawrocki, Sebastian; Wlodarczyk, Marcin; Rudnicka, Wiesława

    2015-01-01

    Bacillus Calmette-Guérin (BCG) and pertussis vaccines have been found to be insufficient and their further improvement is required. In order to develop improved vaccines, a better understanding of the main pathways involved in the host's protective immunity to the pathogens is crucial. We address the question as to whether the balance between pro- and anti-inflammatory cytokine production might affect the host responses to BCG and diphtheria-tetanus toxoids-whole cell pertussis (DTwP) vaccines. The study population consisted of 118 healthy people, age range 18-30 years, who had been subjected to BCG and DTwP vaccination according to the state policy. Tuberculin skin testing (TST) revealed a delayed type hypersensitivity (DTH) to PPD (purified protein derivative) in 53% volunteers. The variability in development of the BCG-driven DTH to tuberculin prompted us to address a question as to whether Th1/Th2 polarization is involved in the lack of skin responsiveness to PPD. PPD-stimulated blood lymphocytes from TST(+) participants produced significantly more IFN-γ and less IL-10 than lymphocytes from TST(-) volunteers. However, TST(-) volunteers' sera contained more anti-pertussis IgG but not anti-diphtheria toxin IgG. Mycobacterial antigens and particularly PPD induced a higher expression of HLA-DR and co-stimulatory CD80 receptors on DCs from TST(+) than TST(-) participants. BCG but not PPD pulsed DCs from TST(-) volunteers produced significantly more IL-10. Mycobacterial antigen stimulated DCs from TST(+) volunteers induced a more intense IFN-γ production in co-cultures with autologous lymphocytes than the cells from TST(-) participants. Differences among the types of dendritic cell activities contribute to development of tuberculin reactivity in BCG vaccinated volunteers.

  16. T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks

    PubMed Central

    Tkach, Karen E; Barik, Debashis; Voisinne, Guillaume; Malandro, Nicole; Hathorn, Matthew M; Cotari, Jesse W; Vogel, Robert; Merghoub, Taha; Wolchok, Jedd; Krichevsky, Oleg; Altan-Bonnet, Grégoire

    2014-01-01

    Variability within isogenic T cell populations yields heterogeneous ‘local’ signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global’ antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring. DOI: http://dx.doi.org/10.7554/eLife.01944.001 PMID:24719192

  17. Granzymes A and K differentially potentiate LPS-induced cytokine response

    PubMed Central

    Wensink, Annette C; Kok, Helena M; Meeldijk, Jan; Fermie, Job; Froelich, Christopher J; Hack, C Erik; Bovenschen, Niels

    2016-01-01

    Granzymes are serine proteases that, upon release from cytotoxic cells, induce apoptosis in tumor cells and virally infected cells. In addition, a role of granzymes in inflammation is emerging. Recently, we have demonstrated that extracellular granzyme K (GrK) potentiates lipopolysaccharide (LPS)-induced cytokine response from monocytes. GrK interacts with LPS, disaggregates LPS micelles, and stimulates LPS-CD14 binding and Toll-like receptor signaling. Here we show that human GrA also potentiates cytokine responses in human monocytes initiated by LPS or Gram-negative bacteria. Similar to GrK, this effect is independent of GrA catalytic activity. Unlike GrK, however, GrA does not bind to LPS, has little influence on LPS micelle disaggregation, and does not augment LPS-CD14 complex formation. We conclude that GrA and GrK differentially modulate LPS-Toll-like receptor signaling in monocytes, suggesting functional redundancy among cytotoxic lymphocyte proteases in the anti-bacterial innate immune response. PMID:28028441

  18. Dynamics of the microbiota in response to host infection.

    PubMed

    Belzer, Clara; Gerber, Georg K; Roeselers, Guus; Delaney, Mary; DuBois, Andrea; Liu, Qing; Belavusava, Vera; Yeliseyev, Vladimir; Houseman, Andres; Onderdonk, Andrew; Cavanaugh, Colleen; Bry, Lynn

    2014-01-01

    Longitudinal studies of the microbiota are important for discovering changes in microbial communities that affect the host. The complexity of these ecosystems requires rigorous integrated experimental and computational methods to identify temporal signatures that promote physiologic or pathophysiologic responses in vivo. Employing a murine model of infectious colitis with the pathogen Citrobacter rodentium, we generated a 2-month time-series of 16S rDNA gene profiles, and quantitatively cultured commensals, from multiple intestinal sites in infected and uninfected mice. We developed a computational framework to discover time-varying signatures for individual taxa, and to automatically group signatures to identify microbial sub-communities within the larger gut ecosystem that demonstrate common behaviors. Application of this model to the 16S rDNA dataset revealed dynamic alterations in the microbiota at multiple levels of resolution, from effects on systems-level metrics to changes across anatomic sites for individual taxa and species. These analyses revealed unique, time-dependent microbial signatures associated with host responses at different stages of colitis. Signatures included a Mucispirillum OTU associated with early disruption of the colonic surface mucus layer, prior to the onset of symptomatic colitis, and members of the Clostridiales and Lactobacillales that increased with successful resolution of inflammation, after clearance of the pathogen. Quantitative culture data validated findings for predominant species, further refining and strengthening model predictions. These findings provide new insights into the complex behaviors found within host ecosystems, and define several time-dependent microbial signatures that may be leveraged in studies of other infectious or inflammatory conditions.

  19. Aeromonas caviae strain induces Th1 cytokine response in mouse intestinal tract

    SciTech Connect

    Hayes, S L; Lye, D J; McKinstry, Craig A.; Vesper, Sephen J.

    2010-01-01

    Aeromonas caviae has been associated with human gastrointestinal disease. Strains of this species typically lack virulence factors (VFs) such as enterotoxins and hemolysins that are produced by other human pathogens of the Aeromonas genus. Microarray profiling of murine small intestinal extracts, 24 hours after oral infection with an A. caviae strain, provides evidence of a Th1 type immune response. A large number of gamma-interferon (γ-IFN) induced genes are up-regulated as well as several tumor necrosis factor-alpha (TNF-α) transcripts. A. caviae has always been considered as opportunistic pathogen because it lacks obvious virulence factors. This current effort suggests that an A. caviae strain can colonize the murine intestinal tract and cause what has been described by others as a dysregulatory cytokine response. This response could explain why a number of diarrheal waterborne disease cases have been attributed to A. caviae even though it lacks obvious enteropathogenic properties.

  20. Rotavirus-specific subclass antibody and cytokine responses in Bangladeshi children with rotavirus diarrhoea.

    PubMed

    Azim, Tasnim; Zaki, M Hasan; Podder, Goutam; Sultana, Novera; Salam, M Abdus; Rahman, S Moshfiqur; Sefat-e-Khuda; Sack, David A

    2003-02-01

    Rotavirus-specific subclass antibody responses and cytokines, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-8 (IL-8), and IL-10, were measured in children 7-24 months of age with rotavirus diarrhoea (n = 29); the responses were compared with children with watery diarrhoea from whom no enteric pathogens were isolated (controls; n = 11). All children had diarrhoea for < 5 days and were enrolled from the Dhaka Hospital of the Centre for Health and Population Research. Samples of blood and stools were collected on the day of enrollment and 18-21 days after the onset of diarrhoea. Children showing a > or = 4-fold rise in antibody titre between the acute and convalescent stages were considered to have a response. The numbers of children with rotavirus-specific IgA and IgA1 responses in stool were similar in the two groups of children. In the plasma, more children with rotavirus diarrhoea had rotavirus-specific IgA, IgA1, IgG, IgG1, and IgG3 responses than did control children (P = 0.049, 0.007, 0.001, 0.002, and 0.012, respectively). IgA2 was not detectable. Among cytokines measured in supernatants from peripheral blood mononuclear cells (PBMCs) cultured for 6 and 24 hr, IFN-gamma was the only cytokine that was higher in children with rotavirus diarrhoea compared with controls (P = 0.013). Severity of illness did not correlate with nutritional status or antibody titres, but severity did correlate with TNF-alpha during the acute stage of illness. IFN-gamma correlated positively with IgG1 titres. These findings suggest a role for IFN-gamma in the pathogenesis of rotavirus infection, but this needs confirmation by other studies. The immune responses described are relevant to future vaccine trials, as immune responses in vaccinees should mimic those in natural infection.

  1. Plant surface wax affects parasitoid's response to host footprints

    NASA Astrophysics Data System (ADS)

    Rostás, Michael; Ruf, Daniel; Zabka, Vanessa; Hildebrandt, Ulrich

    2008-10-01

    The plant surface is the substrate upon which herbivorous insects and natural enemies meet and thus represents the stage for interactions between the three trophic levels. Plant surfaces are covered by an epicuticular wax layer which is highly variable depending on species, cultivar or plant part. Differences in wax chemistry may modulate ecological interactions. We explored whether caterpillars of Spodoptera frugiperda, when walking over a plant surface, leave a chemical trail (kairomones) that can be detected by the parasitoid Cotesia marginiventris. Chemistry and micromorphology of cuticular waxes of two barley eceriferum wax mutants ( cer-za.126, cer-yp.949) and wild-type cv. Bonus (wt) were assessed. The plants were then used to investigate potential surface effects on the detectability of caterpillar kairomones. Here we provide evidence that C. marginiventris responds to chemical footprints of its host. Parasitoids were able to detect the kairomone on wild-type plants and on both cer mutants but the response to cer-yp.949 (reduced wax, high aldehyde fraction) was less pronounced. Experiments with caterpillar-treated wt and mutant leaves offered simultaneously, confirmed this observation: no difference in wasp response was found when wt was tested against cer-za.126 (reduced wax, wt-like chemical composition) but wt was significantly more attractive than cer-yp.949. This demonstrates for the first time that the wax layer can modulate the detectability of host kairomones.

  2. Host response to laparoscopic surgery: mechanisms and clinical correlates

    PubMed Central

    Hackam, David J.; Rotstein, Ori D.

    1998-01-01

    Minimal access surgery has revolutionized the treatment of a variety of surgical diseases, partly because it is associated with less patient morbidity than nonlaparoscopic surgical procedures. Emerging evidence suggests that alteration in the host response after laparoscopic procedures has significantly contributed to the improved postoperative course. Laparoscopy modulates both afferent stimuli (including tissue trauma, pain and wound size) and efferent responses (via neuroendocrine, metabolic, immunologic and cardiorespiratory systems). These effects lead to a decrease in postoperative pain, fever and disability. Laparoscopy mediates these effects through reduced wound size, the activities of endotoxin and immunomodulatory actions of the insufflated gas, resulting in impaired macrophage activity. Although clearly beneficial in reducing postoperative morbidity after elective surgery, this immunosuppression could increase the risk of complications during procedures for infection or neoplasia. PMID:9575992

  3. Air pollution and cytokine responsiveness in asthmatic and non-asthmatic children.

    PubMed

    Klümper, Claudia; Krämer, Ursula; Lehmann, Irina; von Berg, Andrea; Berdel, Dietrich; Herberth, Gunda; Beckmann, Christina; Link, Elke; Heinrich, Joachim; Hoffmann, Barbara; Schins, Roel P F

    2015-04-01

    Epidemiological studies indicate that asthmatic children are more susceptible to traffic-related air pollution exposure than non-asthmatic children. Local and systemic inflammation in combination with oxidative stress have been suggested as a possible susceptibility factor. We investigated effect modification by asthma status for the association between air pollution exposure and systemic effects using whole blood cytokine responsiveness as an inflammatory marker. The study was nested within the two German birth cohort studies GINIplus and LISAplus and initially designed as a random sub-sample enriched with asthmatic children. Using data from 27 asthmatic and 59 non-asthmatic six-year-old children we measured the production of Interleukin-6 (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in whole blood after ex-vivo stimulation with urban particulate matter (EHC-93). Air pollution exposure (nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter with an aerodynamic diameter <10μm (PM10), particulate matter with an aerodynamic diameter <2.5μm (PM2.5mass), coarse particulate matter (PMcoarse) and PM2.5absorbance (PM2.5abs)) was modelled for children´s home addresses applying land-use regression. To assess effect modification by asthma status linear regression models with multiplicative interaction terms were used. In asthmatics exposure to NO2 was associated with higher production of pro-inflammatory cytokines: adjusted means ratio (MR) 2.22 (95% confidence interval 1.22-4.04) for IL-6 per 2.68µg/m³ NO2. The interaction term between asthma status and NO2 exposure was significant. Results for NOx, PM10, PM2.5mass and PM2.5abs were in the same direction. No association between air pollution and cytokine responsiveness was found in the group of non-asthmatic children and in the overall group. Traffic-related air pollution exposure is associated with higher pro

  4. Vitamin D inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response

    PubMed Central

    He, Xiyue; Yan, Juan; Zhu, Xiaotong; Wang, Qinghui; Pang, Wei; Qi, Zanmei; Wang, Meilian; Luo, Enjie; Parker, Daniel M.; Cantorna, Margherita T.; Cui, Liwang; Cao, Yaming

    2014-01-01

    In animal models of experimental cerebral malaria (ECM), neuropathology is associated with an overwhelming inflammatory response and sequestration of leucocytes and parasite-infected red blood cells in the brain. Here we explored the effect of vitamin D (VD, cholecalciferol) treatment on host immunity and outcome of ECM in C57BL/6 mice during Plasmodium berghei ANKA (PbA) infection. We observed that oral administration of VD both before and after PbA infection completely protected mice from ECM. VD administration significantly dampened the inducible systemic inflammatory responses with reduced circulating cytokines IFN-γ and TNF and decreased expression of these cytokines by the spleen cells. Meanwhile, VD also resulted in decreased expression of the chemokines CXCL9 and CXCL10 and cytoadhesion molecules (ICAM-1, VCAM-1 and CD36) in the brain, leading to reduced accumulation of pathogenic T cells in the brain and ultimately substantial improvement of the blood-brain barriers of PbA-infected mice. In addition, VD inhibited the differentiation, activation and maturation of splenic dendritic cells. Meanwhile, regulatory T cells and IL-10 expression levels were upregulated upon VD treatment. These data collectively demonstrated the suppressive function of VD on host inflammatory responses, which provides significant survival benefits in the murine ECM model. PMID:24965778

  5. EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection.

    PubMed

    Anderson, Mark; Ohr, Ryan Jay; Aly, Khaled A; Nocadello, Salvatore; Kim, Hwan K; Schneewind, Chloe E; Schneewind, Olaf; Missiakas, Dominique

    2017-01-01

    Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS pathway to secrete proteins (EsxA, EsxB, EsxC, and EsxD) during infection. Expression of ess genes is required for S. aureus establishment of persistent abscess lesions following bloodstream infection; however, the mechanisms whereby effectors of the ESS pathway implement their virulence strategies were heretofore not known. Here, we show that EssE forms a complex with other members of the ESS secretion pathway and its substrates, promoting the secretion of EsxA, EsxB, EsxC, EsxD, and EssD. During bloodstream infection of mice, the S. aureus essE mutant displays defects in host cytokine responses, specifically in the production of interleukin-12 (IL-12) (p40/p70) and the suppression of RANTES (CCL5), activators of TH1 T cell responses and immune cell chemotaxis, respectively. Thus, essE-mediated secretion of protein effectors via the ESS pathway may enable S. aureus to manipulate host immune responses by modifying the production of cytokines.

  6. The Surface-Associated Exopolysaccharide of Bifidobacterium longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local TH17 Responses.

    PubMed

    Schiavi, Elisa; Gleinser, Marita; Molloy, Evelyn; Groeger, David; Frei, Remo; Ferstl, Ruth; Rodriguez-Perez, Noelia; Ziegler, Mario; Grant, Ray; Moriarty, Thomas Fintan; Plattner, Stephan; Healy, Selena; O'Connell Motherway, Mary; Akdis, Cezmi A; Roper, Jennifer; Altmann, Friedrich; van Sinderen, Douwe; O'Mahony, Liam

    2016-12-15

    The immune-modulating properties of certain bifidobacterial strains, such as Bifidobacterium longum subsp. longum 35624 (B. longum 35624), have been well described, although the strain-specific molecular characteristics associated with such immune-regulatory activity are not well defined. It has previously been demonstrated that B. longum 35624 produces a cell surface exopolysaccharide (sEPS), and in this study, we investigated the role played by this exopolysaccharide in influencing the host immune response. B. longum 35624 induced relatively low levels of cytokine secretion from human dendritic cells, whereas an isogenic exopolysaccharide-negative mutant derivative (termed sEPS(neg)) induced vastly more cytokines, including interleukin-17 (IL-17), and this response was reversed when exopolysaccharide production was restored in sEPS(neg) by genetic complementation. Administration of B. longum 35624 to mice of the T cell transfer colitis model prevented disease symptoms, whereas sEPS(neg) did not protect against the development of colitis, with associated enhanced recruitment of IL-17(+) lymphocytes to the gut. Moreover, intranasal administration of sEPS(neg) also resulted in enhanced recruitment of IL-17(+) lymphocytes to the murine lung. These data demonstrate that the particular exopolysaccharide produced by B. longum 35624 plays an essential role in dampening proinflammatory host responses to the strain and that loss of exopolysaccharide production results in the induction of local TH17 responses.

  7. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients.

    PubMed

    Claushuis, Theodora A M; van Vught, Lonneke A; Scicluna, Brendon P; Wiewel, Maryse A; Klein Klouwenberg, Peter M C; Hoogendijk, Arie J; Ong, David S Y; Cremer, Olaf L; Horn, Janneke; Franitza, Marek; Toliat, Mohammad R; Nürnberg, Peter; Zwinderman, Aeilko H; Bonten, Marc J; Schultz, Marcus J; van der Poll, Tom

    2016-06-16

    Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 10(9)/L, intermediate-low 50 × 10(9) to 99 × 10(9)/L, low 100 × 10(9) to 149 × 10(9)/L, or normal 150 × 10(9) to 399 × 10(9)/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 10(9)/L and 50 × 10(9) to 99 × 10(9)/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 10(9)/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 10(9)/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal

  8. Carbohydrate and the cytokine response to 2.5 h of running.

    PubMed

    Nehlsen-Cannarella, S L; Fagoaga, O R; Nieman, D C; Henson, D A; Butterworth, D E; Schmitt, R L; Bailey, E M; Warren, B J; Utter, A; Davis, J M

    1997-05-01

    This randomized, double-blind, placebo-controlled study was designed to determine the influence of 6% carbohydrate (C) vs. placebo (P) beverage ingestion on cytokine responses (5 total samples over 9 h) to 2.5 h of high-intensity running (76.7 +/- 0.4% maximal O2 uptake) by 30 experienced marathon runners. For interleukin-6 (IL-6), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C immediately postrun (753 vs. 421%) and 1.5 h postrun (193 vs. 86%) [F(4,112) = 3.77, P = 0.006]. For interleukin-1-receptor antagonist (IL-1ra), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C 1.5 h postrun (231 vs. 72%) [F(2,50) = 6.38, P = 0.003]. No significant interaction effects were seen for bioactive IL-6 or IL-1 beta. The immediate postrun plasma glucose concentrations correlated negatively with those of plasma cortisol (r = -0.67, P < 0.001); postrun plasma cortisol (r = 0.70, P < 0.001) and IL-6 levels (r = 0.54, P = 0.003) correlated positively with levels of IL-1ra. Taken together, the data indicate that carbohydrate ingestion attenuates cytokine levels in the inflammatory cascade in response to heavy exertion.

  9. The angiogenic response of the aorta to injury and inflammatory cytokines requires macrophages

    PubMed Central

    Gelati, Maurizio; Aplin, Alfred C; Fogel, Eric; Smith, Kelly D; Nicosia, Roberto Francesco

    2008-01-01

    The purpose of this study was to define early events during the angiogenic response of the aortic wall to injury. Rat aortic rings produced neovessels in collagen culture but lost this capacity over time. These quiescent rings responded to vascular endothelial growth factor (VEGF) but not to a cocktail of macrophage-stimulatory cytokines and chemokines that was angiogenically active on fresh rings. Analysis of cytokine receptor expression revealed selective loss in quiescent rings of the proangiogenic chemokine receptor CXCR2, which was expressed predominantly in aortic macrophages. Pharmacologic inhibition of CXCR2 impaired angiogenesis from fresh rings but had no effect on VEGF-induced angiogenesis from quiescent explants. Angiogenesis was also impaired in cultures of aortic rings from CXCR2-deficient mice. Reduced CXCR2 expression in quiescent rat aortic rings correlated with marked macrophage depletion. Pharmacologic ablation of macrophages from aortic explants blocked formation of neovessels in vitro and reduced aortic ring-induced angiogenesis in vivo. The angiogenic response of macrophage-depleted rings was completely restored by adding exogenous macrophages. Moreover, angiogenesis from fresh rings was promoted by macrophage colony stimulating factor (CSF-1) and inhibited with anti-CSF-1 antibody. Thus aortic angiogenic sprouting following injury is strongly influenced by conditions that modulate resident macrophage numbers and function. PMID:18832730

  10. Interleukin-7 Modulates Anti-Tumor CD8+ T Cell Responses via Its Action on Host Cells

    PubMed Central

    Deiser, Katrin; Stoycheva, Diana; Bank, Ute; Blankenstein, Thomas; Schüler, Thomas

    2016-01-01

    The adoptive transfer of antigen-specific CD8+ T cells is a promising approach for the treatment of chronic viral and malignant diseases. In order to improve adoptive T cell therapy (ATT) of cancer, recent strategies aim at the antibody-based blockade of immunosuppressive signaling pathways in CD8+ T cells. Alternatively, adjuvant effects of immunostimulatory cytokines might be exploited to improve therapeutic CD8+ T cell responses. For example, Interleukin-7 (IL-7) is a potent growth, activation and survival factor for CD8+ T cells that can be used to improve virus- and tumor-specific CD8+ T cell responses. Although direct IL-7 effects on CD8+ T cells were studied extensively in numerous models, the contribution of IL-7 receptor-competent (IL-7R+) host cells remained unclear. In the current study we provide evidence that CD8+ T cell-mediated tumor rejection in response to recombinant IL-7 (rIL-7) therapy is strictly dependent on IL-7R+ host cells. On the contrary, CD8+ T cell expansion is independent of host IL-7R expression. If, however, rIL-7 therapy and peptide vaccination are combined, host IL-7R signaling is crucial for CD8+ T cell expansion. Unexpectedly, maximum CD8+ T cell expansion relies mainly on IL-7R signaling in non-hematopoietic host cells, similar to the massive accumulation of dendritic cells and granulocytes. In summary, we provide evidence that IL-7R+ host cells are major targets of rIL-7 that modulate therapeutic CD8+ T cell responses and the outcome of rIL-7-assisted ATT. This knowledge may have important implications for the design and optimization of clinical ATT protocols. PMID:27447484

  11. Mycobacterial Dormancy Systems and Host Responses in Tuberculosis

    PubMed Central

    Peddireddy, Vidyullatha; Doddam, Sankara Narayana; Ahmed, Niyaz

    2017-01-01

    Tuberculosis (TB) caused by the intracellular pathogen, Mycobacterium tuberculosis (Mtb), claims more than 1.5 million lives worldwide annually. Despite promulgation of multipronged strategies to prevent and control TB, there is no significant downfall occurring in the number of new cases, and adding to this is the relapse of the disease due to the emergence of antibiotic resistance and the ability of Mtb to remain dormant after primary infection. The pathology of Mtb is complex and largely attributed to immune-evading strategies that this pathogen adopts to establish primary infection, its persistence in the host, and reactivation of pathogenicity under favorable conditions. In this review, we present various biochemical, immunological, and genetic strategies unleashed by Mtb inside the host for its survival. The bacterium enables itself to establish a niche by evading immune recognition via resorting to masking, establishment of dormancy by manipulating immune receptor responses, altering innate immune cell fate, enhancing granuloma formation, and developing antibiotic tolerance. Besides these, the regulatory entities, such as DosR and its regulon, encompassing various putative effector proteins play a vital role in maintaining the dormant nature of this pathogen. Further, reactivation of Mtb allows relapse of the disease and is favored by the genes of the Rtf family and the conditions that suppress the immune system of the host. Identification of target genes and characterizing the function of their respective antigens involved in primary infection, dormancy, and reactivation would likely provide vital clues to design novel drugs and/or vaccines for the control of dormant TB. PMID:28261197

  12. Cytokine and lipid mediator networks in tuberculosis

    PubMed Central

    Mayer-Barber, Katrin D.; Sher, Alan

    2014-01-01

    Summary A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebra fish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections. PMID:25703565

  13. Quantification of T cell Antigen-specific Memory Responses in Rhesus Macaques, Using Cytokine Flow Cytometry (CFC, also Known as ICS and ICCS): Analysis of Flow Data

    PubMed Central

    Sylwester, Andrew W.; Hansen, Scott G.; Picker, Louis J.

    2016-01-01

    highly-characterize the phenotypes of antigen-responding cells, or else simultaneously quantify the responses according to many cytokines or activation markers. Powerful software like FlowJo (TreeStar) and SPICE (NIAID) can be used to analyse the data, and to do sophisticated multivariate analysis of cytokine responses. The method described here is customized for cells from Rhesus macaque monkeys, and the extensive annotating notes represent a decade of accumulated technical experience. The same scheme is readily applicable to other mammalian cells (e.g. human or mouse), though the exact antibody clones will differ according to host system. The basic method described here incubates 1 × 106 Lymphocytes in 1 ml tube culture with antigen and co-stimulatory antibodies in the presence of Brefeldin A, prior to staining and fixation. Note: This is the second part of a two-part procedure. Part one has the same initial title, but the subtitle “From Assay Set-up to Data Acquisition (Sylwester et al., 2014)”. The Abstract and Historical Background is the same for both documents.

  14. Delayed Asthmatic Response to Allergen Challenge and Cytokines Released by Nonspecifically Stimulated Blood Cells

    PubMed Central

    Pelikan, Zdenek

    2013-01-01

    Background. Bronchial asthma patients can develop various asthmatic response types following bronchial allergen challenge, such as immediate (IAR), late (LAR), dual late (DLAR), or delayed (DYAR), due to different immunologic mechanisms. The DYAR, recorded in 24 patients, beginning between 26 and 32 hrs and lasting up to 56 hrs after the bronchial allergen challenge, differs from the IAR, LAR, and DLAR in clinical, diagnostic, and immunologic aspects. Objective. To investigate amounts of particular cytokines released by the blood cells after an additional nonspecific stimulation with Phorbol 12-myristate 13-acetate (PMA) during the DYAR. Methods. In 24 patients, the repeated DYAR was supplemented with determination of cytokines both in the nonstimulated plasma and in the supernatants of the blood cells stimulated with PMA before and up to 72 hours after the bronchial challenge, by means of enzyme-linked immunoassay. Results. No significant changes of the prechallenge cytokine concentrations in the non-stimulated serum were recorded in the DYAR patients as compared with the healthy subjects. The DYAR was accompanied by significantly increased postchallenge concentrations (P < 0.05) of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN-γ, G-CSF, TNF-α, and TGF-β, while decreased concentration of IL-7 (P < 0.05) in the nonstimulated plasma. The significantly increased postchallenge concentrations of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN-γ, TNF-α, and TGF-β were released by peripheral blood cells after stimulation with PMA, as compared with both their prechallenge concentrations and with the PBS control values. Conclusions. These results would support evidence for an important role of the Th1 cells, neutrophils, monocytes, and probably also NK cells in the immunologic mechanism(s) leading to the development of the clinical DYAR. Nevertheless, an additional role of macrophages, endothelial and epithelial cells in these mechanisms cannot be even excluded. PMID:24049660

  15. Pre-exercise carbohydrate status influences carbohydrate-mediated attenuation of post-exercise cytokine responses.

    PubMed

    Cox, A J; Pyne, D B; Cox, G R; Callister, R; Gleeson, M

    2008-12-01

    Most studies investigating the effects of acute carbohydrate (CHO) ingestion on post-exercise cytokine responses have involved fasted athletes. This study characterised the effects of acute CHO beverage ingestion preceded by consumption of a CHO-containing pre-exercise meal. Sixteen highly-trained male cyclists/triathletes (age: 30.6 +/- 5.6 y; V O (2max): 64.8 +/- 4.7 ml . kg . min (-1) [mean +/- SD]) undertook two cycle ergometry trials involving randomised consumption of a 10 % CHO beverage (15 mL . kg (-1) . hr (-1)) or water (H (2)O). Trials were undertaken 2 h after a breakfast providing 2.1 g CHO . kg (-1) body mass (BM) (48 kJ . kg (-1) BM) and consisted of 100 min steady state cycle ergometry at 70 % V O (2max) followed by a time trial of approximately 30 min duration. Blood samples were collected pre-, post- and 1 h post-exercise for measurement of Interleukin (IL)-6, IL-8, IL-10 and IL-1ra. Time-trial performance was not substantially different between CHO and H (2)O trials (4.5 %, p = 0.42). Neither IL-6 nor IL-8 responses were substantially reduced in the CHO compared to the H (2)O trial. There was a substantial reduction in IL-10 (32 %, p = 0.05) and IL-1ra (43 %, p = 0.02) responses at 1 h post-exercise with CHO compared to H (2)O ingestion. In conclusion, the previously shown attenuating effects of CHO ingestion during exercise on cytokine responses appear reduced when athletes consume a CHO-containing pre-exercise meal.

  16. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study

    PubMed Central

    2012-01-01

    Background Surgery launches an inflammatory reaction in the body, as seen through increased peripheral levels of cytokines and cortisol. However, less is known about perioperative inflammatory changes in the central nervous system (CNS). Our aim was to compare inflammatory markers in serum and cerebrospinal fluid (CSF) before and after surgery and evaluate their association with measures of blood–brain barrier (BBB) integrity. Methods Thirty-five patients undergoing knee arthroplastic surgery with spinal anesthesia had CSF and serum samples drawn before, after and on the morning following surgery. Cytokines and albumin in serum and CSF and cortisol in CSF were assessed at all three points. Results Cytokines and cortisol were significantly increased in serum and CSF after surgery (Ps <0.01) and CSF increases were greater than in serum. Ten individuals had an increased cytokine response and significantly higher CSF/serum albumin ratios (Ps <0.01), five of whom had albumin ratios in the pathological range (>11.8). Serum and CSF levels of cytokines were unrelated, but there were strong correlations between CSF IL-2, IL-10 and IL-13, and albumin ratios (Ps <0.05) following surgery. Conclusion Cytokine increases in the CNS were substantially greater than in serum, indicating that the CNS inflammatory system is activated during peripheral surgery and may be regulated separately from that in the peripheral body. CSF cytokine increase may indicate sensitivity to trauma and is linked to BBB macromolecular permeability. PMID:23095517

  17. Cytokines: Names and Numbers You Should Care About.

    PubMed

    Holdsworth, Stephen R; Gan, Poh-Yi

    2015-12-07

    Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

  18. Host neuro- immuno-endocrine responses in periodontal disease.

    PubMed

    Rettori, Elisa; De Laurentiis, Andrea; Dees, W Les; Endruhn, Axel; Rettori, Valeria

    2014-01-01

    Periodontitis is a chronic inflammatory complex disease caused by microorganisms. It may be influenced by diverse systemic disorders, environmental, genetic and socio-psychological factors with the ability to alter the balance of the host neuro-immunoendocrine responses. It is characterized by the progressive destruction of the tooth supporting apparatus leading to tooth loss, with possible impact on general health. Starting with a brief description of the periodontium, etiopathogenesis, repair processes and several physiological mechanisms and their disarray on periodontium response to bacterial challenge. Following, the negative effects of stress on the disease and some remarks on the recently discovered effects of oxytocin that modulate stress response and its role in individual coping mechanisms to stress. We also focus on the participation of components and functions of endocannabinoid system with anti-inflammatory actions on gingiva. Finally, a discussion that may link between diabetes, cardiovascular diseases, stroke and metabolic syndrome associated with periodontal disease; all of them sharing a common denominator that is inflammation and oxidative stress.

  19. Phosphorus source alters host plant response to ectomycorrhizal diversity.

    PubMed

    Baxter, James W; Dighton, John

    2005-11-01

    We examined the influence of phosphorus source and availability on host plant (Pinus rigida) response to ectomycorrhizal diversity under contrasting P conditions. An ectomycorrhizal richness gradient was established with equimolar P supplied as either inorganic phosphate or organic inositol hexaphosphate. We measured growth and N and P uptake of individual P. rigida seedlings inoculated with one, two, or four species of ectomycorrhizal fungi simultaneously and without mycorrhizas in axenic culture. Whereas colonization of P. rigida by individual species of ectomycorrhizal fungi decreased with increasing fungal richness, colonization of all species combined increased. Plant biomass and N content increased across the ectomycorrhizal richness gradient in the organic but not the inorganic P treatment. Plants grown under organic P conditions had higher N concentration than those grown under inorganic P conditions, but there was no effect of richness. Phosphorus content of plants grown in the organic P treatment increased with increasing ectomycorrhizal richness, but there was no response in the inorganic P treatment. Phosphorus concentration was higher in plants grown at the four-species richness level in the organic P treatment, but there was no effect of diversity under inorganic P conditions. Overall, few ectomycorrhizal composition effects were found on plant growth or nutrient status. Phosphatase activities of individual ectomycorrhizal fungi differed under organic P conditions, but there was no difference in total root system phosphatase expression between the inorganic or organic P treatments or across richness levels. Our results provide evidence that plant response to ectomycorrhizal diversity is dependent on the source and availability of P.

  20. Francisella Infection in Cultured Tilapia in Thailand and the Inflammatory Cytokine Response.

    PubMed

    Jantrakajorn, Sasibha; Wongtavatchai, Janenuj

    2016-06-01

    Francisella infections developed in freshwater Nile Tilapia Oreochromis niloticus and red tilapia Oreochromis spp. farms in Thailand during 2012-2014. The diseased fish were lethargic and pale in color and showed numerous white nodules in their enlarged spleens. Histopathological examination and electron microscopy suggested that the white nodules were multifocal granulomas consisting of coccobacilli within vacuolated cells. Isolation of Francisella-like bacteria was achieved from 42 of 100 samples, while polymerase chain reaction confirmed Francisella infections in all samples. Analysis of the 16S rRNA gene from samples obtained from three different geographical culture areas revealed more than 99% similarity with F. noatunensis subsp. orientalis. The influence of Francisella infection on inflammatory cytokines was determined on splenic cells of fish intraperitoneally injected with the bacteria (0.8 × 10(5) colony-forming units per fish). Infected tilapia showed significantly greater expression of the pro-inflammatory genes interleukin-1β (IL-1β) and tumor necrotic factor-α (TNF-α) within 24 h postinjection (hpi) and for up to 96 hpi. However, down-regulation of an anti-inflammatory gene, transforming growth factor-β (TGF-β) was observed as early as 24 hpi. This investigation demonstrates that an imbalance between pro- and anti-inflammatory cytokines in response to the infection may account for the substantial number of granulomas in fish hematopoietic tissues that was found in the later stage of the disease. Received September 9, 2015; accepted December 13, 2015.

  1. Migrational changes of mesenchymal stem cells in response to cytokines, growth factors, hypoxia, and aging.

    PubMed

    Naaldijk, Yahaira; Johnson, Adiv A; Ishak, Stefan; Meisel, Hans Jörg; Hohaus, Christian; Stolzing, Alexandra

    2015-10-15

    Mesenchymal stem cells (MSCs) are non-immunogenic, multipotent cells with at least trilineage differentiation potential. They promote wound healing, improve regeneration of injured tissue, and mediate numerous other health effects. MSCs migrate to sites of injury and stimulate repair either through direct differentiation or indirectly through the stimulation of endogenous repair mechanisms. Using the in vitro scratch assay, we show that the inflammatory cytokines, chemokines, and growth factors TNF-α, SDF-1, PDGF, and bFGF enhance migration of rat MSCs under normoxic conditions, while TNF-α, IFN-γ, PDGF, and bFGF promote MSC migration under hypoxic conditions. This indicates that the oxygen concentration affects how MSCs will migrate in response to specific factors and, consistent with this, differential expression of cytokines was observed under hypoxic versus normoxic conditions. Using the transwell migration assay, we find that TNF-α, IFN-γ, bFGF, IGF-1, PDGF, and SDF-1 significantly increase transmigration of rat MSCs compared to unstimulated medium. MSCs derived from aged rats exhibited comparable migration to MSCs derived from young rats under hypoxic and normoxic conditions, even after application with specific factors. Similarly, migration in MSCs from aged, human donors did not statistically differ compared to migration in MSCs derived from human umbilical cord tissue or younger donors.

  2. Kainic Acid-Induced Neurotoxicity: Targeting Glial Responses and Glia-Derived Cytokines

    PubMed Central

    Zhang, Xing-Mei; Zhu, Jie

    2011-01-01

    Glutamate excitotoxicity contributes to a variety of disorders in the central nervous system, which is triggered primarily by excessive Ca2+ influx arising from overstimulation of glutamate receptors, followed by disintegration of the endoplasmic reticulum (ER) membrane and ER stress, the generation and detoxification of reactive oxygen species as well as mitochondrial dysfunction, leading to neuronal apoptosis and necrosis. Kainic acid (KA), a potent agonist to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate class of glutamate receptors, is 30-fold more potent in neuro-toxicity than glutamate. In rodents, KA injection resulted in recurrent seizures, behavioral changes and subsequent degeneration of selective populations of neurons in the brain, which has been widely used as a model to study the mechanisms of neurodegenerative pathways induced by excitatory neurotransmitter. Microglial activation and astrocytes proliferation are the other characteristics of KA-induced neurodegeneration. The cytokines and other inflammatory molecules secreted by activated glia cells can modify the outcome of disease progression. Thus, anti-oxidant and anti-inflammatory treatment could attenuate or prevent KA-induced neurodegeneration. In this review, we summarized updated experimental data with regard to the KA-induced neurotoxicity in the brain and emphasized glial responses and glia-oriented cytokines, tumor necrosis factor-α, interleukin (IL)-1, IL-12 and IL-18. PMID:22131947

  3. Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells.

    PubMed

    Agrawal, Anshu; Kaushal, Poonam; Agrawal, Sudhanshu; Gollapudi, Sastry; Gupta, Sudhir

    2007-02-01

    Thimerosal is an organic mercury compound that is used as a preservative in vaccines and pharmaceutical products. Recent studies have shown a TH2-skewing effect of mercury, although the underlying mechanisms have not been identified. In this study, we investigated whether thimerosal can exercise a TH2-promoting effect through modulation of functions of dendritic cells (DC). Thimerosal, in a concentration-dependent manner, inhibited the secretion of LPS-induced proinflammatory cytokines TNF-alpha, IL-6, and IL-12p70 from human monocyte-derived DC. However, the secretion of IL-10 from DC was not affected. These thimerosal-exposed DC induced increased TH2 (IL-5 and IL-13) and decreased TH1 (IFN-gamma) cytokine secretion from the T cells in the absence of additional thimerosal added to the coculture. Thimerosal exposure of DC led to the depletion of intracellular glutathione (GSH), and addition of exogenous GSH to DC abolished the TH2-promoting effect of thimerosal-treated DC, restoring secretion of TNF-alpha, IL-6, and IL-12p70 by DC and IFN-gamma secretion by T cells. These data suggest that modulation of TH2 responses by mercury and thimerosal, in particular, is through depletion of GSH in DC.

  4. Dynamically analyte-responsive macrocyclic host-fluorophore systems.

    PubMed

    Ghale, Garima; Nau, Werner M

    2014-07-15

    CONSPECTUS: Host-guest chemistry commenced to a large degree with the work of Pedersen, who in 1967 first reported the synthesis of crown ethers. The past 45 years have witnessed a substantial progress in the field, from the design of highly selective host molecules as receptors to their application in drug delivery and, particularly, analyte sensing. Much effort has been expended on designing receptors and signaling mechanism for detecting compounds of biological and environmental relevance. Traditionally, the design of a chemosensor comprises one component for molecular recognition, frequently macrocycles of the cyclodextrin, cucurbituril, cyclophane, or calixarene type. The second component, used for signaling, is typically an indicator dye which changes its photophysical properties, preferably its fluorescence, upon analyte binding. A variety of signal transduction mechanisms are available, of which displacement of the dye from the macrocyclic binding site is one of the simplest and most popular ones. This constitutes the working principle of indicator displacement assays. However, indicator displacement assays have been predominantly exploited in a static fashion, namely, to determine absolute analyte concentrations, or, by using combinations of several reporter pairs, to achieve a differential sensing and, thus, identification of specific food products or brands. In contrast, their use in biological systems, for example, with membranes, cells, or with enzymes has been comparably less explored, which led us to the design of the so-called tandem assays, that is, dynamically analyte-responsive host-dye systems, in which the change in analyte concentrations is induced by a biological reaction or process. This methodological variation has practical application potential, because the ability to monitor these biochemical pathways or to follow specific molecules in real time is of paramount interest for both biochemical laboratories and the pharmaceutical industry

  5. Well-controlled proinflammatory cytokine responses of Peyer’s patch cells to probiotic Lactobacillus casei

    PubMed Central

    Chiba, Yukihide; Shida, Kan; Nagata, Satoru; Wada, Mariko; Bian, Lei; Wang, Chongxin; Shimizu, Toshiaki; Yamashiro, Yuichiro; Kiyoshima-Shibata, Junko; Nanno, Msanobu; Nomoto, Koji

    2010-01-01

    In order to clarify the probiotic features of immunomodulation, cytokine production by murine spleen and Peyer’s patch (PP) cells was examined in response to probiotic and pathogenic bacteria. In spleen cells, probiotic Lactobacillus casei induced interleukin (IL)-12 production by CD11b+ cells more strongly than pathogenic Gram-positive and Gram-negative bacteria and effectively promoted the development of T helper (Th) type 1 cells followed by high levels of secretion of interferon (IFN)-γ. Although the levels of IL-12 secreted by PP cells in response to L. casei were lower in comparison with spleen cells, Th1 cells developed as a result of this low-level induction of IL-12. However, IFN-γ secretion by the L. casei-induced Th1 cells stimulated with a specific antigen was down-regulated in PP cells. Development of IL-17-producing Th17 cells was efficiently induced in PP cells by antigen stimulation. Lactobacillus casei slightly, but significantly, inhibited the antigen-induced secretion of IL-17 without a decrease in the proportion of Th17 cells. No bacteria tested induced the development of IL-10-producing, transforming growth factor-β-producing or Foxp3-expressing regulatory T cells, thus suggesting that certain probiotics might regulate proinflammatory responses through as yet unidentified mechanisms in PP cells. These data show probiotic L. casei to have considerable potential to induce IL-12 production and promote Th1 cell development, but the secretion of proinflammatory cytokines such as IL-12 and IL-17 may be well controlled in PP cells. PMID:20636824

  6. Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria.

    PubMed

    Brant, Fatima; Miranda, Aline S; Esper, Lisia; Gualdrón-López, Melisa; Cisalpino, Daniel; de Souza, Danielle da Gloria; Rachid, Milene Alvarenga; Tanowitz, Herbert B; Teixeira, Mauro Martins; Teixeira, Antônio Lucio; Machado, Fabiana Simão

    2016-05-01

    Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental

  7. microRNA function is limited to cytokine control in the acute response to virus infection

    PubMed Central

    Aguado, Lauren C.; Schmid, Sonja; Sachs, David; Shim, Jaehee V.; Lim, Jean K.; tenOever, Benjamin R.

    2015-01-01

    SUMMARY With the capacity to fine-tune protein expression via sequence-specific interactions, microRNAs (miRNAs) help regulate cell maintenance and differentiation. While some studies have also implicated miRNAs as regulators of the antiviral response, others have found that the RISC complex that facilitates miRNA-mediated silencing is rendered non-functional during cellular stress, including virus infection. To determine the global role of miRNAs in the cellular response to virus infection, we generated a vector that rapidly eliminates total cellular miRNA populations in terminally differentiated primary cultures. Loss of miRNAs has a negligible impact on both innate sensing of and immediate response to acute viral infection. In contrast, miRNA depletion specifically enhances cytokine expression, providing a post-translational mechanism for immune cell activation during cellular stress. This work highlights the physiological role of miRNAs during the antiviral response and suggests their contribution is limited to chronic infections and the acute activation of the adaptive immune response. PMID:26651947

  8. Peripheral CD4+ T cell cytokine responses following human challenge and re-challenge with Campylobacter jejuni.

    PubMed

    Fimlaid, Kelly A; Lindow, Janet C; Tribble, David R; Bunn, Janice Y; Maue, Alexander C; Kirkpatrick, Beth D

    2014-01-01

    Campylobacter jejuni is a leading cause of human gastroenteritis worldwide; however, our understanding of the human immune response to C. jejuni infection is limited. A previous human challenge model has shown that C. jejuni elicits IFNγ production by peripheral blood mononuclear cells, a response associated with protection from clinical disease following re-infection. In this study, we investigate T lymphocyte profiles associated with campylobacteriosis using specimens from a new human challenge model in which C. jejuni-naïve subjects were challenged and re-challenged with C. jejuni CG8421. Multiparameter flow cytometry was used to investigate T lymphocytes as a source of cytokines, including IFNγ, and to identify cytokine patterns associated with either campylobacteriosis or protection from disease. Unexpectedly, all but one subject evaluated re-experienced campylobacteriosis after re-challenge. We show that CD4+ T cells make IFNγ and other pro-inflammatory cytokines in response to infection; however, multifunctional cytokine response patterns were not found. Cytokine production from peripheral CD4+ T cells was not enhanced following re-challenge, which may suggest deletion or tolerance. Evaluation of alternative paradigms or models is needed to better understand the immune components of protection from campylobacteriosis.

  9. Host immune responses after hypoxic reactivation of IFN-γ induced persistent Chlamydia trachomatis infection

    PubMed Central

    Jerchel, Stefan; Kaufhold, Inga; Schuchardt, Larissa; Shima, Kensuke; Rupp, Jan

    2014-01-01

    Genital tract infections with Chlamydia trachomatis (C. trachomatis) are the most frequent sexually transmitted disease worldwide. Severe clinical sequelae such as pelvic inflammatory disease (PID), tubal occlusion, and tubal infertility are linked to inflammatory processes of chronically infected tissues. The oxygen concentrations in the female urogenital tract are physiologically low and further diminished (0.5–5% O2, hypoxia) during an ongoing inflammation. However, little is known about the effect of a low oxygen environment on genital C. trachomatis infections. In this study, we investigated the host immune responses during reactivation of IFN-γ induced persistent C. trachomatis infection under hypoxia. For this purpose, the activation of the MAP-kinases p44/42 and p38 as well as the induction of the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 were analyzed. Upon hypoxic reactivation of IFN-γ induced persistent C. trachomatis infection, the phosphorylation of the p44/42 but not of the p38 MAP-kinase was significantly diminished compared to IFN-γ induced chlamydial persistence under normoxic condition. In addition, significantly reduced IL-6 and IL-8 mRNA expression levels were observed for reactivated Chlamydiae under hypoxia compared to a persistent chlamydial infection under normoxia. Our findings indicate that hypoxia not only reactivates IFN-γ induced persistent C. trachomatis infections resulting in increased bacterial growth and progeny but also dampens inflammatory host immune signaling responses that are normally observed in a normoxic environment. PMID:24783060

  10. Similarly Lethal Strains of Extraintestinal Pathogenic Escherichia coli Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

    PubMed Central

    Barber, Amelia E.; Fleming, Brittany A.

    2016-01-01

    ABSTRACT In individuals with sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation while the host background is considered the primary variable affecting disease progression and outcome. To study the effects of bacterial strain differences on the maladaptive immune responses that are induced during sepsis, we employed a novel zebrafish embryo infection model using extraintestinal pathogenic Escherichia coli (ExPEC) isolates. These genetically diverse pathogens are a leading cause of sepsis and are becoming increasingly dangerous because of the rise of multidrug-resistant strains. Zebrafish infected with ExPEC isolates exhibit many of the pathophysiological features seen in septic human patients, including dysregulated inflammatory responses (cytokine storms), tachycardia, endothelial leakage, and progressive edema. However, only a limited subset of ExPEC isolates can trigger a sepsis-like state and death of the host when introduced into the bloodstream. Mirroring the situation in human patients, antibiotic therapy reduced ExPEC titers and improved host survival rates but was only effective within limited time frames that varied, depending on the infecting pathogen. Intriguingly, we find that phylogenetically distant but similarly lethal ExPEC isolates can stimulate markedly different host transcriptional responses, including disparate levels of inflammatory mediators. These differences correlate with the amounts of bacterial flagellin expression during infection, as well as differential activation of Toll-like receptor 5 by discrete flagellar serotypes. Altogether, this work establishes zebrafish as a relevant model of key aspects of human sepsis and highlights the ability of genetically distinct ExPEC isolates to induce divergent host responses independently of baseline host attributes. IMPORTANCE Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In

  11. Aggressive Periodontitis: microbes and host response, who to blame?

    PubMed Central

    Nibali, Luigi

    2015-01-01

    A paradigm shift several decades ago elucidated that aggressive periodontitis (AgP) was not a degenerative disorder but a rapid progressive form of plaque-induced inflammatory periodontal disease. Ensuing years of research have led to linkage analysis identification of specific genetic defects responsible for AgP in some families and to the finding that subgingival detection of A. actinomycet-emcomitans JP2 clone is a predictive factor for disease onset and progression. However, rather disappointingly, these ‘proven’ risk factors are only detected in a small subset of AgP cases. Recent advances are leading to a new paradigm shift, with the realization that genetically-driven dysbiotic changes in the subgingival microbiota may predispose to a cascade of events leading to the rapid periodontal tissue destruction seen in AgP. This review tries to dissect the existing literature on the host response-microbial axis of AgP and to propose possible pathogenic pathways in line with current theories. PMID:25654663

  12. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response.

    PubMed

    Stojanov, Silvia; Hoffmann, Florian; Kéry, Anja; Renner, Ellen D; Hartl, Dominik; Lohse, Peter; Huss, Kristina; Fraunberger, Peter; Malley, James D; Zellerer, Stephanie; Albert, Michael H; Belohradsky, Bernd H

    2006-06-01

    PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response.

  13. Vitamin A modifies the intestinal chemokine and cytokine responses to norovirus infection in Mexican children.

    PubMed

    Long, Kurt Z; Garcia, Coralith; Ko, GwangPyo; Santos, Jose I; Al Mamun, Abdullah; Rosado, Jorge L; DuPont, Herbert L; Nathakumar, Nanda

    2011-05-01

    Vitamin A supplementation is associated with divergent clinical norovirus (NoV) outcomes in Mexican children. Fecal cytokine concentrations following NoV genogroup infections among 127 Mexican children 5-15 mo old enrolled in a randomized, double-blind, placebo-controlled, vitamin A supplementation trial were determined to clarify the role the gut immune response plays in these associations. Stools collected from supplemented children [20,000 IU retinol (3.3 IU = 1 μg retinol) for children < 12 mo of age; 45,000 iu for children ≥ 12 mo] or children in the placebo group were screened for NoV genogroups I (GI) and II (GII). Monocyte chemoattractant protein-1 (MCP-1), TNFα, IL-5, IL-6, IL-8, IL-4, IFNγ, and IL-10 fecal concentrations were also determined. Differences in cytokine levels between the 2 groups following GI and GII infections were determined using ordered logistic regression models. MCP-1 and IL-8 levels were greater among GI- and GII-infected children, respectively, compared with uninfected children, whereas IL-5 levels were greater following both genogroup infections. MCP-1, IL-8, and IL-6 fecal levels were reduced among supplemented children with GII-associated diarrhea compared with the placebo group. Vitamin A-supplemented, GII-infected children had reduced MCP-1 and TNFα levels compared with GII-infected children in the placebo group (P-interaction = 0.02 and 0.03, respectively). Supplemented children with GI-associated diarrhea had higher TNFα and IL-4 levels compared with children in the placebo group with diarrhea (P-interaction = 0.02 and 0.02, respectively). The divergent effects of supplementation on NoV outcomes may result from the different effects vitamin A has on the genogroup-specific immune responses.

  14. Cytokines and cytokine-specific therapy in asthma.

    PubMed

    Desai, Dhananjay; Brightling, Christopher

    2012-01-01

    Asthma is increasing in prevalence worldwide. It is characterized by typical symptoms and variable airway obstruction punctuated with episodes of worsening symptoms known as exacerbations. Underlying this clinical expression of disease is airway inflammation and remodeling. Cytokines and their networks are implicated in the innate and adaptive immune responses driving airway inflammation in asthma and are modulated by host-environment interactions. Asthma is a complex heterogeneous disease, and the paradigm of Th2 cytokine-mediated eosinophilic inflammation as a consequence of allergic sensitization has been challenged and probably represents a subgroup of asthma. Indeed, as attention has switched to the importance of severe asthma, which represents the highest burden both to the patient and health care provider, there is an increasing recognition of inflammatory subphenotypes that are likely to be driven by different cytokine networks. Interestingly, these networks may be specific to aspects of clinical expression as well as inflammatory cell profiles and therefore present novel phenotype-specific therapeutic strategies. Here, we review the breadth of cytokines implicated in the pathogenesis of asthma and focus upon the outcomes of early clinical trials conducted using cytokines or cytokine-blocking therapies.

  15. Flexible cytokine production by macrophages and T cells in response to probiotic bacteria: a possible mechanism by which probiotics exert multifunctional immune regulatory activities.

    PubMed

    Shida, Kan; Nanno, Masanobu; Nagata, Satoru

    2011-01-01

    Probiotics have been reported to be efficacious against cancers, infections, allergies, inflammatory bowel diseases and autoimmune diseases, and it is important to explain how such multifunctional activities are realized. Lactobacillus casei Shirota (LcS) is one of these multifunctional probiotics, and its ability to augment the host immune system has been extensively examined. We have shown that the cell wall structure of this probiotic strain is responsible for potently inducing IL-12 production. In addition, we have recently found that LcS differentially controls the inflammatory cytokine responses of macrophages and T cells in either Peyer's patches or the spleen. Other studies revealed that LcS-induced IL-12 production by macrophages is modified when other bacteria or their cell components are simultaneously present. These findings can provide a theoretical basis for understanding the multifunctional activities of specific probiotics.

  16. Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices

    SciTech Connect

    Switalla, S.; Lauenstein, L.; Prenzler, F.; Knothe, S.; Foerster, C.; Fieguth, H.-G.; Pfennig, O.; Schaumann, F.; Martin, C.; Guzman, C.A.; Ebensen, T.; Mueller, M.; Hohlfeld, J.M.; Krug, N.; Braun, A.; Sewald, K.

    2010-08-01

    Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. The initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1{beta}, MIP-1{beta}, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-{gamma}, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation > 0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1{beta}, and IFN-{gamma}. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans.

  17. Cytokine response in the intestinal mucosa of hamsters infected with Taenia solium.

    PubMed

    Avila, Guillermina; Aguilar, Laura; Romero-Valdovinos, Mirza; Garcia-Vazquez, Francisco; Flisser, Ana

    2008-12-01

    Taenia solium grows in experimentally infected hamsters. An inflammatory reaction in the intestinal mucosa surrounding the scolex of the worms is produced. We searched for mRNA of Th1 and Th2 cytokines by in situ hybridization in intestinal biopsies. Hamsters were infected with T. solium cysticerci and necropsied on different days post infection (d.p.i.). Tissue from the small intestine was taken from the area surrounding the tapeworm scolex, fixed, and processed for histology. Antisense probes for the detection of interferon (IFN)-gamma, interleukin (IL)-4, IL-5, and IL-13 were used. Kinetics of each cytokine was defined through detection on specific mRNA by counting the number of positive infected hamsters and of positive cells per 100 enterocytes on different d.p.i. IFN-gamma was detected as of d.p.i. 2; all animals were positive on d.p.i. 4 and 8; and on d.p.i. 16, only 20% were still positive. IL-13 had a pattern similar to IFN-gamma, but all hamsters remained positive until d.p.i. 16 when the experiment was terminated. IL-4 was positive in 40% of infected hamsters on d.p.i. 6. On d.p.i. 8, IL-5 was only detected in 20% but increased to 100% by d.p.i. 16. These data suggest that tapeworms induce a mixed Th1/Th2 response with a polarization toward Th2 at 2 weeks post infection, which may influence the expulsion of worms.

  18. Analysis of complex biomarkers for human immune-mediated disorders based on cytokine responsiveness of peripheral blood cells123

    PubMed Central

    Davis, John M.; Knutson, Keith L.; Strausbauch, Michael A.; Crowson, Cynthia S.; Therneau, Terry M.; Wettstein, Peter J.; Matteson, Eric L.; Gabriel, Sherine E.

    2010-01-01

    The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMC using a multi-stimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early vs. late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNFα, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV/EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to HSP60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic ‘signatures’ that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases. PMID:20495063

  19. Grapevine Pathogenic Microorganisms: Understanding Infection Strategies and Host Response Scenarios

    PubMed Central

    Armijo, Grace; Schlechter, Rudolf; Agurto, Mario; Muñoz, Daniela; Nuñez, Constanza; Arce-Johnson, Patricio

    2016-01-01

    Grapevine (Vitis vinifera L.) is one of the most important fruit crop worldwide. Commercial cultivars are greatly affected by a large number of pathogenic microorganisms that cause diseases during pre- and/or post-harvest periods, affecting production, processing and export, along with fruit quality. Among the potential threats, we can find bacteria, fungi, oomycete, or viruses with different life cycles, infection mechanisms and evasion strategies. While plant–pathogen interactions are cycles of resistance and susceptibility, resistance traits from natural resources are selected and may be used for breeding purposes and for a sustainable agriculture. In this context, here we summarize some of the most important diseases affecting V. vinifera together with their causal agents. The aim of this work is to bring a comprehensive review of the infection strategies deployed by significant types of pathogens while understanding the host response in both resistance and susceptibility scenarios. New approaches being used to uncover grapevine status during biotic stresses and scientific-based procedures needed to control plant diseases and crop protection are also addressed. PMID:27066032

  20. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response.

    PubMed

    Jayawardena, Uthpala A; Ratnasooriya, Wanigasekara D; Wickramasinghe, Deepthi D; Udagama, Preethi V

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~5ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~9360pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P<0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P<0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P<0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco-challenges.

  1. Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response.

    PubMed

    Ohara, Tatsuki; Kojio, Seiichi; Taneike, Ikue; Nakagawa, Saori; Gondaira, Fumio; Tamura, Yukiko; Gejyo, Fumitake; Zhang, Hui-Min; Yamamoto, Tatsuo

    2002-11-01

    Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the human intestinal mucosa, produces Stx from phage, and causes the development of hemolytic-uremic syndrome via Stx-induced inflammatory cytokine production. Azithromycin exhibited strong in vitro activity against STEC without inducing Stx-converting phage, in marked contrast to norfloxacin. Azithromycin decreased the tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 production from Stx-treated human peripheral mononuclear cells or monocytes to a greater extent than did clarithromycin. In Stx-injected mice, azithromycin significantly suppressed Stx-induced TNF-alpha, IL-1beta, and IL-6 levels in serum and improved the outcome as assessed by survival rate. In the STEC oral infection experiment using immature mice immediately after weaning (weaned immature-mouse model), all mice died within 7 days postinfection. Azithromycin administration gave the mice 100% protection from killing, while ciprofloxacin administration gave them 67% protection. The data suggest that azithromycin (at least at higher concentrations) has a strong effect on Stx production by STEC and on the Stx-induced inflammatory host response and prevents death in mice. Azithromycin may have a beneficial effect on STEC-associated disease.

  2. Host responses associated with chronic staphylococcal mastitis in rabbits.

    PubMed

    Guerrero, Irene; Ferrian, Selena; Penadés, Mariola; García-Quirós, Ana; Pascual, Juan J; Selva, Laura; Viana, David; Corpa, Juan M

    2015-06-01

    Staphylococcal infection causes substantial economic losses in commercial rabbit production systems, and is associated with a wide variety of lesions, including chronic suppurative mastitis, which mainly affects breeding females. Most chronic staphylococcal infections in rabbits are caused by the ST121 lineage of Staphylococcus aureus, although other less common lineages, such as ST96 can also be involved. The aims of the present study were to characterise the host immune response in natural cases of mastitis in rabbits caused by S. aureus, to evaluate any relationship between peripheral and local immunity and to investigate the effect of different S. aureus genotypes on these immune responses. Adult multiparous female rabbits that were affected with chronic staphylococcal mastitis (n = 204) were enrolled into the study. Histological and immunohistochemical evaluations of mammary glands were undertaken, as well as flow cytometric analyses of blood. S. aureus isolates from the mammary glands were identified by multilocus sequence typing. Differences in the number of infiltrating cells were detected, depending on the type of pathology, with more immature lesions demonstrating greater cellularity, characterised by greater numbers of T lymphocytes, macrophages and plasma cells. A relationship was seen between the cells in blood and mammary tissues, the most notable being the positive correlation between monocytes and tissue macrophages. When glands were infected with ST96 strains, fewer granulocytes (P < 0.01) and greater numbers of B cells (P < 0.01), T cells (P < 0.001), CD4(+) T cells (P < 0.001) and CD8(+) T cells (P < 0.01) were detected, compared with mammary glands that were infected by ST121 strains of S. aureus.

  3. An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics.

    PubMed

    Reed, Daniel M; Paschalaki, Koralia E; Starke, Richard D; Mohamed, Nura A; Sharp, Giles; Fox, Bernard; Eastwood, David; Bristow, Adrian; Ball, Christina; Vessillier, Sandrine; Hansel, Trevor T; Thorpe, Susan J; Randi, Anna M; Stebbings, Richard; Mitchell, Jane A

    2015-06-01

    There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm-inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.

  4. The Host Response to a Clinical MDR Mycobacterial Strain Cultured in a Detergent-Free Environment: A Global Transcriptomics Approach.

    PubMed

    Leisching, Gina; Pietersen, Ray-Dean; Mpongoshe, Vuyiseka; van Heerden, Carel; van Helden, Paul; Wiid, Ian; Baker, Bienyameen

    2016-01-01

    During Mycobacterium tuberculosis (M.tb) infection, the initial interactions between the pathogen and the host cell determines internalization and innate immune response events. It is established that detergents such as Tween alter the mycobacterial cell wall and solubilize various lipids and proteins. The implication of this is significant since induced changes on the cell wall affect macrophage uptake and the immune response to M.tb. Importantly, during transmission between hosts, aerosolized M.tb enters the host in its native form, i.e. in a detergent-free environment, thus in vitro and in vivo studies should mimic this as closely as possible. To this end, we have optimized a procedure for growing and processing detergent-free M.tb and assessed the response of murine macrophages (BMDM) infected with multi drug-resistant M.tb (R179 Beijing 220 clinical isolate) using RNAseq. We compared the effects of the host response to M.tb cultured under standard laboratory conditions (Tween 80 containing medium -R179T), or in detergent-free medium (R179NT). RNAseq comparisons reveal 2651 differentially expressed genes in BMDMs infected with R179T M.tb vs. BMDMs infected with R179NT M.tb. A range of differentially expressed genes involved in BMDM receptor interaction with M.tb (Mrc1, Ifngr1, Tlr9, Fpr1 and Itgax) and pro-inflammatory cytokines/chemokines (Il6, Il1b, Tnf, Ccl5 and Cxcl14) were selected for analysis through qPCR. BMDMs infected with R179NT stimulate a robust inflammatory response. Interestingly, R179NT M.tb induce transcription of Fpr1, a receptor which detects bacterial formyl peptides and initiates a myriad of immune responses. Additionally we show that the host components Cxcl14, with an unknown role in M.tb infection, and Tlr9, an emerging role player, are only stimulated by infection with R179NT M.tb. Taken together, our results suggest that the host response differs significantly in response to Tween 80 cultured M.tb and should therefore not be used in

  5. Glycans from Fasciola hepatica Modulate the Host Immune Response and TLR-Induced Maturation of Dendritic Cells

    PubMed Central

    Rodríguez, Ernesto; Noya, Verónica; Cervi, Laura; Chiribao, María Laura; Brossard, Natalie; Chiale, Carolina; Carmona, Carlos; Giacomini, Cecilia; Freire, Teresa

    2015-01-01

    Helminths express various carbohydrate-containing glycoconjugates on their surface, and they release glycan-rich excretion/secretion products that can be very important in their life cycles, infection and pathology. Recent evidence suggests that parasite glycoconjugates could play a role in the evasion of the immune response, leading to a modified Th2-polarized immune response that favors parasite survival in the host. Nevertheless, there is limited information about the nature or function of glycans produced by the trematode Fasciola hepatica, the causative agent of fasciolosis. In this paper, we investigate whether glycosylated molecules from F. hepatica participate in the modulation of host immunity. We also focus on dendritic cells, since they are an important target of immune-modulation by helminths, affecting their activity or function. Our results indicate that glycans from F. hepatica promote the production of IL-4 and IL-10, suppressing IFNγ production. During infection, this parasite is able to induce a semi-mature phenotype of DCs expressing low levels of MHCII and secrete IL-10. Furthermore, we show that parasite glycoconjugates mediate the modulation of LPS-induced maturation of DCs since their oxidation restores the capacity of LPS-treated DCs to secrete high levels of the pro-inflammatory cytokines IL-6 and IL-12/23p40 and low levels of the anti-inflammatory cytokine IL-10. Inhibition assays using carbohydrates suggest that the immune-modulation is mediated, at least in part, by the recognition of a mannose specific-CLR that signals by recruiting the phosphatase Php2. The results presented here contribute to the understanding of the role of parasite glycosylated molecules in the modulation of the host immunity and might be useful in the design of vaccines against fasciolosis. PMID:26720149

  6. Glycans from Fasciola hepatica Modulate the Host Immune Response and TLR-Induced Maturation of Dendritic Cells.

    PubMed

    Rodríguez, Ernesto; Noya, Verónica; Cervi, Laura; Chiribao, María Laura; Brossard, Natalie; Chiale, Carolina; Carmona, Carlos; Giacomini, Cecilia; Freire, Teresa

    2015-12-01

    Helminths express various carbohydrate-containing glycoconjugates on their surface, and they release glycan-rich excretion/secretion products that can be very important in their life cycles, infection and pathology. Recent evidence suggests that parasite glycoconjugates could play a role in the evasion of the immune response, leading to a modified Th2-polarized immune response that favors parasite survival in the host. Nevertheless, there is limited information about the nature or function of glycans produced by the trematode Fasciola hepatica, the causative agent of fasciolosis. In this paper, we investigate whether glycosylated molecules from F. hepatica participate in the modulation of host immunity. We also focus on dendritic cells, since they are an important target of immune-modulation by helminths, affecting their activity or function. Our results indicate that glycans from F. hepatica promote the production of IL-4 and IL-10, suppressing IFNγ production. During infection, this parasite is able to induce a semi-mature phenotype of DCs expressing low levels of MHCII and secrete IL-10. Furthermore, we show that parasite glycoconjugates mediate the modulation of LPS-induced maturation of DCs since their oxidation restores the capacity of LPS-treated DCs to secrete high levels of the pro-inflammatory cytokines IL-6 and IL-12/23p40 and low levels of the anti-inflammatory cytokine IL-10. Inhibition assays using carbohydrates suggest that the immune-modulation is mediated, at least in part, by the recognition of a mannose specific-CLR that signals by recruiting the phosphatase Php2. The results presented here contribute to the understanding of the role of parasite glycosylated molecules in the modulation of the host immunity and might be useful in the design of vaccines against fasciolosis.

  7. Agents to reduce cytokine storm

    PubMed Central

    Gerlach, Herwig

    2016-01-01

    The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term “cytokine storm” in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock. PMID:28105327

  8. Agents to reduce cytokine storm.

    PubMed

    Gerlach, Herwig

    2016-01-01

    The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term "cytokine storm" in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock.

  9. Host responses to historical climate change shape parasite communities in North America’s intermountain west

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Host-parasite co-speciation, in which parasite divergence occurs in response to host divergence, is commonly proposed as a driver of parasite diversification, yet few empirical examples of strict co-speciation exist. Host-parasite co-evolutionary histories commonly reflect complex mosaics of co-spe...

  10. Transcriptomic profile of host response in mouse brain after exposure to plant toxin abrin.

    PubMed

    Bhaskar, A S Bala; Gupta, Nimesh; Rao, P V Lakshmana

    2012-09-04

    Abrin toxin is a plant glycoprotein, which is similar in structure and properties to ricin and is obtained from the seeds of Abrus precatorius (jequirity bean). Abrin is highly toxic, with an estimated human fatal dose of 0.1-1 μg/kg, and has caused death after accidental and intentional poisoning. Abrin is a potent biological toxin warfare agent. There are no chemical antidotes available against the toxin. Neurological symptoms like delirium, hallucinations, reduced consciousness and generalized seizures were reported in human poisoning cases. Death of a patient with symptoms of acute demyelinating encephalopathy with gastrointestinal bleeding due to ingestion of abrin seeds was reported in India. The aim of this study was to examine both dose and time-dependent transcriptional responses induced by abrin in the adult mouse brain. Mice (n=6) were exposed to 1 and 2 LD50 (2.83 and 5.66 μg/kg respectively) dose of abrin by intraperitoneal route and observed over 3 days. A subset of animals (n=3) were sacrificed at 1 and 2 day intervals for microarray and histopathology analysis. None of the 2 LD50 exposed animals survived till 3 days. The histopathological analysis showed the severe damage in brain and the infiltration of inflammatory cells in a dose and time dependent manner. The abrin exposure resulted in the induction of rapid immune and inflammatory response in brain. Clinical biochemistry parameters like lactate dehydrogenase, aspartate aminotransferase, urea and creatinine showed significant increase at 2-day 2 LD50 exposure. The whole genome microarray data revealed the significant regulation of various pathways like MAPK pathway, cytokine-cytokine receptor interaction, calcium signaling pathway, Jak-STAT signaling pathway and natural killer cell mediated toxicity. The comparison of differential gene expression at both the doses showed dose dependent effects of abrin toxicity. The real-time qRT-PCR analysis of selected genes supported the microarray data

  11. Systems-level comparison of host-responses elicited by avian H5N1 and seasonal H1N1 influenza viruses in primary human macrophages.

    PubMed

    Lee, Suki M Y; Gardy, Jennifer L; Cheung, C Y; Cheung, Timothy K W; Hui, Kenrie P Y; Ip, Nancy Y; Guan, Y; Hancock, Robert E W; Peiris, J S Malik

    2009-12-14

    Human disease caused by highly pathogenic avian influenza (HPAI) H5N1 can lead to a rapidly progressive viral pneumonia leading to acute respiratory distress syndrome. There is increasing evidence from clinical, animal models and in vitro data, which suggests a role for virus-induced cytokine dysregulation in contributing to the pathogenesis of human H5N1 disease. The key target cells for the virus in the lung are the alveolar epithelium and alveolar macrophages, and we have shown that, compared to seasonal human influenza viruses, equivalent infecting doses of H5N1 viruses markedly up-regulate pro-inflammatory cytokines in both primary cell types in vitro. Whether this H5N1-induced dysregulation of host responses is driven by qualitative (i.e activation of unique host pathways in response to H5N1) or quantitative differences between seasonal influenza viruses is unclear. Here we used microarrays to analyze and compare the gene expression profiles in primary human macrophages at 1, 3, and 6 h after infection with H5N1 virus or low-pathogenic seasonal influenza A (H1N1) virus. We found that host responses to both viruses are qualitatively similar with the activation of nearly identical biological processes and pathways. However, in comparison to seasonal H1N1 virus, H5N1 infection elicits a quantitatively stronger host inflammatory response including type I interferon (IFN) and tumor necrosis factor (TNF)-alpha genes. A network-based analysis suggests that the synergy between IFN-beta and TNF-alpha results in an enhanced and sustained IFN and pro-inflammatory cytokine response at the early stage of viral infection that may contribute to the viral pathogenesis and this is of relevance to the design of novel therapeutic strategies for H5N1 induced respiratory disease.

  12. Glia in the cytokine-mediated onset of depression: fine tuning the immune response

    PubMed Central

    Jo, Wendy K.; Zhang, Yuanyuan; Emrich, Hinderk M.; Dietrich, Detlef E.

    2015-01-01

    Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system’s (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted. PMID:26217190

  13. Human MAIT-cell responses to Escherichia coli: activation, cytokine production, proliferation, and cytotoxicity

    PubMed Central

    Dias, Joana; Sobkowiak, Michał J.; Sandberg, Johan K.; Leeansyah, Edwin

    2016-01-01

    Mucosa-associated invariant T cells are a large and relatively recently described innate-like antimicrobial T-cell subset in humans. These cells recognize riboflavin metabolites from a range of microbes presented by evolutionarily conserved major histocompatibility complex, class I-related molecules. Given the innate-like characteristics of mucosa-associated invariant T cells and the novel type of antigens they recognize, new methodology must be developed and existing methods refined to allow comprehensive studies of their role in human immune defense against microbial infection. In this study, we established protocols to examine a range of mucosa-associated invariant T-cell functions as they respond to antigen produced by Escherichia coli. These improved and dose- and time-optimized experimental protocols allow detailed studies of MR1-dependent mucosa-associated invariant T-cell responses to Escherichia coli pulsed antigen-presenting cells, as assessed by expression of activation markers and cytokines, by proliferation, and by induction of apoptosis and death in major histocompatibility complex, class I-related–expressing target cells. The novel and optimized protocols establish a framework of methods and open new possibilities to study mucosa-associated invariant T-cell immunobiology, using Escherichia coli as a model antigen. Furthermore, we propose that these robust experimental systems can also be adapted to study mucosa-associated invariant T-cell responses to other microbes and types of antigen-presenting cells. PMID:27034405

  14. Neonatal and Adult AMphi Upregulate Cytokine Gene Transcription Via p38 MAPK Signaling in Response to RSV

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis in premature and newborn infants. Alveolar macrophages (AMphi) are important innate cytokine-secreting cells in the lung, with critical roles in pathogen clearance and antigen presentation. As the neonatal AMphi response is not co...

  15. Association of the Host Immune Response with Protection Using a Live Attenuated African Swine Fever Virus Model

    PubMed Central

    Carlson, Jolene; O’Donnell, Vivian; Alfano, Marialexia; Velazquez Salinas, Lauro; Holinka, Lauren G.; Krug, Peter W.; Gladue, Douglas P.; Higgs, Stephen; Borca, Manuel V.

    2016-01-01

    African swine fever (ASF) is a lethal hemorrhagic disease of swine caused by a double-stranded DNA virus, ASF virus (ASFV). There is no vaccine to prevent the disease and current control measures are limited to culling and restricting animal movement. Swine infected with attenuated strains are protected against challenge with a homologous virulent virus, but there is limited knowledge of the host immune mechanisms generating that protection. Swine infected with Pretoriuskop/96/4 (Pret4) virus develop a fatal severe disease, while a derivative strain lacking virulence-associated gene 9GL (Pret4Δ9GL virus) is completely attenuated. Swine infected with Pret4Δ9GL virus and challenged with the virulent parental virus at 7, 10, 14, 21, and 28 days post infection (dpi) showed a progressive acquisition of protection (from 40% at 7 dpi to 80% at 21 and 28 dpi). This animal model was used to associate the presence of host immune response (ASFV-specific antibody and interferon (IFN)-γ responses, or specific cytokine profiles) and protection against challenge. With the exception of ASFV-specific antibodies in survivors challenged at 21 and 28 dpi, no association between the parameters assessed and protection could be established. These results, encompassing data from 65 immunized swine, underscore the complexity of the system under study, suggesting that protection relies on the concurrence of different host immune mechanisms. PMID:27782090

  16. Pathogenesis of amoebic encephalitis: Are the amoebae being credited to an 'inside job' done by the host immune response?

    PubMed

    Baig, Abdul Mannan

    2015-08-01

    Pathogenic free living amoeba like Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris are known to cause fatal "amoebic meningoencephalitis" by acquiring different route of entries to the brain. The host immune response to these protist pathogens differs from each another, as evidenced by the postmortem gross and microscopic findings from the brains of the affected patients. Cited with the expression of 'brain eating amoeba' when the infection is caused by N. fowleri, this expression is making its way into parasitology journals and books. The impression that it imparts is, as if the brain damage is substantially due to the enzymes and toxins produced by this amoeba. A detailed review of the literature, analysis of archived specimens and with our experimental assays, here we establish that with N. fowleri, Acanthamoeba and Balamuthia spp., the infections result in an extensive brain damage that in fact is substantially caused by the host immune response rather than the amoeba. Due to the comparatively larger sizes of these pathogens and the prior exposure of the amoebal antigen to the human body, the host immune system launches an amplified response that not only breaches the blood brain barrier (BBB), but also becomes the major cause of brain damage in Amoebic meningoencephalitis. It is our understanding that for N. fowleri the host immune response is dominated by acute inflammatory cytokines and that, in cases of Acanthamoeba and Balamuthia spp., it is the type IV hypersensitivity reaction that fundamentally not only contributes to disruption and leakiness of the blood brain barrier (BBB) but also causes the neuronal damage. The further intensification of brain damage is done by toxins and enzymes secreted by the amoeba, which causes the irreversible brain damage.

  17. Microbiota and host immune responses: a love-hate relationship.

    PubMed

    Tomkovich, Sarah; Jobin, Christian

    2016-01-01

    A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another.

  18. Dysregulation of Cytokine Response in Canadian First Nations Communities: Is There an Association with Persistent Organic Pollutant Levels?

    PubMed Central

    Imbeault, Pascal; Findlay, C. Scott; Robidoux, Michael A.; Haman, François; Blais, Jules M.; Tremblay, Angelo; Springthorpe, Susan; Pal, Shinjini; Seabert, Tim; Krümmel, Eva M.; Maal-Bared, Rasha; Tetro, Jason A.; Pandey, Sunita; Sattar, Syed A.; Filion, Lionel G.

    2012-01-01

    In vitro and animal studies report that some persistent organic pollutants (POPs) trigger the secretion of proinflammatory cytokines. Whether POP exposure is associated with a dysregulation of cytokine response remains to be investigated in humans. We studied the strength of association between plasma POP levels and circulating cytokines as immune activation markers. Plasma levels of fourteen POPs and thirteen cytokines were measured in 39 Caucasians from a comparator sample in Québec City (Canada) and 72 First Nations individuals from two northern communities of Ontario (Canada). Caucasians showed significantly higher levels of organochlorine insecticides (β-HCH, p,p′-DDE and HCB) compared to First Nations. Conversely, First Nations showed higher levels of Mirex, Aroclor 1260, PCB 153, PCB 170, PCB 180 and PCB 187 compared to Caucasians. While there was no difference in cytokine levels of IL-4, IL-6, IL-10 and IL-22 between groups, First Nations had significantly greater average levels of IFNγ, IL-1β, IL-2, IL-5, IL-8, IL-12p70, IL-17A, TNFα and TNFβ levels compared to Caucasians. Among candidate predictor variables (age, body mass index, insulin resistance and POP levels), high levels of PCBs were the only predictor accounting for a small but significant effect of observed variance (∼7%) in cytokine levels. Overall, a weak but significant association is detected between persistent organochlorine pollutant exposure and elevated cytokine levels. This finding augments the already existing information that environmental pollution is related to inflammation, a common feature of several metabolic disorders that are known to be especially prevalent in Canada's remote First Nations communities. PMID:22768323

  19. Pathogenicity mechanisms and host response during oral Candida albicans infections.

    PubMed

    Hebecker, Betty; Naglik, Julian R; Hube, Bernhard; Jacobsen, Ilse D

    2014-07-01

    Oral candidiasis remains one of the most common forms of Candida infections and occurs if the balance between host, Candida and microbiota is disturbed, e.g., by broad spectrum antibiotics or immunosuppression. In recent years, identification of fungal factors contributing to host cell damage and new insights into host defense mechanisms have significantly extended our understanding of the pathogenesis of oral candidiasis. In this review, we will provide an overview of the pathogenicity mechanisms during oral Candida infections and discuss some approaches by which this knowledge could be transferred into therapeutic approaches.

  20. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

    PubMed Central

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-01-01

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  1. Mucosal cytokine network in inflammatory bowel disease

    PubMed Central

    Andoh, Akira; Yagi, Yuhki; Shioya, Makoto; Nishida, Atsushi; Tsujikawa, Tomoyuki; Fujiyama, Yoshihide

    2008-01-01

    Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by ongoing mucosal inflammation in which dysfunction of the host immunologic response against dietary factors and commensal bacteria is involved. The chronic inflammatory process leads to disruption of the epithelial barrier, and the formation of epithelial ulceration. This permits easy access for the luminal microbiota and dietary antigens to cells resident in the lamina propria, and stimulates further pathological immune cell responses. Cytokines are essential mediators of the interactions between activated immune cells and non-immune cells, including epithelial and mesenchymal cells. The clinical efficacy of targeting TNF-α clearly indicates that cytokines are the therapeutic targets in IBD patients. In this manuscript, we focus on the biological activities of recently-reported cytokines [Interleukin (IL)-17 cytokine family, IL-31 and IL-32], which might play a role through interaction with TNF-α in the pathophysiology of IBD. PMID:18777592

  2. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.

    PubMed

    Powell, Timothy R; Schalkwyk, Leonard C; Heffernan, Andrew L; Breen, Gerome; Lawrence, Timothy; Price, Tom; Farmer, Anne E; Aitchison, Katherine J; Craig, Ian W; Danese, Andrea; Lewis, Cathryn; McGuffin, Peter; Uher, Rudolf; Tansey, Katherine E; D'Souza, Ursula M

    2013-09-01

    Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12 wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.

  3. Suitable in vitro Eimeria arloingi macromeront formation in host endothelial cells and modulation of adhesion molecule, cytokine and chemokine gene transcription.

    PubMed

    Silva, Liliana M R; Vila-Viçosa, Maria J M; Cortes, Helder C E; Taubert, Anja; Hermosilla, Carlos

    2015-01-01

    Eimeria arloingi infections can cause severe haemorrhagic enteritis in young goat kids, thereby leading to high economic losses in goat industry worldwide. We aimed to isolate a new E. arloingi strain and establish a suitable in vitro culture system for the first merogony. E. arloingi oocysts were collected from naturally infected goat kids in the province of Alentejo, Portugal. For the maintenance of E. arloingi (strain A), kids kept under strict parasite-free conditions were orally infected with 10(3) sporulated oocysts each. Further, a new excystation protocol was successfully established to obtain viable sporozoites for further in vitro development in primary bovine umbilical vein endothelial cells (BUVEC). Overall, E. arloingi first merogony was successfully accomplished in BUVEC leading to macromeront formation (up to 150 μm) and the release of fully developed merozoites I stages. Moreover, host endothelial cell-parasite interactions were investigated in order to determine the extent of modulation carried out by E. arloingi in BUVEC during the first merogony. Gene transcription of adhesion molecules (E-selectin, P-selectin, VCAM-1, ICAM-1) was enhanced in the first hours post-infection (p.i.) in E. arloingi-infected BUVEC. BUVEC activation due to invasion was also shown by increased chemokine (CXCL8, CCL2, CCL5), cytokine (GM-CSF) and COX-2 gene transcription. The new E. arloingi (strain A) will be useful for better comprehension of early host innate immune reactions against this parasite in vitro/in vivo as well as to further our investigations in the complex Eimeria-host endothelial cell interactions.

  4. Development of ileal cytokine and immunoglobulin expression levels in response to early feeding in broilers and layers.

    PubMed

    Simon, K; de Vries Reilingh, G; Kemp, B; Lammers, A

    2014-12-01

    Provision of feed in the immediate posthatch period may influence interaction between intestinal microbiota and immune system, and consequently immunological development of the chick. This study addressed ileal immune development in response to early feeding in 2 chicken breeds selected for different production traits: broilers and layers. Chicks of both breeds either received feed and water immediately posthatch or were subjected to a 72-h feed and water delay. Ileal cytokine and immunoglobulin mRNA expression levels were determined at different time points. Effects of early feeding were limited, but breeds differed strikingly regarding cytokine and immunoglobulin expression levels. Cytokine expression levels in broilers were low compared with layers and showed a transient drop in the second to third week of life. In contrast, broilers showed considerably higher expression levels of IgA, IgM, and IgY. These findings indicate that the 2 breeds use different immune strategies, at least on the ileal level.

  5. Chemokine Binding Protein M3 of Murine Gammaherpesvirus 68 Modulates the Host Response to Infection in a Natural Host

    PubMed Central

    Hughes, David J.; Kipar, Anja; Leeming, Gail H.; Bennett, Elaine; Howarth, Deborah; Cummerson, Joanne A.; Papoula-Pereira, Rita; Flanagan, Brian F.; Sample, Jeffery T.; Stewart, James P.

    2011-01-01

    Murine γ-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an attractive model of γ-herpesvirus infection. Surprisingly, however, ablation of expression of MHV-68 M3, a secreted protein with broad chemokine-binding properties in vitro, has no discernable effect during experimental infection via the respiratory tract. Here we demonstrate that M3 indeed contributes significantly to MHV-68 infection, but only in the context of a natural host, the wood mouse (Apodemus sylvaticus). Specifically, M3 was essential for two features unique to the wood mouse: virus-dependent inducible bronchus-associated lymphoid tissue (iBALT) in the lung and highly organized secondary follicles in the spleen, both predominant sites of latency in these organs. Consequently, lack of M3 resulted in substantially reduced latency in the spleen and lung. In the absence of M3, splenic germinal centers appeared as previously described for MHV-68-infected laboratory strains of mice, further evidence that M3 is not fully functional in the established model host. Finally, analyses of M3's influence on chemokine and cytokine levels within the lungs of infected wood mice were consistent with the known chemokine-binding profile of M3, and revealed additional influences that provide further insight into its role in MHV-68 biology. PMID:21445235

  6. Differential Regulation of Proinflammatory Cytokine Expression by Mitogen-Activated Protein Kinases in Macrophages in Response to Intestinal Parasite Infection

    PubMed Central

    Lim, Mei Xing; Png, Chin Wen; Tay, Crispina Yan Bing; Teo, Joshua Ding Wei; Jiao, Huipeng; Lehming, Norbert

    2014-01-01

    Blastocystis is a common enteric protistan parasite that can cause acute, as well as chronic, infection and is associated with irritable bowel syndrome (IBS). However, the pathogenic status of Blastocystis infection remains unclear. In this study, we found that Blastocystis antigens induced abundant expression of proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α), in mouse intestinal explants, in mouse colitis colon, and in macrophages. Further investigation utilizing RAW264.7 murine macrophages showed that Blastocystis treatment in RAW264.7 macrophages induced the activation of ERK, JNK, and p38, the three major groups of mammalian mitogen-activated protein (MAP) kinases that play essential roles in the expression of proinflammatory cytokines. ERK inhibition in macrophages significantly suppressed both mRNA and protein expression of IL-6 and TNF-α and mRNA expression of IL-1β. On the other hand, JNK inhibition resulted in reductions in both c-Jun and ERK activation and significant suppression of all three proinflammatory cytokines at both the mRNA and protein levels. Inhibition of p38 suppressed only IL-6 protein expression with no effect on the expression of IL-1β and TNF-α. Furthermore, we found that serine proteases produced by Blastocystis play an important role in the induction of ERK activation and proinflammatory cytokine expression by macrophages. Our study thus demonstrated for the first time that Blastocystis could induce the expression of various proinflammatory cytokines via the activation of MAP kinases and that infection with Blastocystis may contribute to the pathogenesis of inflammatory intestinal diseases through the activation of inflammatory pathways in host immune cells, such as macrophages. PMID:25156742

  7. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function.

    PubMed

    Krug, Anne; French, Anthony R; Barchet, Winfried; Fischer, Jens A A; Dzionek, Andrzej; Pingel, Jeanette T; Orihuela, Michael M; Akira, Shizuo; Yokoyama, Wayne M; Colonna, Marco

    2004-07-01

    Natural interferon-producing cells (IPC) respond to viruses by secreting type I interferon (IFN) and interleukin-12 (IL-12). Toll-like receptor (TLR) 9 mediates IPC recognition of some of these viruses in vitro. However, whether TLR9-induced activation of IPC is necessary for an effective antiviral response in vivo is not clear. Here, we demonstrate that IPC and dendritic cells (DC) recognize murine cytomegalovirus (MCMV) through TLR9. TLR9-mediated cytokine secretion promotes viral clearance by NK cells that express the MCMV-specific receptor Ly49H. Although depletion of IPC leads to a drastic reduction of the IFN-alpha response, this allows other cell types to secrete IL-12, ensuring normal IFN-gamma and NK cell responses to MCMV. We conclude that the TLR9/MyD88 pathway mediates antiviral cytokine responses by IPC, DC, and possibly other cell types, which are coordinated to promote effective NK cell function and MCMV clearance.

  8. Looking into Candida albicans infection, host response, and antifungal strategies

    PubMed Central

    Wang, Yan

    2015-01-01

    Candida albicans, a commonly encountered fungal pathogen, causes diseases varying from superficial mucosal complaints to life-threatening systemic disorders. Among the virulence traits of C. albicans, yeast-to-hypha transition is most widely acknowledged. Host innate immunity to C. albicans critically requires pattern recognition receptors (PRRs), and defence against C. albicans infection is provided by an exquisite interplay between the innate and adaptive arms of the host immune system. PMID:25590793

  9. Looking into Candida albicans infection, host response, and antifungal strategies.

    PubMed

    Wang, Yan

    2015-01-01

    Candida albicans, a commonly encountered fungal pathogen, causes diseases varying from superficial mucosal complaints to life-threatening systemic disorders. Among the virulence traits of C. albicans, yeast-to-hypha transition is most widely acknowledged. Host innate immunity to C. albicans critically requires pattern recognition receptors (PRRs), and defence against C. albicans infection is provided by an exquisite interplay between the innate and adaptive arms of the host immune system.

  10. Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and FcγRIIIa-Triggered Responses.

    PubMed

    Wagner, Julia A; Berrien-Elliott, Melissa M; Rosario, Maximillian; Leong, Jeffrey W; Jewell, Brea A; Schappe, Timothy; Abdel-Latif, Sara; Fehniger, Todd A

    2017-03-01

    Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-γ production triggered by leukemia targets or FcγRIIIa ligation within licensed NK cells, which exhibited the highest functionality of the NK cell subsets interrogated. IFN-γ production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to FcγRIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NK cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy.

  11. Immunization with Protein D from Non-Typeable Haemophilus influenzae (NTHi) Induced Cytokine Responses and Bioactive Antibody Production

    PubMed Central

    Davoudi Vijeh Motlagh, Atefeh; Siadat, Seyed Davar; Abedian Kenari, Saeid; Mahdavi, Mehdi; Behrouzi, Ava; Asgarian-Omran, Hossein

    2016-01-01

    Background Outer membrane protein D (PD) is a highly conserved and stable protein in the outer membrane of both encapsulated (typeable) and non-capsulated (non-typeable) strains of Haemophilus influenzae. As an immunogen, PD is a potential candidate vaccine against non-typeable H. influenzae (NTHi) strains. Objectives The aim of this study was to determine the cytokine pattern and the opsonic antibody response in a BALB/c mouse model versus PD from NTHi as a vaccine candidate. Methods Protein D was formulated with Freund’s and outer membrane vesicle (OMV) adjuvants and injected into experimental mice. Sera from all groups were collected. The bioactivity of the anti-PD antibody was determined by opsonophagocytic killing test. To evaluate the cytokine responses, the spleens were assembled, suspension of splenocytes was recalled with antigen, and culture supernatants were analyzed by ELISA for IL-4, IL-10, and IFN-γ cytokines. Results Anti-PD antibodies promoted phagocytosis of NTHi in both immunized mice groups (those administered PD + Freund’s and those administered PD + OMV adjuvants, 92.8% and 83.5%, respectively, compared to the control group). In addition, the concentrations of three cytokines were increased markedly in immunized mice. Conclusions We conclude that immunization with PD protects mice against NTHi. It is associated with improvements in both cellular and humoral immune responses and opsonic antibody activity. PMID:27942362

  12. Coexistent Malnutrition Is Associated with Perturbations in Systemic and Antigen-Specific Cytokine Responses in Latent Tuberculosis Infection.

    PubMed

    Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukthi; Kumar, Nathalla Pavan; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

    2016-04-01

    Malnutrition, as defined by low body mass index (BMI), is a major risk factor for the development of active tuberculosis (TB), although the biological basis underlying this susceptibility remains poorly characterized. To verify whether malnutrition affects the systemic and antigen-specific cytokine levels in individuals with latent TB (LTB), we examined circulating and TB antigen-stimulated levels of cytokines in individuals with LTB and low BMI (LBMI) and compared them with those in individuals with LTB and normal BMI (NBMI). Coexistent LBMI with LTB was characterized by diminished circulating levels of type 1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), type 2 (interleukin-4 [IL-4]), type 17 (IL-22), and other proinflammatory (IL-1α, IL-1β, and IL-6) cytokines but elevated levels of other type 2 (IL-5 and IL-13) and regulatory (IL-10 and transforming growth factor beta [TGF-β]) cytokines. In addition, LBMI with LTB was associated with diminished TB antigen-induced IFN-γ, TNF-α, IL-6, IL-1α, and IL-1β levels. Finally, there was a significant positive correlation between BMI values and TNF-α and IL-1β levels and a significant negative correlation between BMI values and IL-2, IL-10, and TGF-β levels in individuals with LTB. Therefore, our data reveal that latent TB with a coexistent low BMI is characterized by diminished protective cytokine responses and heightened regulatory cytokine responses, providing a potential biological mechanism for the increased risk of developing active TB.

  13. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals

    PubMed Central

    Ly, Judy; Lagman, Minette; Saing, Tommy; Singh, Manpreet Kaur; Tudela, Enrique Vera; Morris, Devin; Anderson, Jessica; Daliva, John; Ochoa, Cesar; Patel, Nishita; Pearce, Daniel

    2015-01-01

    Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4+ T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response

  14. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

    PubMed

    Ly, Judy; Lagman, Minette; Saing, Tommy; Singh, Manpreet Kaur; Tudela, Enrique Vera; Morris, Devin; Anderson, Jessica; Daliva, John; Ochoa, Cesar; Patel, Nishita; Pearce, Daniel; Venketaraman, Vishwanath

    2015-11-01

    Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response

  15. Increased Age, but Not Parity Predisposes to Higher Bacteriuria Burdens Due to Streptococcus Urinary Tract Infection and Influences Bladder Cytokine Responses, Which Develop Independent of Tissue Bacterial Loads

    PubMed Central

    Sullivan, Matthew J.; Carey, Alison J.; Leclercq, Sophie Y.; Tan, Chee K.

    2016-01-01

    Streptococcus agalactiae causes urinary tract infection (UTI) in pregnant adults, non-pregnant adults, immune-compromised individuals and the elderly. The pathogenesis of S. agalactiae UTI in distinct patient populations is poorly understood. In this study, we used murine models of UTI incorporating young mice, aged and dam mice to show that uropathogenic S. agalactiae causes bacteriuria at significantly higher levels in aged mice compared to young mice and this occurs coincident with equivalent levels of bladder tissue colonisation at 24 h post-infection (p.i.). In addition, aged mice exhibited significantly higher bacteriuria burdens at 48 h compared to young mice, confirming a divergent pattern of bacterial colonization in the urinary tract of aged and young mice. Multiparous mice, in contrast, exhibited significantly lower urinary titres of S. agalactiae compared to age-matched nulliparous mice suggesting that parity enhances the ability of the host to control S. agalactiae bacteriuria. Additionally, we show that both age and parity alter the expression levels of several key regulatory and pro-inflammatory cytokines, which are known to be important the immune response to UTI, including Interleukin (IL)-1β, IL-12(p40), and Monocyte Chemoattractant Protein-1 (MCP-1). Finally, we demonstrate that other cytokines, including IL-17 are induced significantly in the S. agalactiae-infected bladder regardless of age and parity status. Collectively, these findings show that the host environment plays an important role in influencing the severity of S. agalactiae UTI; infection dynamics, particularly in the context of bacteriuria, depend on age and parity, which also affect the nature of innate immune responses to infection. PMID:27936166

  16. Homotypic NK cell-to-cell communication controls cytokine responsiveness of innate immune NK cells.

    PubMed

    Kim, Tae-Jin; Kim, Miju; Kim, Hye Mi; Lim, Seon Ah; Kim, Eun-Ok; Kim, Kwanghee; Song, Kwang Hoon; Kim, Jiyoung; Kumar, Vinay; Yee, Cassian; Doh, Junsang; Lee, Kyung-Mi

    2014-12-05

    While stationary organ cells are in continuous contact with neighboring cells, immune cells circulate throughout the body without an apparent requirement for cell-cell contact to persist in vivo. This study challenges current convention by demonstrating, both in vitro and in vivo, that innate immune NK cells can engage in homotypic NK-to-NK cell interactions for optimal survival, activation, and proliferation. Using a specialized cell-laden microwell approach, we discover that NK cells experiencing constant NK-to-NK contact exhibit a synergistic increase in activation status, cell proliferation, and anti-tumor function in response to IL-2 or IL-15. This effect is dependent on 2B4/CD48 ligation and an active cytoskeleton, resulting in amplification of IL-2 receptor signaling, enhanced CD122/CD132 colocalization, CD25 upregulation, and Stat3 activation. Conversely, 'orphan' NK cells demonstrate no such synergy and fail to persist. Therefore, our data uncover the existence of homotypic cell-to-cell communication among mobile innate lymphocytes, which promotes functional synergy within the cytokine-rich microenvironment.

  17. Label-free quantitative phosphoproteomic profiling of cellular response induced by an insect cytokine paralytic peptide.

    PubMed

    Song, Liang; Wang, Fei; Dong, Zhaoming; Hua, Xiaoting; Xia, Qingyou

    2017-02-10

    Paralytic peptide (PP) participates in diverse physiological processes as an insect cytokine, such as immunity control, paralysis induction, regulation of cell morphology and proliferation. To investigate the molecular mechanism underlying those physiological activities, we systematically investigated the global phosphorylation events in fat body of silkworm larvae induced by PP through label-free quantitative phosphoproteomics. 2534 phosphosites were finally identified, of which the phosphorylation level of 620 phosphosites on 244 proteins was significantly up-regulated and 67 phosphosites on 43 proteins was down-regulated. Among those proteins, 13 were protein kinases (PKs), 13 were transcription factors (TFs) across 10 families and 17 were metabolism related enzymes. Meanwhile, Motif-X analysis of the phosphorylation sites showed that 16 motifs are significantly enriched, including 8 novel phosphorylation motifs. In addition, KEGG and functional interacting network analysis revealed that phosphorylation cascades play the crucial regulation roles in PP-dependent signaling pathways, and highlighted the potential central position of the mitogen-activated protein kinases (MAPKs) in them. These analyses provide direct insights into the molecule mechanisms of cellular response induced by PP.

  18. Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes

    PubMed Central

    Wensink, Annette C.; Kemp, Vera; Fermie, Job; García Laorden, M. Isabel; van der Poll, Tom; Hack, C. Erik; Bovenschen, Niels

    2014-01-01

    Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK synergistically enhances LPS-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of LPS challenge. Intriguingly, these extracellular effects are independent of GrK catalytic activity. GrK disaggregates LPS from micelles and augments LPS–CD14 complex formation, thereby likely boosting monocyte activation by LPS. We conclude that extracellular GrK is an unexpected direct modulator of LPS–TLR4 signaling during the antimicrobial innate immune response. PMID:24711407

  19. Systemic vs. local cytokine and leukocyte responses to unilateral wrist flexion exercise.

    PubMed

    Nemet, Dan; Hong, Suzi; Mills, Paul J; Ziegler, Michael G; Hill, Maryann; Cooper, Dan M

    2002-08-01

    We hypothesized that brief exercise of a small muscle group would lead to local rather than systemic alterations in cytokines, peripheral blood mononuclear cells, and mediators of angiogenesis. Fifteen men and eight women (age range 22-36 yr old) performed 10 min of unilateral wrist flexion exercise. Blood was sampled from venous catheters in the resting and exercising arm at baseline, at the end of exercise, and at 10, 30, 60, and 120 min after exercise. Lactate was significantly elevated in the exercising arm (+276 +/- 35%; P < 0.0005) with no change in the resting arm. In contrast, increases in both arms were observed for interleukin-6 (+139 +/- 51%; P < 0.0005), growth hormone (+1,104 +/- 284%; P < 0.003), natural killer cells (+81 +/- 9%; P < 0.0005), and lymphocytes expressing CD62L, CD11a, and CD54. There were no significant differences in these increases between the resting and exercising arm. Catecholamines increased in both arms [epinephrine peak increase, +226 +/- 36% (P < 0.001); norepinephrine peak increase, +90 +/- 15% (P < 0.01)]. Fibroblast growth factor-2 initially decreased with exercise in both arms, and this was followed by a rebound increase. Vascular endothelial growth factor demonstrated a small but significant increase in both arms (+124 +/- 31%; P < 0.05). Brief, low-intensity exercise leads to a systemic rather than local response of mediators that could be involved in inflammation, repair, or angiogenic adaptation to physical activity.

  20. High-throughput screening of brief naturalistic stress-responsive cytokines in university students taking examinations.

    PubMed

    Katsuura, Sakurako; Kamezaki, Yoshiko; Tominaga, Kumiko; Masuda, Kiyoshi; Nishida, Kensei; Yamamoto, Yuta; Takeo, Keiko; Yamagishi, Naoko; Tanahashi, Toshihito; Kawai, Tomoko; Rokutan, Kazuhito

    2010-08-01

    This study was designed to prospectively examine the impact of a brief naturalistic stressor (academic examination) on salivary/serum cortisol, measures of anxiety and depressive mood, and 50 circulating immune mediators assessed 7 days before, the first day of, and 2 days after the first term examination period (5 days) among 20 male and 6 female medical students (19.7+/-3.1 years, mean+/-SD). Of 42 serum factors detected, repeated measures ANOVA and Bonferroni post hoc testing indicated that concentrations of macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein (MCP)-3, and beta-nerve growth factor (beta-NGF) were significantly decreased 2 days after finishing examinations, compared with the levels on the first day of examinations (p<0.05) in association with a concomitant post-examination decreases (p<0.05) in anxiety and salivary cortisol levels. In contrast, interleukin (IL)-16 was reciprocally increased between the two time points (p<0.05). However, after correction for multiple comparisons, only changes in MIF were significant (p<0.05/42=0.00119), and MIF levels peaked on the first day of examinations was significantly higher than those measured both 7 days before and 2 days after the examination. The present high-throughput analysis with multiplex cytokine panels reconfirms the impact of brief naturalistic stressors on immune outcomes, and suggests a potential role of MIF in the acute stress response.

  1. Exercise Improves Host Response to Influenza Viral Infection in Obese and Non-Obese Mice through Different Mechanisms

    PubMed Central

    Warren, Kristi J.; Olson, Molly M.; Thompson, Nicholas J.; Cahill, Mackenzie L.; Wyatt, Todd A.; Yoon, Kyoungjin J.; Loiacono, Christina M.; Kohut, Marian L.

    2015-01-01

    Obesity has been associated with greater severity of influenza virus infection and impaired host defense. Exercise may confer health benefits even when weight loss is not achieved, but it has not been determined if regular exercise improves immune defense against influenza A virus (IAV) in the obese condition. In this study, diet-induced obese mice and lean control mice exercised for eight weeks followed by influenza viral infection. Exercise reduced disease severity in both obese and non-obese mice, but the mechanisms differed. Exercise reversed the obesity-associated delay in bronchoalveolar-lavage (BAL) cell infiltration, restored BAL cytokine and chemokine production, and increased ciliary beat frequency and IFNα-related gene expression. In non-obese mice, exercise treatment reduced lung viral load, increased Type-I-IFN-related gene expression early during infection, but reduced BAL inflammatory cytokines and chemokines. In both obese and non-obese mice, exercise increased serum anti-influenza virus specific IgG2c antibody, increased CD8+ T cell percentage in BAL, and reduced TNFα by influenza viral NP-peptide-responding CD8+ T cells. Overall, the results suggest that exercise “restores” the immune response of obese mice to a phenotype similar to non-obese mice by improving the delay in immune activation. In contrast, in non-obese mice exercise treatment results in an early reduction in lung viral load and limited inflammatory response. PMID:26110868

  2. Evaluation of cytokine and chemokine response elicited by Rv2204c and Rv0753c to detect latent tuberculosis infection.

    PubMed

    Pathakumari, Balaji; Prabhavathi, Maddineni; Raja, Alamelu

    2015-12-01

    Latent TB infection (LTBI) is one of the major contributing factors for the high incidence of TB in India that in turn significantly contributes to the pool of active TB. Hence, identification and treatment of LTBI is of utmost importance. Currently, no specific diagnostic test is available for LTBI. Earlier, in our immunoproteomic analysis, we identified Rv2204c and Rv0753c protein-containing fractions induced significantly higher interferon-gamma (IFN-γ) response in LTBI than in active TB. In this study, we evaluated cytokine and chemokine response against M. tuberculosis antigens for improving LTBI identification. Two M. tb proteins Rv2204c and Rv0753c were cloned, over expressed in E. coli and purified by affinity chromatography. Antigen-specific immune response was evaluated in 39 pulmonary TB patients (PTB) and 35 healthy house-hold contacts (HHC). After whole blood culture for 6 days, the secretion of cytokines and chemokines were quantified in culture supernatants using Enzyme Linked Immune Sorbent Assay (ELISA). Antigen specific cytokines such as interferon gamma (IFN-γ), interleukin-6 (IL-6), IL-8, IL-12p40 and chemokines like monocyte chemotactic proteins MCP-1, MCP-2 were significantly higher in HHC than PTB. In contrast to other cytokines, tumor necrosis factor-alpha (TNF)-α response was significantly increased in PTB compared with HHC. Both Rv2204c and Rv0753c antigen specific IFN-γ response showed 86% positivity in HHC; whereas in PTB, these antigens showed 18% and 21% positivity respectively. Rv2204c antigen-specific IFN-γ/TNF-α response displayed maximum positivity of 91% in HHC and minimum positivity of 10% (4/39) in PTB. Rv2204c and Rv0753c specific IFN-γ and IFN-γ/TNF-α responses showed the most promising accuracy in identifying LTBI.

  3. Assessment of in vitro cytokine response in hemophilia A patients with or without factor VIII inhibitory antibody.

    PubMed

    Towfighi, Farzaneh; Gharagozlou, Soheila; Kardar, Gholam-Ali; Sharifian, Ramazan-Ali; Karimi, Katayoon; Lak, Manijheh; Pourfathollah, Ali-Akbar; Soleimani, Sedigheh; Shokri, Fazel

    2007-08-01

    Factor VIII (FVIII) inhibitor antibodies are produced in a proportion of hemophilia A patients. Development of anti-FVIII inhibitor antibodies is a T cell-dependent response, mediated by FVIII specific CD4(+) T cells. This study was performed to investigate the contribution of T helper (Th) cell-mediated cytokine response in inhibitor production. Peripheral blood mononuclear cells (PBMCs) were obtained from hemophilia A patients with (n = 14) or without inhibitor (n = 14) and from normal individuals (n = 14). Following stimulation of PBMCs with rFVIII and phytohemagglutinin (PHA) mitogen, the secreted cytokines, interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and transforming growth factor-beta1 (TGF-beta1), in culture supernatant and the proliferative response were assessed using sandwich ELISA and (3)H-thymidine incorporation, respectively. No significant proliferative response to FVIII was observed, whereas PHA induced a strong response in all groups. No cytokine secretion was observed in response to FVIII stimulation. Although PHA induced IL-10, TGF-beta1 and IFN-gamma secretion in all groups, the level of IFN-gamma was significantly lower in hemophilia A patients than in normal individuals (p < 0.0001). The levels of TGF-beta1 and IL-10 were similarly higher in patients compared with normal subjects, but the difference was not statistically significant. Lack of FVIII-induced proliferative response and cytokine production together with reduced secretion of PHA-induced IFN-gamma in both groups of patients suggest involvement of nonspecific immunosuppression possibly due to hepatitis C virus (HCV) infection observed in the majority of patients.

  4. Neosporosis. Aspects of epidemiology and host immune response.

    PubMed

    Innes, E A; Buxton, D; Maley, S; Wright, S; Marks, J; Esteban, I; Rae, A; Schock, A; Wastling, J

    2000-01-01

    Neospora caninum is a recently recognized protozoan parasite which has been described as causing a neuromuscular paralysis in dogs and is emerging as a major cause of bovine infertility and abortion worldwide. The parasite is known to infect a range of warm blooded animals but the disease predominates in dogs and cattle. It is not yet known if N. caninum can infect and cause disease in people. The dog has recently been identified as the definitive host and the parasite may be transmitted through the ingestion of oocysts or congenitally from mother to fetus. N. caninum is known to infect red foxes (Vulpes vulpes) and coyotes (Canis latrans) and the role of wildlife species as reservoirs of infection requires further investigation. Little is known about the range of parasite genotypes within the environment or the variation in virulence between different strains. RAPD-PCR analysis of geographically distinct bovine and canine isolates has revealed little genetic variation. Epidemiological studies from different areas of the world have investigated the importance of N. caninum as an abortifacient agent and longitudinal studies have shown the high rate (approximately 80%) of congenital transmission within infected herds. Information on the rates of repeat abortion due to neosporosis are less well defined however current estimates put this at 5% suggesting that cattle may develop some form of protective immunity against N. caninum-induced abortion. Diagnosis of the disease is based upon detection of the parasite in the tissues, most commonly using immunohistochemistry with additional information provided by serology. However, although positive fetal serology is a strong indicator of exposure to the parasite, care should be taken in the interpretation of maternal serology. As we understand more about the epidemiology of neosporosis we are also better able to interpret the results of diagnostic tests. The mere presence of the parasite does not necessarily infer that this

  5. A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection

    PubMed Central

    Ng, Lisa FP; Hibberd, Martin L; Ooi, Eng-Eong; Tang, Kin-Fai; Neo, Soek-Ying; Tan, Jenny; Krishna Murthy, Karuturi R; Vega, Vinsensius B; Chia, Jer-Ming; Liu, Edison T; Ren, Ee-Chee

    2004-01-01

    Background The molecular basis of severe acute respiratory syndrome (SARS) coronavirus (CoV) induced pathology is still largely unclear. Many SARS patients suffer respiratory distress brought on by interstitial infiltration and frequently show peripheral blood lymphopenia and occasional leucopenia. One possible cause of this could be interstitial inflammation, following a localized host response. In this study, we therefore examine the immune response of SARS-CoV in human peripheral blood mononuclear cells (PBMCs) over the first 24 hours. Methods PBMCs from normal healthy donors were inoculated in vitro with SARS-CoV and the viral replication kinetics was studied by real-time quantitative assays. SARS-CoV specific gene expression changes were examined by high-density oligonucleotide array analysis. Results We observed that SARS-CoV was capable of infecting and replicating in PBMCs and the kinetics of viral replication was variable among the donors. SARS-CoV antibody binding assays indicated that SARS specific antibodies inhibited SARS-CoV viral replication. Array data showed monocyte-macrophage cell activation, coagulation pathway upregulation and cytokine production together with lung trafficking chemokines such as IL8 and IL17, possibly activated through the TLR9 signaling pathway; that mimicked clinical features of the disease. Conclusions The identification of human blood mononuclear cells as a direct target of SARS-CoV in the model system described here provides a new insight into disease pathology and a tool for investigating the host response and mechanisms of pathogenesis. PMID:15357874

  6. Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

    SciTech Connect

    Yoshida, Ryoko; Suzuki, Mayu; Sakaguchi, Ryota; Hasegawa, Eiichi; Kimura, Akihiro; Shichita, Takashi; Sekiya, Takashi; Shiraishi, Hiroshi; Shimoda, Kouji; Yoshimura, Akihiko

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKK{beta}-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-{alpha}, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.

  7. Neonatal mycobacterial specific cytotoxic T-lymphocyte and cytokine profiles in response to distinct BCG vaccination strategies

    PubMed Central

    Hussey, Gregory D; Watkins, Marcia L V; Goddard, Elizabeth A; Gottschalk, Sean; Hughes, Elizabeth J; Iloni, Karen; Kibel, Maurice A; Ress, Stanley R

    2002-01-01

    This study evaluated whether different bacillus Calmette–Gue´rin (BCG) strains, routes of administration, vaccination age and percutaneous tools influenced immune responses to BCG vaccination in infants. Proliferative responses, cytokine production and cell-mediated cytotoxicity obtained in post-vaccinated children were compared to baseline cord bloods and unvaccinated 10-week-old infants. BCG vaccination generally induced strong lymphoproliferative and T helper type 1 (Th1)-type cytokine responses. There was a trend for greater responsiveness following the intradermal route of vaccination, with Japanese-172 strain and with delaying vaccination until 10 weeks. Cord mononuclear cells differentially stimulated the Th2-type cytokines interleukin-5 (IL-5) and IL-10 selectively in response to BCG, as compared to H37Rv or purified protein derivative stimulation. We document for the first time the generation of mycobacterium-specific cytotoxic T lymphocytes in neonates, following BCG vaccination. Cytotoxic activity correlated with the ratio of interferon-γ to IL-5, aside from a single instance where use of the Biovac® tool resulted in a striking dissociation selectively against H37Rv targets. These data have implications for correlates of protective immunity in design of vaccine studies. PMID:11918693

  8. Host and non-host roots in rice: cellular and molecular approaches reveal differential responses to arbuscular mycorrhizal fungi

    PubMed Central

    Fiorilli, Valentina; Vallino, Marta; Biselli, Chiara; Faccio, Antonella; Bagnaresi, Paolo; Bonfante, Paola

    2015-01-01

    Oryza sativa, a model plant for Arbuscular Mycorrhizal (AM) symbiosis, has both host and non-host roots. Large lateral (LLR) and fine lateral (FLR) roots display opposite responses: LLR support AM colonization, but FLR do not. Our research aimed to study the molecular, morphological and physiological aspects related to the non-host behavior of FLR. RNA-seq analysis revealed that LLR and FLR displayed divergent expression profiles, including changes in many metabolic pathways. Compared with LLR, FLR showed down-regulation of genes instrumental for AM establishment and gibberellin signaling, and a higher expression of nutrient transporters. Consistent with the transcriptomic data, FLR had higher phosphorus content. Light and electron microscopy demonstrated that, surprisingly, in the Selenio cultivar, FLR have a two-layered cortex, which is theoretically compatible with AM colonization. According to RNA-seq, a gibberellin inhibitor treatment increased anticlinal divisions leading to a higher number of cortex cells in FLR. We propose that some of the differentially regulated genes that lead to the anatomical and physiological properties of the two root types also function as genetic factors regulating fungal colonization. The rice root apparatus offers a unique tool to study AM symbiosis, allowing direct comparisons of host and non-host roots in the same individual plant. PMID:26322072

  9. Expression of Toll-like receptors and their association with cytokine responses in peripheral blood mononuclear cells of children with acute rotavirus diarrhoea.

    PubMed

    Xu, J; Yang, Y; Sun, J; Ding, Y; Su, L; Shao, C; Jiang, B

    2006-06-01

    To understand virus and host interactions and host responses to rotavirus infection in children, we analysed by real-time polymerase chain reaction (PCR) the expression of mRNA for five Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR7 and TLR8) and four T helper (Th)1 and Th2 cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-gamma and IL-4) in peripheral blood mononuclear cells (PBMC) of children with acute rotavirus diarrhoea. We observed significantly higher expression of genes encoding TLR2, TLR3, TLR4, TLR7 and TLR8 in PBMC of 41% (31/75) patients within 3 days of illness onset than those in healthy children. After 3 days of illness onset, only TLR3 and TLR8 mRNA expressions were still significantly (P<0.05) increased in 59% (44/75) children with diarrhoea. We also observed significantly (P<0.05) elevated expression of IL-12p40 and IFN-gamma in PBMC of patients during the entire period of illness and the first 3 days of illness, respectively. We further demonstrated a weak but significant association between elevated levels of gene expression of four TLRs (TLR2, TLR3, TLR4 and TLR8) and IFN-gamma. Our results suggest that multiple TLRs may modulate the immune response in the acute phase of rotavirus infection and play a role in the activation of IFN-gamma.

  10. Cytokine and satellite cell responses to muscle damage: interpretation and possible confounding factors in human studies.

    PubMed

    van de Vyver, M; Myburgh, K H

    2012-08-01

    It is plausible that multiple muscle biopsies following a muscle damaging intervention can exacerbate the inflammatory and subsequent satellite cell responses. To elucidate confounding effects of muscle biopsy procedure on satellite cell number, indirect markers of damage and the inflammatory response following acute downhill running (DHR) were investigated. 10 healthy male participant were divided into a non-exercising control (n = 4) and DHR (12 × 5min bouts, 10 % decline at 85 % VO(2)max) (n = 6) group. Blood samples were taken pre, post and every 24 h for 9 days. Serum was analysed for creatine kinase (CK), myoglobin (Mb), lactate dehydrogenase (LDH), TNF-α, IL-6 and IL-10. Muscle biopsies taken on days 1 and 2 post intervention from opposing legs were analysed for Pax7(+) satellite cells. In the DHR group, Mb (536 ± 277 ng mL(-1)), IL-6 (12.6 ± 4.7 pg mL(-1)) and IL-10 (27.3 ± 11.5 pg mL(-1)) peaked immediately post DHR, while CK (2651 ± 1911 U L(-1)), LDH (202 ± 47 U L(-1)) and TNF-α (25.1 ± 8.7 pg mL(-1)) peaked on day 1. A 30 % increase in Pax7(+) satellite cells on day 1 in the DHR group was no longer apparent on day 2. H&E staining show evidence of phagocytosis in the DHR group. No significant changes over time were observed in the control group for any of the variables measured. Events observed in the DHR group were as a result of the intervention protocol and subsequent muscle damage. The relationship between SC proliferation and pro-inflammatory cytokine release appears to be complex since the IL-6/IL-10 response time differs significantly from the TNF-α response.

  11. Prenatal fluoxetine exposure affects cytokine and behavioral response to an immune challenge.

    PubMed

    Avitsur, Ronit; Levy, Sigal; Grinshpahet, Rachel; Goren, Naama; Hirsh, Ofer; Zalko, Assaf

    2015-07-15

    Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) is a commonly prescribed antidepressant drug in pregnant women. FLX readily crosses the placenta, consequently altering serotonergic neurotransmission in the fetus and causing physiological and behavioral disturbances in the newborn. Studies have shown that serotonin plays a role in modulating immune signaling. Thus, the goal of this study was to assess the effects of prenatal exposure to FLX on the response to an immune challenge in offspring mice. Male and female mice were prenatally exposed to FLX and later injected with lipopolysaccharide (LPS) at different stages of development. Results indicated that prenatal FLX modulated aspects of the response to the endotoxin challenge. Prenatal FLX diminished the secretion of interleukin (IL)-6 in adult male and female mice. Prenatal exposure to FLX further suppressed TNFα and augmented IL-1β secretion in adult males. Early effects of LPS (within 24h of administration) on body weight and food consumption were diminished by prenatal exposure to FLX in adult mice. Delayed effects of LPS (within 60h of administration) were modulated by prenatal FLX in young animals. These results provide an indication that prenatal modulations of the serotonergic system had lasting implications for host response to an immune challenge. These findings may contribute to the understanding of the effects of prenatal environment on the development of physiological systems that are important to coping with infectious challenges, and assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.

  12. Interaction of Bovine Peripheral Blood Polymorphonuclear Cells and Leptospira Species; Innate Responses in the Natural Bovine Reservoir Host

    PubMed Central

    Wilson-Welder, Jennifer H.; Frank, Ami T.; Hornsby, Richard L.; Olsen, Steven C.; Alt, David P.

    2016-01-01

    Cattle are the reservoir hosts of Leptospira borgpetersenii serovar Hardjo, and can also be reservoir hosts of other Leptospira species such as L. kirschneri, and Leptospira interrogans. As a reservoir host, cattle shed Leptospira, infecting other animals, including humans. Previous studies with human and murine neutrophils have shown activation of neutrophil extracellular trap or NET formation, and upregulation of inflammatory mediators by neutrophils in the presence of Leptospira. Humans, companion animals and most widely studied models of Leptospirosis are of acute infection, hallmarked by systemic inflammatory response, neutrophilia, and septicemia. In contrast, cattle exhibit chronic infection with few outward clinical signs aside from reproductive failure. Taking into consideration that there is host species variation in innate immunity, especially in pathogen recognition and response, the interaction of bovine peripheral blood polymorphonuclear cells (PMNs) and several Leptospira strains was evaluated. Studies including bovine-adapted strains, human pathogen strains, a saprophyte and inactivated organisms. Incubation of PMNs with Leptospira did induce slight activation of neutrophil NETs, greater than unstimulated cells but less than the quantity from E. coli P4 stimulated PMNs. Very low but significant from non-stimulated, levels of reactive oxygen peroxides were produced in the presence of all Leptospira strains and E. coli P4. Similarly, significant levels of reactive nitrogen intermediaries (NO2) was produced from PMNs when incubated with the Leptospira strains and greater quantities in the presence of E. coli P4. PMNs incubated with Leptospira induced RNA transcripts of IL-1β, MIP-1α, and TNF-α, with greater amounts induced by live organisms when compared to heat-inactivated leptospires. Transcript for inflammatory cytokine IL-8 was also induced, at similar levels regardless of Leptospira strain or viability. However, incubation of Leptospira strains

  13. How the devil facial tumor disease escapes host immune responses.

    PubMed

    Siddle, Hannah V; Kaufman, Jim

    2013-08-01

    The devil facial tumor disease (DFTD) is a contagious cancer that has recently emerged among Tasmanian devils, rapidly decimating the population. We have recently discovered that DFTD cells lose the expression MHC molecules on the cell surface, explaining how this tumor avoids recognition by host CD8(+) T cells.

  14. Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens.

    PubMed

    Chasman, Deborah; Walters, Kevin B; Lopes, Tiago J S; Eisfeld, Amie J; Kawaoka, Yoshihiro; Roy, Sushmita

    2016-07-01

    Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection.

  15. Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens

    PubMed Central

    Chasman, Deborah; Walters, Kevin B.; Lopes, Tiago J. S.; Eisfeld, Amie J.; Kawaoka, Yoshihiro; Roy, Sushmita

    2016-01-01

    Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection. PMID:27403523

  16. MyD88-dependent pro-inflammatory cytokine response contributes to lethal toxicity of staphylococcal enterotoxin B in mice.

    PubMed

    Kissner, Teri L; Ruthel, Gordon; Cisney, Emily D; Ulrich, Robert G; Fernandez, Stefan; Saikh, Kamal U

    2011-10-01

    An elevated pro-inflammatory cytokine response is the primary cause of death by toxic shock after exposure to staphylococcal enterotoxin B (SEB). Identifying an intracellular signal mediator that predominantly controls the pro-inflammatory response is important for developing a therapeutic strategy. We examined the role of the signaling adaptor MyD88 in cell culture and in a mouse model of toxic shock. Our results indicated that elevated tumor necrosis factor-α, interferon-γ, interleukin (IL)-1α/β and IL-6 production from mouse spleen cells treated with SEB alone or in combination with lipopolysaccharide (LPS) was regulated by MyD88. Elevated levels of MyD88 protein in spleen cells, as well as in CD11c(+) or Mac3(+) cells, and activation of nuclear factor-κB in spleen cells were observed in mice treated with SEB. An SEB-dose dependent lethality was observed in LPS-potentiated and in D-galactosamine-sensitized mice. D-Galactosamine treatment of spleen cells had no effect in cytokine induction but rather increased the sensitivity to toxic shock in mice. Our results demonstrated an impaired pro-inflammatory cytokine production by spleen cells of MyD88(-/-) mice in response to SEB or SEB plus LPS. Most importantly, MyD88(-/-) mice were resistant to SEB-induced death. These results demonstrate that MyD88-dependent pro-inflammatory signaling is responsible for SEB intoxication. In addition, our studies also demonstrated that LPS potentiation, in comparison to D-galactosamine sensitization, contributes to a stronger SEB-induced lethality. This is due to the pro-inflammatory cytokine response elicited by MyD88 after exposure to SEB and LPS. These findings offer an important insight upon SEB intoxication and subsequent therapy targeting MyD88.

  17. Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

    PubMed Central

    Kong, Eric F.; Tsui, Christina; Nguyen, M. Hong; Clancy, Cornelius J.; Fidel, Paul L.; Noverr, Mairi

    2016-01-01

    Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of Candida albicans, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably, C. albicans infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses. PMID:27430274

  18. RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model.

    PubMed

    Brady, Rebecca A; Bruno, Vincent M; Burns, Drusilla L

    2015-01-01

    Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of

  19. RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model

    PubMed Central

    Brady, Rebecca A.; Bruno, Vincent M.; Burns, Drusilla L.

    2015-01-01

    Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of

  20. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production.

    PubMed

    Helmy, Adel; Carpenter, Keri L H; Menon, David K; Pickard, John D; Hutchinson, Peter J A

    2011-02-01

    The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1β, platelet derived growth factor (PDGF)-AA, MIP1β, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1α, IL1β, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1α, MIP1β, PDGF-AA, transforming growth factor (TGF)α and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI.

  1. Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses

    PubMed Central

    Mayer-Barber, Katrin D; Yan, Bo

    2017-01-01

    Over the past decades the notion of ‘inflammation' has been extended beyond the original hallmarks of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus. We have gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other. PMID:27264686

  2. Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

    NASA Astrophysics Data System (ADS)

    Kewcharoenwong, Chidchamai; Rinchai, Darawan; Utispan, Kusumawadee; Suwannasaen, Duangchan; Bancroft, Gregory J.; Ato, Manabu; Lertmemongkolchai, Ganjana

    2013-11-01

    Type 2 diabetes mellitus is a major risk factor for melioidosis, which is caused by Burkholderia pseudomallei. Our previous study has shown that polymorphonuclear neutrophils (PMNs) from diabetic subjects exhibited decreased functions in response to B. pseudomallei. Here we investigated the mechanisms regulating cytokine secretion of PMNs from diabetic patients which might contribute to patient susceptibility to bacterial infections. Purified PMNs from diabetic patients who had been treated with glibenclamide (an ATP-sensitive potassium channel blocker for anti-diabetes therapy), showed reduction of interleukin (IL)-1β and IL-8 secretion when exposed to B. pseudomallei. Additionally, reduction of these pro-inflammatory cytokines occurred when PMNs from diabetic patients were treated in vitro with glibenclamide. These findings suggest that glibenclamide might be responsible for the increased susceptibility of diabetic patients, with poor glycemic control, to bacterial infections as a result of its effect on reducing IL-1β production by PMNs.

  3. Inflammatory cytokine response to titanium chemical composition and nanoscale calcium phosphate surface modification.

    PubMed

    Hamlet, Stephen; Ivanovski, Saso

    2011-05-01

    Nanoscale surface modification of titanium dental implants with calcium phosphate (CaP) has been shown to achieve superior bone wound healing and osseointegration compared with smooth or microrough titanium surfaces alone. As bone healing has been shown to be influenced by the action of cytokines, this study examined whether changes in cytokine gene expression from RAW 264.7 cells cultured on commercially pure and titanium alloy (Ti-6Al-4V) microrough or nanoscale crystalline CaP-modified surfaces, may influence downstream events in bone wound healing and osseointegration. Whilst no significant difference in the attachment or proliferation of RAW 264.7 cells was observed, the nanoscale CaP-modified surface elicited a gene expression profile with marked down-regulation of a number of pro-inflammatory cytokines and chemokines. Inflammatory cytokine gene expression was further influenced by chemical composition, with lower levels of pro-inflammatory markers noted following exposure of the macrophage-like cells to titanium alloy (Ti-6Al-4V) compared with the commercially pure titanium surface. Down-regulation of pro-inflammatory cytokine gene expression (confirmed at the protein level for TNFα and CCL5), may thus facilitate the enhanced bone wound healing and osseointegration observed clinically with nanoscale calcium phosphate-modified implant surfaces.

  4. Immunomodulation in host-protective immune response against murine tuberculosis through regulation of the T regulatory cell function.

    PubMed

    Das, Shibali; Halder, Kuntal; Goswami, Avranil; Chowdhury, Bidisha Paul; Pal, Nishith K; Majumdar, Subrata

    2015-11-01

    Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is characterized by an infection in lung and spleen. In the present study, we have elucidated the mechanism by which Mycobacterium indicus pranii renders protection in in vivo Mycobacterium tuberculosis infection. We observed that Mycobacterium indicus pranii treated infected C57BL/6 mice showed a strong host-protective Th1 immune response along with a marked decrease in immunosuppressive cytokines, TGF-β, and IL-10-secreting CD4(+) T cells. This Mycobacterium indicus pranii mediated decrease in immunosuppressive cytokines was correlated with the reduction in the elevated frequency of CD4(+)CD25(+) T regulatory cells, along with the reduced TGF-β production from these T regulatory cells in tuberculosis-infected mice. This reduction in the T regulatory cell population was a result of effective modulation of STAT4-STAT5 transcription factor counter-regulation by Mycobacterium indicus pranii, which in turn, reduced the immunosuppressive activity of T regulatory cells. Thus, these findings put forward a detailed mechanistic insight into Mycobacterium indicus pranii mediated regulation of the T regulatory cell functioning during experimental murine tuberculosis, which might be helpful in combating Mycobacterium-induced pathogenesis.

  5. Infection Strategies of Intestinal Parasite Pathogens and Host Cell Responses

    PubMed Central

    Di Genova, Bruno M.; Tonelli, Renata R.

    2016-01-01

    Giardia lamblia, Cryptosporidium sp., and Entamoeba histolytica are important pathogenic intestinal parasites and are amongst the leading causes worldwide of diarrheal illness in humans. Diseases caused by these organisms, giardiasis, cryptosporidiosis, and amoebiasis, respectively, are characterized by self-limited diarrhea but can evolve to long-term complications. The cellular and molecular mechanisms underlying the pathogenesis of diarrhea associated with these three pathogens are being unraveled, with knowledge of both the strategies explored by the parasites to establish infection and the methods evolved by hosts to avoid it. Special attention is being given to molecules participating in parasite–host interaction and in the mechanisms implicated in the diseases’ pathophysiologic processes. This review focuses on cell mechanisms that are modulated during infection, including gene transcription, cytoskeleton rearrangements, signal transduction pathways, and cell death. PMID:26973630

  6. Zinc deficiency alters host response and pathogen virulence in a mouse model of enteroaggregative Escherichia coli-induced diarrhea.

    PubMed

    Bolick, David T; Kolling, Glynis L; Moore, John H; de Oliveira, Luís Antônio; Tung, Kenneth; Philipson, Casandra; Viladomiu, Monica; Hontecillas, Raquel; Bassaganya-Riera, Josep; Guerrant, Richard L

    2014-01-01

    Enteroaggregative Escherichia coli (EAEC) is increasingly recognized as a major cause of diarrheal disease globally. In the current study, we investigated the impact of zinc deficiency on the host and pathogenesis of EAEC. Several outcomes of EAEC infection were investigated including weight loss, EAEC shedding and tissue burden, leukocyte recruitment, intestinal cytokine expression, and virulence expression of the pathogen in vivo. Mice fed a protein source defined zinc deficient diet (dZD) had an 80% reduction of serum zinc and a 50% reduction of zinc in luminal contents of the bowel compared to mice fed a protein source defined control diet (dC). When challenged with EAEC, dZD mice had significantly greater weight loss, stool shedding, mucus production, and, most notably, diarrhea compared to dC mice. Zinc deficient mice had reduced infiltration of leukocytes into the ileum in response to infection suggesting an impaired immune response. Interestingly, expression of several EAEC virulence factors were increased in luminal contents of dZD mice. These data show a dual effect of dietary zinc in benefitting the host while impairing virulence of the pathogen. The study demonstrates the critical importance of zinc and may help elucidate the benefits of zinc supplementation in cases of childhood diarrhea and malnutrition.

  7. The nucleocapsid protein of measles virus blocks host interferon response

    SciTech Connect

    Takayama, Ikuyo; Sato, Hiroki; Watanabe, Akira; Omi-Furutani, Mio; Sugai, Akihiro; Kanki, Keita; Yoneda, Misako; Kai, Chieko

    2012-03-01

    Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN-{alpha}/{beta} and {gamma}-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways.

  8. The host immunological response to cancer therapy: An emerging concept in tumor biology

    SciTech Connect

    Voloshin, Tali; Voest, Emile E.; Shaked, Yuval

    2013-07-01

    Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.

  9. The stressed host response to infection: the disruptive signals and rhythms of systemic inflammation.

    PubMed

    Lowry, Stephen F

    2009-04-01

    The cognate signals from sterile or pathogen-induced sources converge on the same recognition or response pathways. In the surgical patient, a systemic response to infection most often occurs in the context of ongoing inflammatory stress. Such an inflammatory response is modulated initially by the magnitude of injury and by patient-specific (endogenous) factors, such as confounding illness, age, and genetic variation. Over an extended period of stress, treatmentrelated (exogenous) factors add unpredictability to host responses to subsequent challenges, such as acquired infection. The host response is discussed in the context of how existing sterile stressors may modify the response to acquired infection in surgical patients.

  10. Cryptococcus gattii infection dampens Th1 and Th17 responses by attenuating dendritic cell function and pulmonary chemokine expression in the immunocompetent hosts.

    PubMed

    Angkasekwinai, Pornpimon; Sringkarin, Nuntarat; Supasorn, Oratai; Fungkrajai, Madtika; Wang, Yui-Hsi; Chayakulkeeree, Methee; Ngamskulrungroj, Popchai; Angkasekwinai, Nasikarn; Pattanapanyasat, Kovit

    2014-09-01

    Cryptococcal infections are primarily caused by two related fungal species: Cryptococcus neoformans and Cryptococcus gattii. It is well known that C. neoformans generally affects immunocompromised hosts; however, C. gattii infection can cause diseases in not only immunocompromised hosts but also immunocompetent individuals. While recent studies suggest that C. gattii infection could dampen pulmonary neutrophil recruitment and inflammatory cytokine production in immunocompetent hosts, the impact of C. gattii infection on the development of their adaptive T helper cell immune response has not been addressed. Here, we report that C. neoformans infection with highly virulent and less virulent strains preferentially induced pulmonary Th1 and Th17 immune responses in the host, respectively. However, fewer pulmonary Th1 and Th17 cells could be detected in mice infected with C. gattii strains. Notably, dendritic cells (DC) in mice infected with C. gattii expressed much lower levels of surface MHC-II and Il12 or Il23 transcripts and failed to induce effective Th1 and Th17 differentiation in vitro. Furthermore, the expression levels of Ip10 and Cxcl9 transcripts, encoding Th1-attracting chemokines, were significantly reduced in the lungs of mice infected with the highly virulent C. gattii strain. Thus, our data suggest that C. gattii infection dampens the DC-mediated effective Th1/Th17 immune responses and downregulates the pulmonary chemokine expression, thus resulting in the inability to mount protective immunity in immunocompetent hosts.

  11. Cytokines, Chaperones and Neuroinflammatory Responses in Heroin-Related Death: What Can We Learn from Different Patterns of Cellular Expression?

    PubMed Central

    Neri, Margherita; Panata, Laura; Bacci, Mauro; Fiore, Carmela; Riezzo, Irene; Turillazzi, Emanuela; Fineschi, Vittorio

    2013-01-01

    Heroin (3,6-diacetylmorphine) has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of many cell types such as leucocytes and endothelial and glial cells, especially microglia, the predominant immunocompetent cell type within the central nervous system. The aim of this study is to clarify the correlation between intravenous heroin administration in heroin related death and the neuroinflammatory response. We selected 45 cases among autopsies executed for heroin-related death (358 total cases); immunohistochemical studies and Western blotting analyses were used to investigate the expression of brain markers such as tumor necrosis factor-α, oxygen-regulated protein 150, (interleukins) IL-1β, IL-6, IL-8, IL-10, IL-15, cyclooxygenase-2, heat shock protein 70, and CD68 (MAC387). Findings demonstrated that morphine induces inflammatory response and cytokine release. In particular, oxygen-regulated protein 150, cyclooxygenase-2, heat shock protein 70, IL-6 and IL-15 cytokines were over-expressed with different patterns of cellular expression. PMID:24084728

  12. Neisseria lactamica attenuates TLR-1/2-induced cytokine responses in nasopharyngeal epithelial cells using PPAR-γ.

    PubMed

    Tezera, L B; Hampton, J; Jackson, S K; Davenport, V

    2011-04-01

    The upper respiratory tract commensal Neisseria lactamica (Nlac) induces protective humoral immunity against pathogenic Nmen serogroup B (Nmen), but whether it also affords anti-inflammatory mucosal protection, as reported for several gut commensals, has not been investigated. Here we demonstrate for the first time that Nlac weakly induces inflammatory responses compared with Nmen in the nasopharyngeal epithelial cell line, Detroit 562, and that Nlac achieves this by attenuation of secretory cytokine (TNF-α and IL-6) and to a lesser extent chemokine (IL-8 and RANTES) responses. Culture of Detroit cells with Nlac inhibited the induction of cytokine-chemokine mRNA by Nmen, reduced Nmen-induced NF-κβ activity and increased constitutive PPAR-γ protein expression. Pretreatment of Detroit cells with a PPAR-γ antagonist abrogated the attenuation of inflammatory IL-6 by Nlac, as did heat-killing of the organisms and preventing their invasion with cytochalasin D. Inflammatory responses from Detroit cells were readily attenuated by Nlac following stimulation with pathogenic Nmen but more specifically following stimulation with the TLR-1/2 agonist Pam3Cys and pro-inflammatory cytokines (IL-1β, TNF-α) but not LTA or LPS. These results indicate that Nlac plays an important role in suppressing pathogen-induced inflammation in the nasopharyngeal mucosa, mediated through TLR-1/2 stimulation, by activating PPAR-γ and inhibiting NF-κβ activity.

  13. Functional response, host stage preference and interference of two whitefly parasitoids.

    PubMed

    Xu, Hai-Yun; Yang, Nian-Wan; Duan, Min; Wan, Fang-Hao

    2016-02-01

    The functional responses of two parasitoids, Eretmocerus hayati Zolnerowich & Rose and Encarsia sophia Girault & Dodd, of whitefly Bemisia tabaci Gennadius Middle East-Asia Minor 1 were studied under laboratory conditions. In addition, the influence of host density and host stage on the competitive interactions between the two parasitoids, and biological control effect on whitefly were evaluated. In the functional response study, adult parasitoids were tested individually, with a conspecific or heterospecific competitor. Both Er. hayati and En. sophia exhibited a type II response to increasing host density, whether a conspecific or heterospecific competitor was present or not. Difference of searching rates and handling times between treatments suggested interference interactions existed between two parasitoid species. In the host stage preference study, two parasitoid species were jointly tested. Er. hayati had a competitive advantage over En. sophia when provided young host instars (first and second instar), whereas no advantage was found on old host instars (third and fourth instar). The biological control effect of Er. hayati and En. sophia in different introductions varied with host density. However, the effect of host instar on host mortality was not significant. These findings provide information for the practice of biological control and give better insight into how parasitoid species may coexist in diverse environments.

  14. Cytokines as a predictor of clinical response following hip arthroscopy: minimum 2-year follow-up

    PubMed Central

    Shapiro, Lauren M.; Safran, Marc R.; Maloney, William J.; Goodman, Stuart B.; Huddleston, James I.; Bellino, Michael J.; Scuderi, Gaetano J.; Abrams, Geoffrey D.

    2016-01-01

    Hip arthroscopy in patients with osteoarthritis has been shown to have suboptimal outcomes. Elevated cytokine concentrations in hip synovial fluid have previously been shown to be associated with cartilage pathology. The purpose of this study was to determine whether a relationship exists between hip synovial fluid cytokine concentration and clinical outcomes at a minimum of 2 years following hip arthroscopy. Seventeen patients without radiographic evidence of osteoarthritis had synovial fluid aspirated at time of portal establishment during hip arthroscopy. Analytes included fibronectin–aggrecan complex as well as a multiplex cytokine array. Patients completed the modified Harris Hip Score, Western Ontario and McMaster Universities Arthritis Index and the International Hip Outcomes Tool pre-operatively and at a minimum of 2 years following surgery. Pre and post-operative scores were compared with a paired t-test, and the association between cytokine values and clinical outcome scores was performed with Pearson’s correlation coefficient with an alpha value of 0.05 set as significant. Sixteen of seventeen patients completed 2-year follow-up questionnaires (94%). There was a significant increase in pre-operative to post-operative score for each clinical outcome measure. No statistically significant correlation was seen between any of the intra-operative cytokine values and either the 2-year follow-up scores or the change from pre-operative to final follow-up outcome values. No statistically significant associations were seen between hip synovial fluid cytokine concentrations and 2-year follow-up clinical outcome assessment scores for those undergoing hip arthroscopy. PMID:27583163

  15. What Is a Host? Incorporating the Microbiota into the Damage-Response Framework

    PubMed Central

    Pirofski, Liise-anne

    2014-01-01

    Since proof of the germ theory of disease in the late 19th century, a major focus of the fields of microbiology and infectious diseases has been to seek differences between pathogenic and nonpathogenic microbes and the role that the host plays in microbial pathogenesis. Remarkably, despite the increasing recognition that host immunity plays a role in microbial pathogenesis, there has been little discussion about what constitutes a host. Historically, hosts have been viewed in the context of their fitness or immunological status and characterized by adjectives such as immune, immunocompetent, immunosuppressed, immunocompromised, or immunologically impaired. However, in recent years it has become apparent that the microbiota has profound effects on host homeostasis and susceptibility to microbial diseases in addition to its effects on host immunity. This raises the question of how to incorporate the microbiota into defining a host. This definitional problem is further complicated because neither host nor microbial properties are adequate to predict the outcome of host-microbe interaction because this outcome exhibits emergent properties. In this essay, we revisit the damage-response framework (DRF) of microbial pathogenesis and demonstrate how it can incorporate the rapidly accumulating information being generated by the microbiome revolution. We use the tenets of the DRF to put forth the following definition of a host: a host is an entity that houses an associated microbiome/microbiota and interacts with microbes such that the outcome results in damage, benefit, or indifference, thus resulting in the states of symbiosis, colonization, commensalism, latency, and disease. PMID:25385796

  16. Hybridization in endophyte symbionts alters host response to moisture and nutrient treatments.

    PubMed

    Hamilton, Cyd E; Dowling, Thomas E; Faeth, Stanley H

    2010-05-01

    When a host organism is infected by a symbiont, the resulting symbiotum has a phenotype distinct from uninfected hosts. Genotypic interactions between the partners may increase phenotypic variation of the host at the population level. Neotyphodium is an asexual, vertically transmitted endophytic symbiont of grasses often existing in hybrid form. Hybridization in Neotyphodium rapidly increases the symbiotum's genomic content and is likely to increase the phenotypic variation of the host. This phenotypic variation is predicted to enhance host performance, especially in stressful environments. We tested this hypothesis by comparing the growth, survival, and resource allocation of hybrid and nonhybrid infected host plants exposed to controlled variation in soil moisture and nutrients. Infection by a hybrid endophyte did not fit our predictions of comparatively higher root and total biomass production under low moisture/low nutrient treatments. Regardless of whether the host was infected by a hybrid or nonhybrid endophyte, both produced significantly higher root/total biomass when both nutrient and moisture were high compared to limited nutrient/moisture treatments. However, infection by hybrid Neotyphodium did result in significantly higher total biomass and host survival compared to nonhybrid infected hosts, regardless of treatment. Endophyte hybridization alters host strategies in response to stress by increasing survival in depauperate habitats and thus, potentially increasing the relative long-term host fitness.

  17. Cytokine responses to Mycobacterium leprae unique proteins differentiate between Mycobacterium leprae infected and naive armadillos.

    PubMed

    Pena, Maria; Geluk, Annemieke; Van Der Ploeg-Van Schip, Jolien J; Franken, Kees L M C; Sharma, Rahul; Truman, Richard

    2011-12-01

    New diagnostic tools for early detection of leprosy are necessary to help reduce its transmission and severity. M. leprae unique proteins have been used to assess differences in human T-cell responses in leprosy patients, household contacts and endemic controls. In this study, we examined the response of M. leprae-infected armadillos to a variety of M. leprae recombinant antigen candidates currently being examined for diagnostic efficacy in humans. Among recently M. leprae infected armadillos, IFN-gamma expression was enhanced after stimulation of PBMC with all M. leprae recombinant proteins except for ML2283 (mean: 2.65 Relative Quantification (RQ)). The group mean stimulation index for M. leprae proteins ML0009, ML1601, ML2478 and ML2531 averaged 35.2 RQ and was significantly higher (P < 0.05) than that measured among the non-infected, naive group (mean 6.2 RQ). Although ML0840 tended to enhance IFN-gamma levels, the mean IFN-gamma transcript levels of the currently experimentally inoculated group (20.1 RQ) was not significantly different statistically (P = 0.10) from the mean of the naive group (7.5 RQ). Also no statistically significant differences were observed in IFN-gamma transcript levels between the resistant and currently experimentally inoculated group (P > 0.05) or between the resistant and the naive group (P > 0.05) after stimulation of PBMCs with all M. leprae recombinant proteins. Only low levels of TNF-alpha were observed across all groups after in vitro stimulation with all the antigens examined. These data suggest that armadillos can be used effectively to help identify M. leprae specific proteins that may be applied for monitoring T-cell responses in M. leprae infected hosts as their disease progresses as well as for the early diagnosis of leprosy.

  18. Targeting multiple response regulators of Mycobacterium tuberculosis augments the host immune response to infection

    PubMed Central

    Banerjee, Srijon Kaushik; Kumar, Manish; Alokam, Reshma; Sharma, Arun Kumar; Chatterjee, Ayan; Kumar, Ranjeet; Sahu, Sanjaya Kumar; Jana, Kuladip; Singh, Ramandeep; Yogeeswari, Perumal; Sriram, Dharmarajan; Basu, Joyoti; Kundu, Manikuntala

    2016-01-01

    The genome of M. tuberculosis (Mtb) encodes eleven paired two component systems (TCSs) consisting of a sensor kinase (SK) and a response regulator (RR). The SKs sense environmental signals triggering RR-dependent gene expression pathways that enable the bacterium to adapt in the host milieu. We demonstrate that a conserved motif present in the C-terminal domain regulates the DNA binding functions of the OmpR family of Mtb RRs. Molecular docking studies against this motif helped to identify two molecules with a thiazolidine scaffold capable of targeting multiple RRs, and modulating their regulons to attenuate bacterial replication in macrophages. The changes in the bacterial transcriptome extended to an altered immune response with increased autophagy and NO production, leading to compromised survival of Mtb in macrophages. Our findings underscore the promise of targeting multiple RRs as a novel yet unexplored approach for development of new anti-mycobacterial agents particularly against drug-resistant Mtb. PMID:27181265

  19. Cytokine & chemokine response in the lungs, pleural fluid and serum in thoracic surgery using one-lung ventilation

    PubMed Central

    2011-01-01

    Background Thoracic surgery mandates usually a one-lung ventilation (OLV) strategy with the collapse of the operated lung and ventilation of the non-operated lung. These procedures trigger a substantial inflammatory response. The aim of this study was to analyze the cytokine and chemokine reaction in both lungs, pleural space and blood in patients undergoing lung resection with OLV with special interest in the chemokine growth-regulated peptide alpha (GROα) which is the human equivalent to the rat cytokine-induced neutrophil chemoattractant-1 (CINC-1). Methods Broncho-alveolar lavage (BAL) fluid of both the collapsed, operated and the ventilated, non-operated lung, respectively, pleural space drainage fluid and blood was collected and the concentrations of interleukin (IL)-6, IL-1RA and GROα were determined with enzyme-linked immunosorbent assays in 15 patients. Results Substantial inter-individual differences in the BAL fluid between patients in cytokine and chemokine levels occurred. In the pleural fluid and the blood these inter-individual differences were less pronounced. Both sides of the lung were affected and showed a significant increase in IL-6 and IL-1RA concentrations over time but not in GROα concentrations. Except for IL-6, which increased more in the collapsed, operated lung, no difference between the collapsed, operated and the ventilated, non-operated lung occurred. In the blood, IL-6 and IL-1RA increased early, already at the end of surgery. GROα was not detectable. In the pleural fluid, both cytokine and chemokine concentrations increased by day one. The increase was significantly higher in the pleural fluid compared to the blood. Conclusion The inflammatory response of cytokines affects both the collapsed, operated and the ventilated, non-operated lungs. The difference in extent of response underlines the complexity of the inflammatory processes during OLV. In contrast to the cytokines, the chemokine GROα concentrations did not react in the

  20. Short communication: Cytokine profiles from blood mononuclear cells of dairy cows classified with divergent immune response phenotypes.

    PubMed

    Martin, C E; Paibomesai, M A; Emam, S M; Gallienne, J; Hine, B C; Thompson-Crispi, K A; Mallard, B A

    2016-03-01

    Genetic selection for enhanced immune response has been shown to decrease disease occurrence in dairy cattle. Cows can be classified as high (H), average, or low responders based on antibody-mediated immune response (AMIR), predominated by type-2 cytokine production, and cell-mediated immune response (CMIR) through estimated breeding values for these traits. The purpose of this study was to identify in vitro tests that correlate with in vivo immune response phenotyping in dairy cattle. Blood mononuclear cells (BMC) isolated from cows classified as H-AMIR and H-CMIR through estimated breeding values for immune response traits were stimulated with concanavalin A (ConA; Sigma Aldrich, St. Louis, MO) and gene expression, cytokine production, and cell proliferation was determined at multiple time points. A repeated measures model, which included the effects of immune response group, parity, and stage of lactation, was used to compare differences between immune response phenotype groups. The H-AMIR cows produced more IL-4 protein than H-CMIR cows at 48 h; however, no difference in gene expression of type-2 transcription factor GATA3 or IL4 was noted. The BMC from H-CMIR cows had increased production of IFN-γ protein at 48, 72, and 96 h compared with H-AMIR animals. Further, H-CMIR cows had increased expression of the IFNG gene at 16, 24, and 48 h post-treatment with ConA, although expression of the type-1 transcription factor gene TBX21 did not differ between immune response groups. Although proliferation of BMC increased from 24 to 72 h after ConA stimulation, no differences were found between the immune response groups. Overall, stimulation of H-AMIR and H-CMIR bovine BMC with ConA resulted in distinct cytokine production profiles according to genetically defined groups. These distinct cytokine profiles could be used to define disease resistance phenotypes in dairy cows according to stimulation in vitro; however, other immune response phenotypes should be assessed.

  1. Delivery of cytokines by recombinant virus in early life alters the immune response to adult lung infection.

    PubMed

    Harker, James A; Lee, Debbie C P; Yamaguchi, Yuko; Wang, Belinda; Bukreyev, Alexander; Collins, Peter L; Tregoning, John S; Openshaw, Peter J M

    2010-05-01

    Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, the major cause of hospitalization of infants. An ideal RSV vaccine would be effective for neonates, but the immune responses of infants differ markedly from those of adults, often showing a bias toward T-helper 2 (Th2) responses and reduced gamma interferon (IFN-gamma) production. We previously developed recombinant RSV vectors expressing IFN-gamma and interleukin-4 (IL-4) that allow us to explore the role of these key Th1 and Th2 cytokines during infection. The aim of the current study was to explore whether an immunomodulation of infant responses could enhance protection. The expression of IFN-gamma by a recombinant RSV vector (RSV/IFN-gamma) attenuated primary viral replication in newborn mice without affecting the development of specific antibody or T-cell responses. Upon challenge, RSV/IFN-gamma mice were protected from the exacerbated disease observed for mice primed with wild-type RSV; however, antiviral immunity was not enhanced. Conversely, the expression of IL-4 by recombinant RSV did not affect virus replication in neonates but greatly enhanced Th2 immune responses upon challenge without affecting weight loss. These studies demonstrate that it is possible to manipulate infant immune responses by using cytokine-expressing recombinant viruses and that neonatal deficiency in IFN-gamma responses may lead to enhanced disease during secondary infection.

  2. Micro array analysis of the intestinal host response in Giardia duodenalis assemblage E infected cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Giardia duodenalis is one of the most commonly found intestinal pathogens in humans and animals. However, little is known about the host-parasite interaction in its natural hosts. The objective of this study was to investigate the intestinal response in calves following a G. duodenalis infection, us...

  3. Paeoniflorin inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response and cytokine secretion.

    PubMed

    Zhao, Jingxia; Di, Tingting; Wang, Yan; Wang, Ying; Liu, Xin; Liang, Daiying; Li, Ping

    2016-02-05

    Paeoniflorin (PF) is the main active ingredients of radix paeoniae rubra and radix paeoniae alba, which are used widely in Traditional Chinese Medicine. This study aimed to assess the capacity of PF to inhibit imiquimod (IMQ)-induced psoriasis. Mice treated with IMQ were divided into four groups and administered 240mg/kg/day or 120mg/kg/day of PF, 1mg/kg/day of methotrexate (MTX), or normal saline intragastrically. Weight-matched mice treated with vaseline were used as controls. Morphology, structural features, keratinocyte proliferation and differentiation, inflammatory cell infiltration, levels of Th1/Th2/Th17/Treg cytokine mRNA, and phosphorylation of Th17 differentiation-related proteins were assessed. Mouse spleen cells were incubated under Th17 polarizing conditions, then with PF (2, 20, and 200μg/ml) and cell viability, Th17 differentiation, and Th17 cytokines and the orphan nuclear receptor (RORγt) mRNA levels were assessed. PF alleviated IMQ-induced keratinocyte proliferation and inflammatory cell infiltration, and reduced mRNA levels of Th17 cytokines at day 4 and phosphorylation of Th17 differentiation-related proteins. However, 2, 20, or 200μg/ml PF did not affect spleen cell viability, and 2 and 20μg/ml PF reduced IL-17 secretion under Th17 polarizing conditions. Finally, 2 and 20μg/ml PF inhibited mRNA expression of Th17 cytokines and phosphorylation of Stat3 in spleen cells under Th17 polarizing conditions. These results suggest that PF inhibits IMQ-induced psoriasis by regulating Th17 cell response and cytokine secretion via phosphorylation of Stat3.

  4. Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse.

    PubMed

    Hasegawa-Ishii, Sanae; Takei, Shiro; Inaba, Muneo; Umegaki, Hiroyuki; Chiba, Yoichi; Furukawa, Ayako; Kawamura, Noriko; Hosokawa, Masanori; Shimada, Atsuyoshi

    2011-01-01

    Aging is a result of damage accumulation, and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) has been established as an inbred strain exhibiting accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescence-resistant control (SAMR1) strain. We hypothesized that tissue-protective responses of glial cells are impaired in SAMP10 mice. We injected kainic acid (KA) to induce hippocampal injury and studied how cytokines were upregulated on Day 3 using 3-month-old SAMP10 and SAMR1 mice. Following microarray-based screening for upregulated genes, we performed real-time RT-PCR and immunohistochemistry. Results indicated well-orchestrated cytokine-mediated glial interactions in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon (IFN)-γ stimulated astrocytes via IFN-γ receptor and thereby induced expression of CXCL10 and macrophage inflammatory protein (MIP)-1α, and activated microglia produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and osteopontin (OPN). OPN was the most strongly upregulated cytokine. CD44, an OPN receptor, was also strongly upregulated in the neuropil, especially on neurons and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice compared to SAMR1 mice. On Day 30 after KA injection, SAMP10 but not SAMR1 mice exhibited hippocampal layer atrophy. Since the OPN-CD44 system is essential for neuroprotection and remodeling, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration.

  5. Mce4A protein of Mycobacterium tuberculosis induces pro inflammatory cytokine response leading to macrophage apoptosis in a TNF-α dependent manner.

    PubMed

    Saini, Neeraj Kumar; Sinha, Rajesh; Singh, Pooja; Sharma, Monika; Pathak, Rakesh; Rathor, Nisha; Varma-Basil, Mandira; Bose, Mridula

    2016-11-01

    Mycobacterium tuberculosis subverts the host immune response through numerous immune-evasion strategies. Apoptosis has been identified as one such mechanism and has been well studied in M. tuberculosis infection. Here, we demonstrate that the Mce4A protein of mce4 operon is involved in the induction of host cell apoptosis. Earlier we have shown that the Mce4A was required for the invasion and survival of M. tuberculosis. In this report we present evidence to establish a role for Mce4A in the modulation of THP-1 cell survival. Recombinant Mce4A was expressed and purified from Escherichia coli as inclusion bodies and then refolded. Viability of THP-1 cells decreased in a dose-dependent manner when treated with Mce4A. The secretion of pro-inflammatory cytokines like tumor necrosis factor (TNF-α) or interferon gamma (IFN-γ), and enhanced nitric oxide release was observed when the THP-1 cells, were treated with Mce4A protein. The Mce4A induced apoptosis of the THP-1 cells was TNF-α dependent since blocking with anti TNF-α antibody abrogated this phenomenon. Collectively, these data suggest that Mce4A can induce the THP-1 cells to undergo apoptosis which primarily follows a TNF- α dependent pathway.

  6. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

  7. Host Response to Staphylococcus epidermidis Colonization and Infections

    PubMed Central

    Nguyen, Thuan H.; Park, Matthew D.; Otto, Michael

    2017-01-01

    The majority of research in the Staphylococcus field has been dedicated to the understanding of Staphylococcus aureus infections. In contrast, there is limited information on infections by coagulase-negative Staphylococci (CoNS) and how the host responds to them. S. epidermidis, a member of the coagulase-negative Staphylococci, is an important commensal organism of the human skin and mucous membranes; and there is emerging evidence of its benefit for human health in fighting off harmful microorganisms. However, S. epidermidis can cause opportunistic infections, which include particularly biofilm-associated infections on indwelling medical devices. These often can disseminate into the bloodstream; and in fact, S. epidermidis is the most frequent cause of nosocomial sepsis. The increasing use of medical implants and the dramatic shift in the patient demographic population in recent years have contributed significantly to the rise of S. epidermidis infections. Furthermore, treatment has been complicated by the emergence of antibiotic-resistant strains. Today, S. epidermidis is a major nosocomial pathogen posing significant medical and economic burdens. In this review, we present the current understanding of mechanisms of host defense against the prototypical CoNS species S. epidermidis as a commensal of the skin and mucous membranes, and during biofilm-associated infection and sepsis. PMID:28377905

  8. Host response to infection of a subperiosteal hydroxylapatite implant.

    PubMed

    Reznick, J B; Gilmore, W C

    1989-06-01

    Particulate, nonresorbable hydroxylapatite is currently a popular implant material for the augmentation of atrophic alveolar ridges. Most reports have demonstrated favorable biocompatibility with common usage, but how the host bone will respond to the implant in the presence of an infection has not yet been investigated. Hydroxylapatite was implanted subperiosteally on one side of the mandible in four New Zealand White rabbits. After 3 months were allowed to elapse for stabilization of the implant, an infection was induced in both sides of each mandible by inoculation with Bacteroides melaninogenicus. One month later the animals were put to death and both sides of each mandible were examined microscopically. On the nonaugmented side there was total resolution of the infection. The side of each mandible containing the hydroxylapatite implant showed very mild chronic inflammation throughout the medullary space and periosteum. Although the number of animals used was small, the results suggest that the presence of the hydroxylapatite implant may have interfered with the host's ability to resolve the infection in the underlying bone. The possible mechanism of this interference is discussed.

  9. Immunotoxicity of aflatoxin B1: Impairment of the cell-mediated response to vaccine antigen and modulation of cytokine expression

    SciTech Connect

    Meissonnier, Guylaine M.; Pinton, Philippe; Laffitte, Joelle; Cossalter, Anne-Marie; Gong, Yun Yun; Wild, Christopher P.; Bertin, Gerard; Galtier, Pierre; Oswald, Isabelle P.

    2008-09-01

    Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus or A. parasiticus, is a frequent contaminant of food and feed. This toxin is hepatotoxic and immunotoxic. The present study analyzed in pigs the influence of AFB1 on humoral and cellular responses, and investigated whether the immunomodulation observed is produced through interference with cytokine expression. For 28 days, pigs were fed a control diet or a diet contaminated with 385, 867 or 1807 {mu}g pure AFB1/kg feed. At days 4 and 15, pigs were vaccinated with ovalbumin. AFB1 exposure, confirmed by an observed dose-response in blood aflatoxin-albumin adduct, had no major effect on humoral immunity as measured by plasma concentrations of total IgA, IgG and IgM and of anti-ovalbumin IgG. Toxin exposure did not impair the mitogenic response of lymphocytes but delayed and decreased their specific proliferation in response to the vaccine antigen, suggesting impaired lymphocyte activation in pigs exposed to AFB1. The expression level of pro-inflammatory (TNF-{alpha}, IL-1{beta}, IL-6, IFN-{gamma}) and regulatory (IL-10) cytokines was assessed by real-time PCR in spleen. A significant up-regulation of all 5 cytokines was observed in spleen from pigs exposed to the highest dose of AFB1. In pigs exposed to the medium dose, IL-6 expression was increased and a trend towards increased IFN-{gamma} and IL-10 was observed. In addition we demonstrate that IL-6 impaired in vitro the antigenic- but not the mitogenic-induced proliferation of lymphocytes from control pigs vaccinated with ovalbumin. These results indicate that AFB1 dietary exposure decreases cell-mediated immunity while inducing an inflammatory response. These impairments in the immune response could participate in failure of vaccination protocols and increased susceptibility to infections described in pigs exposed to AFB1.

  10. Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-α responses.

    PubMed

    Collins, Aideen S; Ahmed, Suaad; Napoletano, Silvia; Schroeder, Martina; Johnston, James A; Hegarty, John E; O'Farrelly, Cliona; Stevenson, Nigel J

    2014-08-01

    TNF-α is a proinflammatory cytokine, dramatically elevated during pathogenic infection and often responsible for inflammation-induced disease pathology. SOCS proteins are inhibitors of cytokine signaling and regulators of inflammation. In this study, we found that both SOCS1 and SOCS3 were transiently induced by TNF-α and negatively regulate its NF-κB-mediated signal transduction. We discovered that PBMCs from HCV-infected patients have elevated endogenous SOCS3 expression but less TNF-α-mediated IκB degradation and proinflammatory cytokine production than healthy controls. HCV protein expression in Huh7 hepatocytes also induced SOCS3 and directly inhibited TNF-α-mediated IL-8 production. Furthermore, we found that SOCS3 associates with TRAF2 and inhibits TRAF2-mediated NF-κB promoter activity, suggesting a mechanism by which SOCS3 inhibits TNF-α-mediated signaling. These results demonstrate a role for SOCS3 in regulating proinflammatory TNF-α signal transduction and reveal a novel immune-modulatory mechanism by which HCV suppresses inflammatory responses in primary immune cells and hepatocytes, perhaps explaining mild pathology often associated with acute HCV infection.

  11. SARM is required for neuronal injury and cytokine production in response to central nervous system viral infection.

    PubMed

    Hou, Ying-Ju; Banerjee, Rebecca; Thomas, Bobby; Nathan, Carl; García-Sastre, Adolfo; Ding, Aihao; Uccellini, Melissa B

    2013-07-15

    Four of the five members of the Toll/IL-1R domain-containing adaptor family are required for signaling downstream of TLRs, promoting innate immune responses against different pathogens. However, the role of the fifth member of this family, sterile α and Toll/IL-1R domain-containing 1 (SARM), is unclear. SARM is expressed primarily in the CNS where it is required for axonal death. Studies in Caenorhabditis elegans have also shown a role for SARM in innate immunity. To clarify the role of mammalian SARM in innate immunity, we infected SARM(-/-) mice with a number of bacterial and viral pathogens. SARM(-/-) mice show normal responses to Listeria monocytogenes, Mycobacterium tuberculosis, and influenza virus, but show dramatic protection from death after CNS infection with vesicular stomatitis virus. Protection correlates with reduced CNS injury and cytokine production by nonhematopoietic cells, suggesting that SARM is a positive regulator of cytokine production. Neurons and microglia are the predominant source of cytokines in vivo, supporting a role for SARM as a link between neuronal injury and innate immunity.

  12. MEASURING THERAPEUTIC RESPONSE IN CHRONIC GRAFT-VERSUS-HOST DISEASE

    PubMed Central

    Lee, Stephanie J.; Wolff, Daniel; Kitko, Carrie; Koreth, John; Inamoto, Yoshihiro; Jagasia, Madan; Pidala, Joseph; Olivieri, Attilio; Martin, Paul J.; Przepiorka, Donna; Pusic, Iskra; Dignan, Fiona; Mitchell, Sandra A.; Lawitschka, Anita; Jacobsohn, David; Hall, Anne M.; Flowers, Mary E.D.; Schultz, Kirk R.; Vogelsang, Georgia; Pavletic, Steven

    2016-01-01

    In 2005, the NIH Chronic GVHD Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last nine years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. PMID:25796139

  13. Correlation between TH1 response standard cytokines as biomarkers in patients with the delta virus in the western Brazilian Amazon

    PubMed Central

    Nicolete, Larissa Deadame de Figueiredo; Borzacov, Lourdes Maria Pinheiro; Vieira, Deusilene Souza; Nicolete, Roberto; Salcedo, Juan Miguel Villalobos

    2016-01-01

    Hepatitis D virus (HDV) is endemic in the Amazon Region and its pathophysiology is the most severe among viral hepatitis. Treatment is performed with pegylated interferon and the immune response appears to be important for infection control. HDV patients were studied: untreated and polymerase chain reaction (PCR) positive (n = 9), anti-HDV positive and PCR negative (n = 8), and responders to treatment (n = 12). The cytokines, interleukin (IL)-2 (p = 0.0008) and IL-12 (p = 0.02) were differentially expressed among the groups and were also correlated (p = 0.0143). Future studies will be conducted with patients at different stages of treatment, associating the viral load with serum cytokines produced, thereby attempting to establish a prognostic indicator of the infection. PMID:27074258

  14. Coxiella Burnetii: Host and Bacterial Responses to Infection

    DTIC Science & Technology

    2007-10-16

    investigations into Rocky Mountain spotted fever . Allowing the ticks to feed on guinea pigs resulted in a febrile response [2] and their inflammatory...Introduction .1. History Q fever was first observed in Australia in 1933 as a dis...bacterial response to infection. This review is ntended to provide a basic introduction to C. burnetii and Q fever , while emphasizing immunomodulatory

  15. The Host Immune Response to Streptococcus pneumoniae: Bridging Innate and Adaptive Immunity

    DTIC Science & Technology

    2006-07-06

    caused by penicillin -resistant Streptococcus pneumoniae in rabbits. Antimicrob. Agents Chemother. 46: 1760- 1765. Takeuchi, O., Hoshino, K., and...2006 2. REPORT TYPE 3. DATES COVERED 00-00-2006 to 00-00-2006 4. TITLE AND SUBTITLE The host immune response to Streptococcus pneumoniae ...host immune response to Streptococcus pneumoniae : bridging innate and adaptive immunity Katherine Shi-Hui Lee Thesis directed by: Clifford M

  16. Genomic profiling of host responses to Lassa virus: therapeutic potential from primate to man

    PubMed Central

    Zapata, Juan C; Salvato, Maria S

    2015-01-01

    Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for disease. In addition to assessing mRNA changes, functional studies are also needed to discriminate causes of disease from mechanisms of host resistance. Host responses that drive pathogenesis are likely to be targets for prevention or therapy. Host responses to Lassa or its related arenaviruses have been monitored in cell culture, in animal models of hemorrhagic fever, in Lassa-infected nonhuman primates and, to a limited extent, in infected human beings. Here, we describe results from those studies and discuss potential targets for reducing virus replication and mitigating disease. PMID:25844088

  17. Genomic profiling of host responses to Lassa virus: therapeutic potential from primate to man.

    PubMed

    Zapata, Juan C; Salvato, Maria S

    2015-03-13

    Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for disease. In addition to assessing mRNA changes, functional studies are also needed to discriminate causes of disease from mechanisms of host resistance. Host responses that drive pathogenesis are likely to be targets for prevention or therapy. Host responses to Lassa or its related arenaviruses have been monitored in cell culture, in animal models of hemorrhagic fever, in Lassa-infected nonhuman primates and, to a limited extent, in infected human beings. Here, we describe results from those studies and discuss potential targets for reducing virus replication and mitigating disease.

  18. Behavioral Strategies of Phorid Parasitoids and Responses of Their Hosts, the Leaf-Cutting Ants

    PubMed Central

    Elizalde, Luciana; Folgarait, Patricia Julia

    2012-01-01

    Host-searching and oviposition behaviors of parasitoids, and defensive responses of the hosts, are fundamental in shaping the ecology of host-parasitoid interactions. In order to uncover key behavioral features for the little known interactions between phorid parasitoids (Diptera: Phoridae) and their leaf-cutting ant hosts (Formicidae: Attini), host-related behavioral strategies (i.e., host searching and oviposition) for 13 phorid species, and host defensive responses (i.e., hitchhikers and particular body postures) for 11 ant species, were studied. Data was collected at 14 localities, one of them characterized by its high species richness for this host-parasitoid system. Phorid species showed both great variation and specificity in attacking behaviors. Some chose their hosts using either an ambush or an actively searching strategy, while some species attacked ants on different body parts, and specialized on ants performing different tasks, such as when ants were foraging, removing wastes to refuse piles, or repairing the nest. Combining all the behaviors recorded, most phorid species differed in performance in at least one, making it possible to recognize species in the field through their behavior. Phorid species that attacked hosts with greater activity levels showed overall higher attack rates, although there was no significant correlation between attack rates by most phorid species and ant activity outside the nest while parasitoids were attacking. The presence of phorids was a significant determinant for the presence of defensive behaviors by the ants. Although ant species varied in the incidence levels of these defensive behaviors, most ant species reacted against different phorids by utilizing similar behaviors, in contrast to what parasitoids do. General features of the observed phorid-ant interactions were parasitoid specialization and corresponding high interspecific variation in their behaviors, while their hosts showed generalized responses to attacks

  19. Desensitized morphological and cytokine response after stretch-shortening muscle contractions as a feature of aging in rats.

    PubMed

    Rader, Erik P; Layner, Kayla N; Triscuit, Alyssa M; Kashon, Michael L; Gu, Ja K; Ensey, James; Baker, Brent A

    2015-12-01

    Recovery from contraction-induced injury is impaired with aging. At a young age, the secondary response several days following contraction-induced injury consists of edema, inflammatory cell infiltration, and segmental muscle fiber degeneration to aid in the clearance of damaged tissue and repair. This morphological response has not been wholly established at advanced age. Our aim was to characterize muscle fiber morphology 3 and 10 days following stretch-shortening contractions (SSCs) varying in repetition number (i.e. 0, 30, 80, and 150) for young and old rats. For muscles of young rats, muscle fiber degeneration was overt at 3 days exclusively after 80 or 150 SSCs and returned significantly closer to control values by 10 days. For muscles of old rats, no such responses were observed. Transcriptional microarray analysis at 3 days demonstrated that muscles of young rats differentially expressed up to 2144 genes while muscles of old rats differentially expressed 47 genes. Bioinformatic analysis indicated that cellular movement was a major biological process over-represented with genes that were significantly altered by SSCs especially for young rats. Protein levels in muscle for various cytokines and chemokines, key inflammatory factors for cell movement, increased 3- to 50-fold following high-repetition SSCs for young rats with no change for old rats. This age-related differential response was insightful given that for control (i.e. 0 SSCs) conditions, protein levels of circulatory cytokines/chemokines were increased with age. The results demonstrate ongoing systemic low-grade inflammatory signaling and subsequent desensitization of the cytokine/chemokine and morphological response to contraction-induced injury with aging - features which accompany age-related impairment in muscle recovery.

  20. Interaction between Campylobacter and intestinal epithelial cells leads to a different proinflammatory response in human and porcine host.

    PubMed

    Aguilar, Carmen; Jiménez-Marín, Ángeles; Martins, Rodrigo Prado; Garrido, Juan J

    2014-11-15

    Campylobacter jejuni and Campylobacter coli are recognized as the leading causes of human diarrheal disease throughout the development world. Unlike human beings, gastrointestinal tract of pigs are frequently colonized by Campylobacter to a high level in a commensal manner. The aim of this study was to identify the differences underlying the divergent outcome following Campylobacter challenge in porcine versus human host. In order to address this, a comparative in vitro infection model was combined with microscopy, gentamicin protection assay, ELISA and quantitative PCR techniques. Invasion assays revealed that Campylobacter invaded human cells up to 10-fold more than porcine cells (p<0.05). In addition, gene expression of proinflammatory genes encoding for IL1α, IL6, IL8, CXCL2 and CCL20 were strongly up-regulated by Campylobacter in human epithelial cell at early times of infection, whereas a very reduced cytokine gene expression was detected in porcine epithelial cells. These data indicate that Campylobacter fails to invade porcine cells compared to human cells, and this leads to a lack of proinflammatory response induction, probably due to its pathogenic or commensal behavior in human and porcine host, respectively.

  1. Host Immune Responses That Promote Initial HIV Spread

    DTIC Science & Technology

    2011-07-01

    antiviral activity that vaccines and early interventions seek to exploit/enhance. However the response is dependent on CD4+ T-helper cell 1 (Th1... vaccines and early interventions seek to exploit/enhance. However, the response is dependent on CD4+ T-helper cell 1 (Th1) recruitment and activation...exposure to virus and peak viremia. The vaginal mucosa is the most common site of infection and vaccine strategies focus mainly on promoting

  2. Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection

    PubMed Central

    2010-01-01

    Background An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. Methods Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. Results The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-γ response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-γ production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. Conclusions The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status. PMID:20546583

  3. Individual Members of the Microbiota Disproportionately Modulate Host Innate Immune Responses.

    PubMed

    Rolig, Annah S; Parthasarathy, Raghuveer; Burns, Adam R; Bohannan, Brendan J M; Guillemin, Karen

    2015-11-11

    Predicting host health status based on microbial community structure is a major goal of microbiome research. An implicit assumption of microbiome profiling for diagnostic purposes is that the proportional representation of different taxa determine host phenotypes. To test this assumption, we colonized gnotobiotic zebrafish with zebrafish-derived bacterial isolates and measured bacterial abundance and host neutrophil responses. Surprisingly, combinations of bacteria elicited immune responses that do not reflect the numerically dominant species. These data are consistent with a quantitative model in which the host responses to commensal species are additive but where various species have different per capita immunostimulatory effects. For example, one species has a high per capita immunosuppression that is mediated through a potent secreted factor. We conclude that the proportional representation of bacteria in a community does not necessarily predict its functional capacities; however, characterizing specific properties of individual species offers predictive insights into multi-species community function.

  4. Differential Expression of Inflammatory Cytokines and Stress Genes in Male and Female Mice in Response to a Lipopolysaccharide Challenge

    PubMed Central

    Everhardt Queen, Ashleigh; Moerdyk-Schauwecker, Megan; McKee, Leslie M.; Leamy, Larry J.

    2016-01-01

    Background Sex plays a key role in an individual’s immune response against pathogenic challenges such that females fare better when infected with certain pathogens. It is thought that sex hormones impact gene expression in immune cells and lead to sexually dimorphic responses to pathogens. We predicted that, in the presence of E. coli gram-negative lipopolysaccharide (LPS), there would be a sexually dimorphic response in proinflammatory cytokine production and acute phase stress gene expression and that these responses might vary among different mouse strains and times in a pattern opposite to that of body temperature associated with LPS-induced shock. Materials and Methods Interleukin-6 (IL-6), macrophage inflammatory protein-Iβ (MIP-1β), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) as well as beta-fibrinogen (Fgb) and metallothionein-1 (Mt-1) mRNA expression were measured at four time points (0, 2, 4 and 7 hours) after injection of E. coli LPS in mice from three inbred strains. Results Statistical analysis using analyses of variance (ANOVAs) showed that the levels of the all six traits changed over time, generally peaking at 2 hours after LPS injection. Mt-1, Fgb, and IL-6 showed differences among strains, although these were time-specific. Sexual dimorphism was seen for Fgb and IL6, and was most pronounced at the latest time period (7 hours) where male levels exceeded those for females. Trends for all six cytokine/gene expression traits were negatively correlated with those for body temperatures. Discussion The higher levels of expression of Fgb and IL6 in males compared with females are consistent with the greater vulnerability of males to infection and subsequent inflammation. Temperature appears to be a useful proxy for mortality in endotoxic shock, but sexual dimorphism in cytokine and stress gene expression levels may persist after an LPS challenge even if temperatures in the two sexes are similar and have begun to stabilize. PMID

  5. Stress responses in Streptococcus species and their effects on the host.

    PubMed

    Nguyen, Cuong Thach; Park, Sang-Sang; Rhee, Dong-Kwon

    2015-11-01

    Streptococci cause a variety of diseases, such as dental caries, pharyngitis, meningitis, pneumonia, bacteremia, endocarditis, erysipelas, and necrotizing fasciitis. The natural niche of this genus of bacteria ranges from the mouth and nasopharynx to the skin, indicating that the bacteria will inevitably be subjected to environmental changes during invasion into the host, where it is exposed to the host immune system. Thus, the Streptococcus-host interaction determines whether bacteria are cleared by the host's defenses or whether they survive after invasion to cause serious diseases. If this interaction was to be deciphered, it could aid in the development of novel preventive and therapeutic agents. Streptococcus species possess many virulent factors, such as peroxidases and heat-shock proteins (HSPs), which play key roles in protecting the bacteria from hostile host environments. This review will discuss insights into the mechanism(s) by which streptococci adapt to host environments. Additionally, we will address how streptococcal infections trigger host stress responses; however, the mechanism by which bacterial components modulate host stress responses remains largely unknown.

  6. Maternal endotoxin-induced preterm birth in mice: fetal responses in toll-like receptors, collectins, and cytokines.

    PubMed

    Salminen, Annamari; Paananen, Reija; Vuolteenaho, Reetta; Metsola, Juhani; Ojaniemi, Marja; Autio-Harmainen, Helena; Hallman, Mikko

    2008-03-01

    Major cause of prematurity is spontaneous preterm birth (PTB) associated with intrauterine inflammation. Our aim was to establish a model of endotoxin Lipopolysaccharide-induced PTB of live-born pups and to study early immune activation in fetal and maternal compartments. Expression of several proteins that bind microbes (Toll-like receptors TLR4, TLR2; surfactant proteins SP-A, SP-D) was analyzed. At 16 or 17 d of gestation, C57BL/6 dams received a single dose of intraperitoneal LPS, leading to PTB within 17 h. Cytokine levels increased in maternal serum, followed by a modest increase in fetal serum and in amniotic fluid. In uterus, placenta, and fetal membranes, LPS mostly increased the expressions of TLR, SPs, and cytokines. The number of TLR2-positive macrophages increased in labyrinthine placenta. In fetal lung, intestine, liver, and brain there were modest changes in cytokine expressions. In fetal lung, SP and TLR mRNAs decreased and TLR2-positive macrophages redistributed around vessels. LPS-induced fetal deaths associated with early age (16 d gestation) rather than with proinflammatory activation. Here we propose that maternal LPS response leads to PTB and acute decrease of immune proteins in epithelial lining of fetal lung. Instead, acceleration of lung maturity has been previously observed in intraamniotic inflammation.

  7. Immunomodulatory activity of diethylcarbamazine on humoral, cellular cytokine response and respiratory burst in BALB/c mice.

    PubMed

    Medina-De la Garza, Carlos E; Guerrero-Ramírez, Graciela; García-Hernández, Marisela; Castro-Corona, M Angeles; Torres-López, Ernesto; Brattig, Norbert W; Salinas-Carmona, Mario C

    2012-06-01

    Diethylcarbamazine (DEC) is an anthelmintic piperazine derivative drug with putative immunomodulating properties, including increased platelet and granulocyte adhesion to parasites and enhanced production of cytokines. To further analyse these properties in a well-established animal model, we evaluated the effect of DEC on antibody, cellular cytokine response and respiratory burst in BALB/c mice. Animals were challenged with a thymus-dependent (tetanus toxoid, (TT)) and with a thymus-independent (lipopolysaccharide, (LPS)) antigen and treated with DEC for seven days with two different doses (50 mg/day and 500 mg/day). Serum was assessed for antibody production at 0, 4, 7, 14, 21 and 28 days after stimulation and at 0, 24 and 48 h for IL-2, IFN-γ, IL-10 and IL-12 release. Respiratory burst of neutrophils and monocytes from peripheral blood was measured by flow cytometry. We found low-dose treatment with DEC enhanced cytokine production vs. TT and antibody production vs. LPS, whereas a higher dose enhanced significantly the respiratory burst of both polymorphonuclear leukocytes and monocytes, with a significant higher effect on the former. Our results suggest a stimulating, dose-dependent immunomodulatory effect of DEC with a higher effect on the phagocytic cells.

  8. The Staphylococcal Biofilm: Adhesins, regulation, and host response

    PubMed Central

    Paharik, Alexandra E.; Horswill, Alexander R.

    2015-01-01

    The Staphylococci comprise a diverse genus of Gram-positive, non-motile commensal organisms that inhabit the skin and mucous membranes of humans and other mammals. In general, Staphylococci are benign members of the natural flora, but many species have the capacity to be opportunistic pathogens, mainly infecting individuals who have medical device implants or are otherwise immunocompromised. S. aureus and S. epidermidis are a major source of hospital-acquired infections and are the most common causes of surgical site infections and central line-associated bloodstream infections. The ability of Staphylococci to form biofilms in vivo makes them highly resistant to chemotherapeutics and leads to chronic diseases. These biofilm infections include osteomyelitis, endocarditis, medical device implants, and persistence in the cystic fibrosis lung. Here, we provide a comprehensive analysis of our current understanding of Staphylococcal biofilm formation, with an emphasis on adhesins and regulation, while also addressing how Staphylococcal biofilms interact with the immune system. On the whole, this review will provide a thorough picture of biofilm formation of the Staphylococcus genus and how this mode of growth impacts the host. PMID:27227309

  9. Breaking bad: Manipulation of the host response by Porphyromonas gingivalis

    PubMed Central

    Hajishengallis, George; Lamont, Richard J.

    2014-01-01

    Recent metagenomic and mechanistic studies are consistent with a new model of periodontal pathogenesis. This model proposes that periodontal disease is initiated by a synergistic and dysbiotic microbial community rather than by a select few bacteria traditionally known as “periopathogens”. Low abundance bacteria with community-wide effects that are critical for the development of dysbiosis are now known as keystone pathogens, the best-documented example of which is Porphyromonas gingivalis. Here we review established mechanisms by which P. gingivalis interferes with host immunity and enables the emergence of dysbiotic communities. We integrate the role of P. gingivalis with that of other bacteria acting upstream and downstream in pathogenesis. Accessory pathogens act upstream to facilitate P. gingivalis colonization and coordinate metabolic activities, whereas commensals-turned-pathobionts act downstream and contribute to destructive inflammation. The recent concepts of keystone pathogens, along with polymicrobial synergy and dysbiosis (PSD), have profound implications for the development of therapeutic options for periodontal disease. PMID:24338806

  10. Host response to Candida albicans bloodstream infection and sepsis

    PubMed Central

    Duggan, Seána; Leonhardt, Ines; Hünniger, Kerstin; Kurzai, Oliver

    2015-01-01

    Candida albicans is a major cause of bloodstream infection which may present as sepsis and septic shock - major causes of morbidity and mortality world-wide. After invasion of the pathogen, innate mechanisms govern the early response. Here, we outline the models used to study these mechanisms and summarize our current understanding of innate immune responses during Candida bloodstream infection. This includes protective immunity as well as harmful responses resulting in Candida induced sepsis. Neutrophilic granulocytes are considered principal effector cells conferring protection and recognize C. albicans mainly via complement receptor 3. They possess a range of effector mechanisms, contributing to elimination of the pathogen. Neutrophil activation is closely linked to complement and modulated by activated mononuclear cells. A thorough understanding of these mechanisms will help in creating an individualized approach to patients suffering from systemic candidiasis and aid in optimizing clinical management. PMID:25785541

  11. Organ-Specific Blood Signatures for Host Response to Infections

    DTIC Science & Technology

    2012-04-03

    pandemic H1N1 Influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses. MBio, 2011 September...determines outcome of Streptococcus pneumonia co-infection. Cell Symposia: Influenza : Translating basic insights, Washington, DC, 2010 • Kathie-Anne

  12. Vibrio elicits targeted transcriptional responses from copepod hosts.

    PubMed

    Almada, Amalia A; Tarrant, Ann M

    2016-06-01

    Copepods are abundant crustaceans that harbor diverse bacterial communities, yet the nature of their interactions with microbiota are poorly understood. Here, we report that Vibrio elicits targeted transcriptional responses in the estuarine copepod Eurytemora affinis We pre-treated E. affinis with an antibiotic cocktail and exposed them to either a zooplankton specialist (Vibrio sp. F10 9ZB36) or a free-living species (Vibrio ordalii 12B09) for 24 h. We then identified via RNA-Seq a total of 78 genes that were differentially expressed following Vibrio exposure, including homologs of C-type lectins, chitin-binding proteins and saposins. The response differed between the two Vibrio treatments, with the greatest changes elicited upon inoculation with V. sp. F10 We suggest that these differentially regulated genes play important roles in cuticle integrity, the innate immune response, and general stress response, and that their expression may enable E. affinis to recognize and regulate symbiotic vibrios. We further report that V. sp. F10 culturability is specifically altered upon colonization of E. affinis These findings suggest that rather than acting as passive environmental vectors, copepods discriminately interact with vibrios, which may ultimately impact the abundance and activity of copepod-associated bacteria.

  13. STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and independent mechanisms1

    PubMed Central

    Villarino, Alejandro V.; Gallo, Eugenio; Abbas, Abul K.

    2010-01-01

    Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet-deficient T cells each exhibit a hyper-Th17 phenotype relative to WT controls. However, IL-17 production was higher in the absence of T-bet and, when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines higher in T-bet−/− T cells than in either STAT1−/− or STAT1−/− T-bet−/− counterparts. The ability of IFN-γ and IL-27 to suppress Th17 responses was reduced in T-bet-deficient cells and, most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22 and RORγT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-γ, IL-27 and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses. PMID:20974984

  14. Profiling the host response to malaria vaccination and malaria challenge

    PubMed Central

    Dunachie, Susanna; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528

  15. Profiling the host response to malaria vaccination and malaria challenge.

    PubMed

    Dunachie, Susanna; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research.

  16. Host Immune Status and Response to Hepatitis E Virus Infection

    PubMed Central

    Krain, Lisa J.; Nelson, Kenrad E.

    2014-01-01

    SUMMARY Hepatitis E virus (HEV), identified over 30 years ago, remains a serious threat to life, health, and productivity in developing countries where access to clean water is limited. Recognition that HEV also circulates as a zoonotic and food-borne pathogen in developed countries is more recent. Even without treatment, most cases of HEV-related acute viral hepatitis (with or without jaundice) resolve within 1 to 2 months. However, HEV sometimes leads to acute liver failure, chronic infection, or extrahepatic symptoms. The mechanisms of pathogenesis appear to be substantially immune mediated. This review covers the epidemiology of HEV infection worldwide, the humoral and cellular immune responses to HEV, and the persistence and protection of antibodies produced in response to both natural infection and vaccines. We focus on the contributions of altered immune states (associated with pregnancy, human immunodeficiency virus [HIV], and immunosuppressive agents used in cancer and transplant medicine) to the elevated risks of chronic infection (in immunosuppressed/immunocompromised patients) and acute liver failure and mortality (among pregnant women). We conclude by discussing outstanding questions about the immune response to HEV and interactions with hormones and comorbid conditions. These questions take on heightened importance now that a vaccine is available. PMID:24396140

  17. Th17 cells: critical mediators of host responses to burn injury and sepsis

    PubMed Central

    Rendon, Juan L.; Choudhry, Mashkoor A.

    2012-01-01

    Th cells have long been recognized as vital components of the adaptive immune system. Until recently, CD3+CD4+ Th cells were divided into cell-mediated Th1 or humoral Th2 responses. However, the Th1-Th2 hypothesis failed to accommodate the more recently described Th17 cells. Today, the major Th cell subsets include Th1, Th2, Th9, Th17, Th22, and Tregs, each of which produce specific effector cytokines under unique transcriptional regulation. Specifically, Th17 cells produce effector cytokines IL-17, IL-21, and IL-22 under the regulation of ROR-γt. Th17 lymphocytes were first described as orchestrators of neutrophil recruitment and activation and as key players in chronic inflammation and autoimmunity. More recent evidence suggest that Th17 lymphocytes and their effector cytokines play a crucial role in maintaining mucosal immunity and barrier integrity, including the skin, lung, and gut. Burn injury induces global changes to the systemic immune response, including suppressed immune function and increased susceptibility to infection. Moreover, burn trauma is associated with remote organ injury. This relationship between burn and remote organ injury supports the hypothesis that immune suppression may facilitate the development of sepsis, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome in critically ill burn patients. Herein, we discuss this emerging adaptive cell subset in critical care settings, including burn injury and clinical sepsis, and highlight the potential therapeutic role of IL-22. PMID:22753950

  18. TLR7 and TLR3 Sense Brucella abortus RNA to Induce Proinflammatory Cytokine Production but They Are Dispensable for Host Control of Infection

    PubMed Central

    Campos, Priscila C.; Gomes, Marco Túlio R.; Guimarães, Erika S.; Guimarães, Gabriela; Oliveira, Sergio C.

    2017-01-01

    Brucella abortus is a Gram-negative, facultative intracellular bacterium that causes brucellosis, a worldwide zoonotic disease leading to undulant fever in humans and abortion in cattle. The immune response against this bacterium relies on the recognition of microbial pathogen-associated molecular patterns, such as lipoproteins, lipopolysaccharides, and DNA; however, the immunostimulatory potential of B. abortus RNA remains to be elucidated. Here, we show that dendritic cells (DCs) produce significant amounts of IL-12, IL-6, and IP-10/CXCL10, when stimulated with purified B. abortus RNA. IL-12 secretion by DCs stimulated with RNA depends on TLR7 while IL-6 depends on TLR7 and partially on TLR3. Further, only TLR7 plays a role in IL-12 production induced by B. abortus infection. Moreover, cytokine production in DCs infected with B. abortus or stimulated with bacterial RNA was reduced upon pretreatment with MAPK/NF-κB inhibitors. By confocal microscopy, we demonstrated that TLR7 is colocalized with B. abortus in LAMP-1+ Brucella-containing vacuoles. Additionally, type I IFN expression and IP-10/CXCL10 secretion in DCs stimulated with bacterial RNA were dependent on TLR3 and TLR7. Our results suggest that TLR3 and TLR7 are not required to control Brucella infection in vivo, but they play an important role on sensing B. abortus RNA in vitro. PMID:28167945

  19. A novel intrinsically disordered outer membrane lipoprotein of Aggregatibacter actinomycetemcomitans binds various cytokines and plays a role in biofilm response to interleukin-1β and interleukin-8

    PubMed Central

    Ahlstrand, Tuuli; Tuominen, Heidi; Beklen, Arzu; Torittu, Annamari; Oscarsson, Jan; Sormunen, Raija; Pöllänen, Marja T.; Permi, Perttu; Ihalin, Riikka

    2017-01-01

    ABSTRACT Intrinsically disordered proteins (IDPs) do not have a well-defined and stable 3-dimensional fold. Some IDPs can function as either transient or permanent binders of other proteins and may interact with an array of ligands by adopting different conformations. A novel outer membrane lipoprotein, bacterial interleukin receptor I (BilRI) of the opportunistic oral pathogen Aggregatibacter actinomycetemcomitans binds a key gatekeeper proinflammatory cytokine interleukin (IL)-1β. Because the amino acid sequence of the novel lipoprotein resembles that of fibrinogen binder A of Haemophilus ducreyi, BilRI could have the potential to bind other proteins, such as host matrix proteins. However, from the tested host matrix proteins, BilRI interacted with neither collagen nor fibrinogen. Instead, the recombinant non-lipidated BilRI, which was intrinsically disordered, bound various pro/anti-inflammatory cytokines, such as IL-8, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-10. Moreover, BilRI played a role in the in vitro sensing of IL-1β and IL-8 because low concentrations of cytokines did not decrease the amount of extracellular DNA in the matrix of bilRI− mutant biofilm as they did in the matrix of wild-type biofilm when the biofilms were exposed to recombinant cytokines for 22 hours. BilRI played a role in the internalization of IL-1β in the gingival model system but did not affect either IL-8 or IL-6 uptake. However, bilRI deletion did not entirely prevent IL-1β internalization, and the binding of cytokines to BilRI was relatively weak. Thus, BilRI might sequester cytokines on the surface of A. actinomycetemcomitans to facilitate the internalization process in low local cytokine concentrations. PMID:27459270

  20. A novel intrinsically disordered outer membrane lipoprotein of Aggregatibacter actinomycetemcomitans binds various cytokines and plays a role in biofilm response to interleukin-1β and interleukin-8.

    PubMed

    Ahlstrand, Tuuli; Tuominen, Heidi; Beklen, Arzu; Torittu, Annamari; Oscarsson, Jan; Sormunen, Raija; Pöllänen, Marja T; Permi, Perttu; Ihalin, Riikka

    2017-02-17

    Intrinsically disordered proteins (IDPs) do not have a well-defined and stable 3-dimensional fold. Some IDPs can function as either transient or permanent binders of other proteins and may interact with an array of ligands by adopting different conformations. A novel outer membrane lipoprotein, bacterial interleukin receptor I (BilRI) of the opportunistic oral pathogen Aggregatibacter actinomycetemcomitans binds a key gatekeeper proinflammatory cytokine interleukin (IL)-1β. Because the amino acid sequence of the novel lipoprotein resembles that of fibrinogen binder A of Haemophilus ducreyi, BilRI could have the potential to bind other proteins, such as host matrix proteins. However, from the tested host matrix proteins, BilRI interacted with neither collagen nor fibrinogen. Instead, the recombinant non-lipidated BilRI, which was intrinsically disordered, bound various pro/anti-inflammatory cytokines, such as IL-8, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-10. Moreover, BilRI played a role in the in vitro sensing of IL-1β and IL-8 because low concentrations of cytokines did not decrease the amount of extracellular DNA in the matrix of bilRI(-) mutant biofilm as they did in the matrix of wild-type biofilm when the biofilms were exposed to recombinant cytokines for 22 hours. BilRI played a role in the internalization of IL-1β in the gingival model system but did not affect either IL-8 or IL-6 uptake. However, bilRI deletion did not entirely prevent IL-1β internalization, and the binding of cytokines to BilRI was relatively weak. Thus, BilRI might sequester cytokines on the surface of A. actinomycetemcomitans to facilitate the internalization process in low local cytokine concentrations.

  1. Enhanced natural killer activity and production of pro-inflammatory cytokines in mice selected for high acute inflammatory response (AIRmax).

    PubMed

    Castoldi, Lindsey; Golim, Marjorie Assis; Filho, Orlando Garcia Ribeiro; Romagnoli, Graziela Gorete; Ibañez, Olga Célia Martinez; Kaneno, Ramon

    2007-03-01

    Strains of mice with maximal and minimal acute inflammatory responsiveness (AIRmax and AIRmin, respectively) were developed through selective breeding based on their high- or low-acute inflammatory responsiveness. Previous reports have shown that AIRmax mice are more resistant to the development of a variety of tumours than AIRmin mice, including spontaneous metastasis of murine melanoma. Natural killer activity is involved in immunosurveillance against tumour development, so we analysed the number and activity of natural killer cells (CD49b(+)), T-lymphocyte subsets and in vitro cytokine production by spleen cells of normal AIRmax and AIRmin mice. Analysis of lymphocyte subsets by flow cytometry showed that AIRmax mice had a higher relative number of CD49b(+) cells than AIRmin mice, as well as cytolytic activity against Yac.1 target cells. The number of CD3(+) CD8(+) cells was also higher in AIRmax mice. These findings were associated with the ability of spleen cells from AIRmax mice in vitro to produce higher levels of the pro-inflammatory cytokines tumour necrosis factor-alpha, interleukin-12p40 and interferon-gamma but not the anti-inflammatory interleukin-10. Taken together, our data suggest that the selective breeding to achieve the AIRmax and AIRmin strains was able to polarize the genes associated with cytotoxic activity, which can be responsible for the antitumour resistance observed in AIRmax mice.

  2. Cytokine Profiles in Human Metapneumovirus Infected Children: Identification of Genes Involved in the Antiviral Response and Pathogenesis

    PubMed Central

    Malmo, Jostein; Moe, Nina; Krokstad, Sidsel; Ryan, Liv; Loevenich, Simon; Johnsen, Ingvild B.; Espevik, Terje; Nordbø, Svein Arne; Døllner, Henrik; Anthonsen, Marit W.

    2016-01-01

    Human metapneumovirus (hMPV) causes severe airway infection in children that may be caused by an unfavorable immune response. The nature of the innate immune response to hMPV in naturally occurring infections in children is largely undescribed, and it is unknown if inflammasome activation is implicated in disease pathogenesis. We examined nasopharynx aspirates and blood samples from hMPV-infected children without detectable co-infections. The expression of inflammatory and antiviral genes were measured in nasal airway secretions by relative mRNA quantification while blood plasma proteins were determined by a multiplex immunoassay. Several genes were significantly up-regulated at mRNA and protein level in the hMPV infected children. Most apparent was the expression of the chemokine IP-10, the pro-inflammatory cytokine IL-18 in addition to the interferon inducible gene ISG54. Interestingly, children experiencing more severe disease, as indicated by a severity index, had significantly more often up-regulation of the inflammasome-associated genes IL-1β and NLRP3. Overall, our data point to cytokines, particularly inflammasome-associated, that might be important in hMPV mediated lung disease and the antiviral response in children with severe infection. Our study is the first to demonstrate that inflammasome components are associated with increased illness severity in hMPV-infected children. PMID:27171557

  3. Innate and adaptive immunologic functions of complement in the host response to Listeria monocytogenes infection

    PubMed Central

    Calame, Daniel G.; Mueller-Ortiz, Stacey L.; Wetsel, Rick A.

    2017-01-01

    Listeria monocytogenes is a leading cause of foodborne-illness associated mortality that has attracted considerable attention in recent years due to several significant outbreaks. It has also served as a model organism for the study of intracellular pathogens. For these reasons the host response to L. monocytogenes has long been the subject of investigation. A potent innate and adaptive immune response is required for containment and clearance of L. monocytogenes. However, some elements of this response, such as type 1 interferons, can be detrimental to the host. Recent studies have revealed novel functions for the complement system, an ancient arm of innate immunity, in this process. Here we review the role of complement in the host response to L. monocytogenes. PMID:27476791

  4. Do host species evolve a specific response to slave-making ants?

    PubMed Central

    2012-01-01

    Background Social parasitism is an important selective pressure for social insect species. It is particularly the case for the hosts of dulotic (so called slave-making) ants, which pillage the brood of host colonies to increase the worker force of their own colony. Such raids can have an important impact on the fitness of the host nest. An arms race which can lead to geographic variation in host defenses is thus expected between hosts and parasites. In this study we tested whether the presence of a social parasite (the dulotic ant Myrmoxenus ravouxi) within an ant community correlated with a specific behavioral defense strategy of local host or non-host populations of Temnothorax ants. Social recognition often leads to more or less pronounced agonistic interactions between non-nestmates ants. Here, we monitored agonistic behaviors to assess whether ants discriminate social parasites from other ants. It is now well-known that ants essentially rely on cuticular hydrocarbons to discriminate nestmates from aliens. If host species have evolved a specific recognition mechanism for their parasite, we hypothesize that the differences in behavioral responses would not be fully explained simply by quantitative dissimilarity in cuticular hydrocarbon profiles, but should also involve a qualitative response due to the detection of particular compounds. We scaled the behavioral results according to the quantitative chemical distance between host and parasite colonies to test this hypothesis. Results Cuticular hydrocarbon profiles were distinct between species, but host species did not show a clearly higher aggression rate towards the parasite than toward non-parasite intruders, unless the degree of response was scaled by the chemical distance between intruders and recipient colonies. By doing so, we show that workers of the host and of a non-host species in the parasitized site displayed more agonistic behaviors (bites and ejections) towards parasite than toward non

  5. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts.

    PubMed

    Onda, Masanori; Ghoreschi, Kamran; Steward-Tharp, Scott; Thomas, Craig; O'Shea, John J; Pastan, Ira H; FitzGerald, David J

    2014-07-01

    Immunogenicity remains the "Achilles' heel" of protein-based therapeutics. Anti-drug Abs produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. In this article, we report that monotherapy of mice with tofacitinib (the JAK inhibitor) quells Ab responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. Thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics.

  6. Modulation of host responses by oral commensal bacteria

    PubMed Central

    Devine, Deirdre A.; Marsh, Philip D.; Meade, Josephine

    2015-01-01

    Immunomodulatory commensal bacteria are proposed to be essential for maintaining healthy tissues, having multiple roles including priming immune responses to ensure rapid and efficient defences against pathogens. The default state of oral tissues, like the gut, is one of inflammation which may be balanced by regulatory mechanisms and the activities of anti-inflammatory resident bacteria that modulate Toll-like receptor (TLR) signalling or NF-κB activation, or influence the development and activities of immune cells. However, the widespread ability of normal resident organisms to suppress inflammation could impose an unsustainable burden on the immune system and compromise responses to pathogens. Immunosuppressive resident bacteria have been isolated from the mouth and, for example, may constitute 30% of the resident streptococci in plaque or on the tongue. Their roles in oral health and dysbiosis remain to be determined. A wide range of bacterial components and/or products can mediate immunomodulatory activity, raising the possibility of development of alternative strategies for therapy and health promotion using probiotics, prebiotics, or commensal-derived immunomodulatory molecules. PMID:25661061

  7. Extracellular proteins of Cryptococcus neoformans and host antibody response.

    PubMed Central

    Chen, L C; Pirofski, L A; Casadevall, A

    1997-01-01

    Proteins secreted by the fungal pathogen Cryptococcus neoformans may be involved in invasion and could be useful in vaccine design. Despite the medical importance of this fungus, little is known about its extracellular proteins or the immune response to these antigens. To study C. neoformans extracellular proteins, 12 strains were metabolically radiolabeled and protein supernatants were analyzed. Both strain- and growth condition-dependent differences were observed. Enzymatic assays of filtered culture supernatants revealed butyrate esterase and caprylate esterase lipase activity for 11 of 12 strains, as well as acid phosphatase, naphthol-AS-BI-phosphohydrolase, and beta-glucosidase activities in some strains. Serum from infected rodents immunoprecipitated several secreted proteins, consistent with in vivo expression and development of an antibody response. For strain 24067, two immunodominant species, of approximately 75 and 30 kDa, were recognized. The relative intensity of the autoradiographic bands depended on the route of infection for both rats and mice. In summary, our results indicate that (i) there are multiple proteins in C. neoformans culture supernatants, (ii) there are strain differences in supernatant protein profiles, (iii) there are differences in supernatant protein profile depending on the growth conditions, (iv) there are several new extracellular and/or cell-associated enzymatic activities, and (v) antibodies to several supernatant proteins are made in the course of infection. PMID:9199426

  8. Immune response to Aspergillus fumigatus in compromised hosts: from bedside to bench.

    PubMed

    Chai, Louis Y A; Vonk, Alieke G; Kullberg, Bart-Jan; Netea, Mihai G

    2011-01-01

    The relevance of studies aimed at understanding host immune response against Aspergillus fumigatus takes on much significance given that all patients with invasive aspergillosis are invariably immunocompromised. This article attempts to correlate relevant findings from recent experimental studies to clinical observations made by the physician at the bedside. It is hoped that the increased understanding of host-fungus immune interaction may pave the way for the development of new management strategies against this difficult-to-treat fungal disease.

  9. Infliximab therapy increases the frequency of circulating CD16(+) monocytes and modifies macrophage cytokine response to bacterial infection.

    PubMed

    Nazareth, N; Magro, F; Silva, J; Duro, M; Gracio, D; Coelho, R; Appelberg, R; Macedo, G; Sarmento, A

    2014-09-01

    Crohn's disease (CD) has been correlated with altered macrophage response to microorganisms. Considering the efficacy of infliximab treatment on CD remission, we investigated infliximab effects on circulating monocyte subsets and on macrophage cytokine response to bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, treated or not with infliximab. Macrophages were infected with Escherichia coli, Enterococcus faecalis, Mycobacterium avium subsp. paratuberculosis (MAP) or M. avium subsp avium, and cytokine levels [tumour necrosis factor (TNF) and interleukin (IL)-10] were evaluated at different time-points. To evaluate infliximab-dependent effects on monocyte subsets, we studied CD14 and CD16 expression by peripheral blood monocytes before and after different infliximab administrations. We also investigated TNF secretion by macrophages obtained from CD16(+) and CD16(-) monocytes and the frequency of TNF(+) cells among CD16(+) and CD16(-) monocyte-derived macrophages from CD patients. Infliximab treatment resulted in elevated TNF and IL-10 macrophage response to bacteria. An infliximab-dependent increase in the frequency of circulating CD16(+) monocytes (particularly the CD14(++) CD16(+) subset) was also observed (before infliximab: 4·65 ± 0·58%; after three administrations: 10·68 ± 2·23%). In response to MAP infection, macrophages obtained from CD16(+) monocytes were higher TNF producers and CD16(+) macrophages from infliximab-treated CD patients showed increased frequency of TNF(+) cells. In conclusion, infliximab treatment increased the TNF production of CD macrophages in response to bacteria, which seemed to depend upon enrichment of CD16(+) circulating monocytes, particularly of the CD14(++) CD16(+) subset. Infliximab treatment of CD patients also resulted in increased macrophage IL-10 production in response to bacteria, suggesting an infliximab-induced shift to M2 macrophages.

  10. A Human In Vitro Whole Blood Assay to Predict the Systemic Cytokine Response to Therapeutic Oligonucleotides Including siRNA

    PubMed Central

    Schwickart, Anna; Putschli, Bastian; Renn, Marcel; Höller, Tobias; Barchet, Winfried

    2013-01-01

    Therapeutic oligonucleotides including siRNA and immunostimulatory ligands of Toll-like receptors (TLR) or RIG-I like helicases (RLH) are a promising novel class of drugs. They are in clinical development for a broad spectrum of applications, e.g. as adjuvants in vaccines and for the immunotherapy of cancer. Species-specific immune activation leading to cytokine release is characteristic for therapeutic oligonucleotides either as an unwanted side effect or intended pharmacology. Reliable in vitro tests designed for therapeutic oligonucleotides are therefore urgently needed in order to predict clinical efficacy and to prevent unexpected harmful effects in clinical development. To serve this purpose, we here established a human whole blood assay (WBA) that is fast and easy to perform. Its response to synthetic TLR ligands (R848: TLR7/8, LPS: TLR4) was on a comparable threshold to the more time consuming peripheral blood mononuclear cell (PBMC) based assay. By contrast, the type I IFN profile provoked by intravenous CpG-DNA (TLR9 ligand) in humans in vivo was more precisely replicated in the WBA than in stimulated PBMC. Since Heparin and EDTA, but not Hirudin, displaced oligonucleotides from their delivery agent, only Hirudin qualified as the anticoagulant to be used in the WBA. The Hirudin WBA exhibited a similar capacity as the PBMC assay to distinguish between TLR7-activating and modified non-stimulatory siRNA sequences. RNA-based immunoactivating TLR7/8- and RIG-I-ligands induced substantial amounts of IFN-α in the Hirudin-WBA dependent on delivery agent used. In conclusion, we present a human Hirudin WBA to determine therapeutic oligonucleotide-induced cytokine release during preclinical development that can readily be performed and offers a close reflection of human cytokine response in vivo. PMID:23940691

  11. Curcumin Induces Pro-apoptotic Effects Against Human Melanoma Cells and Modulates The Cellular Response to Immunotherapeutic Cytokines

    PubMed Central

    Bill, Matthew A.; Bakan, Courtney; Benson, Don M.; Fuchs, James; Young, Gregory; Lesinski, Gregory B.

    2009-01-01

    Curcumin has potential as a chemopreventative and chemotherapeutic agent however its interactions with clinically relevant cytokines are poorly characterized. Since cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses >10 µM. Immunoblot analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, PARP cleavage, reduced Bcl-2 and decreased basal phosphorylated STAT3. Despite its pro-apoptotic effects, curcumin pre-treatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and downstream gene transcription following IFN-α and IFN-γ as determined by immunoblot analysis and Real Time PCR, respectively. Pre-treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors with curcumin also inhibited the ability of IFN-α, IFN-γ and IL-2 to phosphorylate STAT proteins critical for their anti-tumor activity (STAT1 and STAT5, respectively) and their respective downstream gene expression as measured by Real Time PCR. Finally, stimulation of natural killer (NK) cells with curcumin reduced the level of IL-12-induced IFN-γ secretion, and production of granzyme b or IFN-γ upon co-culture with A375 melanoma cells or NK sensitive K562 cells as targets. These data demonstrate that although curcumin can induce apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant cytokines that possess anti-tumor properties. PMID:19723881

  12. Profiling the host immune response to tuberculosis vaccines.

    PubMed

    Fletcher, Helen A

    2015-09-29

    There is an urgent need for improved vaccines for protection against tuberculosis (TB) disease and an immune correlate of protection would aid in the design, development and testing of a new TB vaccine candidates. The immune response to TB is likely to be multi-factorial and transcriptional profiling is a potentially useful tool for the simultaneous measurement of multiple immune processes. Although there are 16 candidate TB vaccines in clinical development the only published transcriptomics studies are from the MVA85A trials. With the publication of transcriptional signatures from the South African adolescent cohort study and the GC6 consortium also expected in 2015 the next year could see an increase of interest in the use of transcriptomics in TB vaccine development.

  13. Host response, malnutrition and oral diseases. Part 2

    PubMed Central

    Słotwiński, Robert

    2014-01-01

    Acute phase proteins enhance antioxidant defenses; they are involved in the activation of complement components, opsonization and increase in platelet aggregation as well as inhibition of the respiratory burst in the course of inflammation. Malnutrition plays an important role in the course of response of acute phase proteins. The role of nutrients as antioxidants or as key components of antioxidant enzymes is commonly known. In the course of various inflammatory states, including oral diseases, disorders are observed in caloric requirements of the organism and the requirements for specific amino acids. Numerous experimental studies in animals have also confirmed the relationship between protein- calorie malnutrition and hypofunction of the salivary glands. Studies in children with malnutrition syndrome showed a significantly lower volume of saliva compared to properly nourished children. Depleted nutritional reserves due to long-term chronic malnutrition cause a significant reduction in resistance, progressive damage to the oral mucosa, and reduce resistance to colonization and invasion of pathogenic microorganisms. PMID:26155173

  14. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

    SciTech Connect

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N.; Cormet-Boyaka, Estelle

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  15. The Epidermal Growth Factor Receptor Increases Cytokine Production and Cutaneous Inflammation in Response to Ultraviolet Irradiation

    PubMed Central

    El-Abaseri, Taghrid Bahig; Repertinger, Susan K.; Hansen, Laura A.

    2013-01-01

    The epidermal growth factor receptor (EGFR) is activated in cutaneous keratinocytes upon ultraviolet (UV) exposure and has been implicated in ultraviolet-(UV-)induced inflammation and skin tumorigenesis. Egfr mutant mice and EGFR inhibitors were used to investigate the hypothesis that EGFR activation augments inflammation following UV irradiation. Topical treatment of mouse skin with the EGFR inhibitor AG1478 before UV exposure suppressed UV-induced erythema, edema, mast cell infiltration, and neutrophil infiltration. Genetic ablation of Egfr and EGFR inhibition by AG1478 also suppressed the increase in the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1α, KC (murine IL-8), and cyclooxygenase-2 (COX-2) after UV exposure of cultured keratinocytes. Finally, genetic ablation of inhibition of EGFR in cultured keratinocytes decreased p38 activation after UV, while inhibition of p38 kinase reduced COX-2 expression after UV. These data demonstrate that EGFR regulates multiple aspects of UV-induced inflammation and suggest activation of p38 kinase leading to increased COX-2 and cytokine expression as one mechanism through which it acts. PMID:23878744

  16. Characterization of a distinct host response profile to Pneumocystis murina asci during clearance of pneumocystis pneumonia.

    PubMed

    Linke, Michael J; Ashbaugh, Alan; Collins, Margaret S; Lynch, Keeley; Cushion, Melanie T

    2013-03-01

    Pneumocystis spp. are yeast-like fungi that cause pneumocystis pneumonia (PcP) in immunocompromised individuals and exacerbate chronic lung diseases in immunocompetent individuals. The Pneumocystis life cycle includes trophic forms and asci (cyst forms). The cell walls of Pneumocystis asci contain β-1,3-D-glucan, and treatment of PcP with β-1,3-D-glucan synthase inhibitors, such as anidulafungin, results in depletion of asci, but not trophic forms. The pulmonary host response during immune reconstitution (IR)-mediated clearance of PcP in anidulafungin-treated and untreated mice was characterized to identify ascus-specific responses. During IR, similar numbers of trophic forms were present in the anidulafungin-treated and untreated mice; however, asci were only present in the untreated mice. IR resulted in a significant reduction of trophic forms from the lungs in both groups and asci in the untreated group. The presence of asci in untreated mice correlated with increased β-glucan content in the lungs. The untreated mice mounted immune responses associated with a deleterious host inflammatory response, including increased CD8(+) T cell influx and expression of macrophage inflammatory response markers. A more robust cellular response was also observed in the untreated mice, with increased numbers of macrophages and neutrophils that were associated with greater lung damage. Markers of a Th17 response were also elevated in the untreated mice. These results suggest that the host mounts unique responses to asci and trophic forms. That these 2 life cycle stages provoked distinct host response profiles has significant implications for clearance and interpretation of the host immune responses to PcP.

  17. The Synthetic Triterpenoid, CDDO, Suppresses Alloreactive T Cell Responses and Reduces Murine Early Acute Graft-versus-Host Disease Mortality

    PubMed Central

    Sun, Kai; Li, Minghui; Konopleva, Marina; Konoplev, Sergej; Stephens, L. Clifton; Kornblau, Steven M.; Frolova, Olga; Wilkins, Danice E. C.; Ma, Weihong; Welniak, Lisbeth A.; Andreeff, Michael; Murphy, William J.

    2015-01-01

    Acute graft-versus-host disease (aGVHD) still remains one of the life-threatening complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation of alloreactive donor T cell responses, as well as cytokine secretion is a potential therapeutic approach for the prevention of aGVHD. The synthetic triterpenoid, CDDO (2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid), exhibits potent antitumor activity and has also been shown to mediate anti-inflammatory and immunomodulatory effects. We therefore wanted to assess the effects of CDDO on early lethal aGVHD. In this study, we found that CDDO significantly inhibited in vitro mixed lymphocyte responses and preferentially promoted the apoptosis of proliferating but not resting alloreactive T cells. Using a full major histocompatibility complex (MHC)-disparate murine aGVHD model, we found that the administration of CDDO immediately after transplantation significantly decreased liver pathology as determined by histologic assessment and prolonged survival in mice. Importantly, administration of CDDO did not adversely impair donor myeloid reconstitution as determined by peripheral blood cell count and the extent of donor chimerism. These findings indicate that CDDO has a significant immunomodulatory effects in vitro and on early lethal aGVHD development, particularly affecting the liver, in a murine allo-HSCT model. PMID:17448911

  18. The TIR Domain Containing Locus of Enterococcus faecalis Is Predominant among Urinary Tract Infection Isolates and Downregulates Host Inflammatory Response

    PubMed Central

    Kraemer, Thomas Daniel; Quintanar Haro, Orlando Daniel; Domann, Eugen; Chakraborty, Trinad; Tchatalbachev, Svetlin

    2014-01-01

    Based on Toll/interleukin-1 receptor (TIR) domain structure homology, we detected a previously uncharacterized gene encoding for a TIR domain containing protein (Tcp) in the genome of Enterococcus faecalis. We assigned this gene the name tcpF (as in Tcp of E. faecalis). Screening of E. faecalis samples revealed that tcpF is more common in isolates from urinary tract infections (UTIs) than in human faecal flora. tcpF alleles showed moderate single nucleotide polymorphism (SNP) among UTI isolates. Infection of mouse RAW264.7 macrophages with a tcpF knock-out mutant led to elevated cytokine response compared to the isogenic wild type E. faecalis strain. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1 (TLR1-TIR). When transiently expressed in cultured eukaryotic cells, TcpF caused suppression of TLR2-dependent NF-κB activation suggesting for TcpF a role as a factor in E. faecalis that benefits colonization by modulating the host's immune responses. PMID:25147569

  19. Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine

    PubMed Central

    Kiraly, Drew D.; Walker, Deena M.; Calipari, Erin S.; Labonte, Benoit; Issler, Orna; Pena, Catherine J.; Ribeiro, Efrain A.; Russo, Scott J.; Nestler, Eric J.

    2016-01-01

    Addiction to cocaine and other psychostimulants represents a major public health crisis. The development and persistence of addictive behaviors comes from a complex interaction of genes and environment - the precise mechanisms of which remain elusive. In recent years a surge of evidence has suggested that the gut microbiome can have tremendous impact on behavioral via the microbiota-gut-brain axis. In this study we characterized the influence of the gut microbiota on cocaine-mediated behaviors. Groups of mice were treated with a prolonged course of non-absorbable antibiotics via the drinking water, which resulted in a substantial reduction of gut bacteria. Animals with reduced gut bacteria showed an enhanced sensitivity to cocaine reward and enhanced sensitivity to the locomotor-sensitizing effects of repeated cocaine administration. These behavioral changes were correlated with adaptations in multiple transcripts encoding important synaptic proteins in the brain’s reward circuitry. This study represents the first evidence that alterations in the gut microbiota affect behavioral response to drugs of abuse. PMID:27752130

  20. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

    PubMed Central

    Sternberg, Esther M.

    2006-01-01

    The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system. PMID:16557263

  1. THE OLFACTORY NERVE HAS A ROLE IN THE BODY TEMPERATURE AND BRAIN CYTOKINE RESPONSES TO INFLUENZA VIRUS

    PubMed Central

    Leyva-Grado, Victor H.; Churchill, Lynn; Harding, Joseph; Krueger, James M.

    2009-01-01

    Mouse-adapted human influenza virus is detectable in the olfactory bulbs of mice within hours after intranasal challenge and is associated with enhanced local cytokine mRNA and protein levels. To determine whether signals from the olfactory nerve influence the unfolding of the acute phase response (APR), we surgically transected the olfactory nerve in mice prior to influenza infection. We then compared the responses of olfactory nerve-transected (ONT) mice to those recorded in sham-operated control mice using measurements of body temperature, food intake, body weight, locomotor activity and immunohistochemistry for cytokines and the viral antigen, H1N1. ONT did not change baseline body temperature (Tb); however, the onset of virus-induced hypothermia was delayed for about 13 h in the ONT mice. Locomotor activity, food intake and body weights of the two groups were similar. At 15 h post-challenge fewer viral antigen-immunoreactive (IR) cells were observed in the olfactory bulb (OB) of ONT mice compared to sham controls. The number of tumor necrosis factor alpha (TNFα)- and interleukin 1 beta (IL1β)-IR cells in ONT mice was also reduced in the OB and other interconnected regions in the brain compared to sham controls. These results suggest that the olfactory nerve pathway is important for the initial pathogenesis of the influenza-induced APR. PMID:19836444

  2. Correlated response of peripheral blood cytokines with selection for reduced mycoplasma pneumonia of swine lesions in Landrace pigs.

    PubMed

    Sato, Takumi; Okamura, Toshihiro; Kojima-Shibata, Chihiro; Kadowaki, Hiroshi; Suzuki, Eisaku; Uenishi, Hirohide; Suzuki, Keiichi

    2016-04-01

    Mycoplasma pneumonia of swine (MPS) is responsible for significant economic losses in the swine industry. We selected Landrace pigs for reduced MPS pulmonary lesions over five generations, and measured concentrations of the following cytokines: interleukin (IL)-10, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ to estimate their correlation with MPS lesions. Sheep red blood cells (SRBC) were injected twice intramuscularly at 70 and 95 kg body weight. Blood serum samples were collected after 1 week of secondary SRBC inoculation and cytokine concentrations were analyzed by ELISA. Genetic parameters and breeding values were estimated. The heritability estimates of IL-10, IL-13, IL-17, TNF-α and IFN-γ were 0.20 ± 0.06, 0.12 ± 0.06, 0.27 ± 0.07, 0.20 ± 0.10 and 0.05 ± 0.03, respectively. Genetic correlations of IL-17 and TNF-α with pulmonary MPS lesions were high (-0.86 ± 0.13 and 0.69 ± 0.29, respectively) and those of IFN-γ and IL-13 with MPS lesions were moderately negative (-0.45). Through selection, the breeding values of IL-17 and IFN-γ increased substantially and those of TNF-α decreased. These results suggest that innate and cellular immunity are more important for the suppression of pulmonary lesions in MPS than humoral-mediated immunity, such as antibody response.

  3. Inflammatory Cytokines and White Blood Cell Counts Response to Environmental Levels of Diesel Exhaust and Ozone Inhalation Exposures

    PubMed Central

    Stiegel, Matthew A.; Pleil, Joachim D.; Sobus, Jon R.; Madden, Michael C.

    2016-01-01

    Epidemiological observations of urban inhalation exposures to diesel exhaust (DE) and ozone (O3) have shown pre-clinical cardiopulmonary responses in humans. Identifying the key biological mechanisms that initiate these health bioindicators is difficult due to variability in environmental exposure in time and from person to person. Previously, environmentally controlled human exposure chambers have been used to study DE and O3 dose-response patterns separately, but investigation of co-exposures has not been performed under controlled conditions. Because a mixture is a more realistic exposure scenario for the general public, in this study we investigate the relationships of urban levels of urban-level DE exposure (300 μg/m3), O3 (0.3 ppm), DE + O3 co-exposure, and innate immune system responses. Fifteen healthy human volunteers were studied for changes in ten inflammatory cytokines (interleukins 1β, 2, 4, 5, 8, 10, 12p70 and 13, IFN-γ, and TNF-α) and counts of three white blood cell types (lymphocytes, monocytes, and neutrophils) following controlled exposures to DE, O3, and DE+O3. The results show subtle cytokines responses to the diesel-only and ozone-only exposures, and that a more complex (possibly synergistic) relationship exists in the combination of these two exposures with suppression of IL-5, IL-12p70, IFN-γ, and TNF-α that persists up to 22-hours for IFN-γ and TNF-α. The white blood cell differential counts showed significant monocyte and lymphocyte decreases and neutrophil increases following the DE + O3 exposure; lymphocytes and neutrophils changes also persist for at least 22-hours. Because human studies must be conducted under strict safety protocols at environmental levels, these effects are subtle and are generally only seen with detailed statistical analysis. This study indicates that the observed associations between environmental exposures and cardiopulmonary effects are possibly mediated by inflammatory response mechanisms. PMID:27058360

  4. Alteration in lymphocyte responses, cytokine and chemokine profiles in chickens infected with genotype VII and VIII velogenic Newcastle disease virus.

    PubMed

    Rasoli, Mehdi; Yeap, Swee Keong; Tan, Sheau Wei; Moeini, Hassan; Ideris, Aini; Bejo, Mohd Hair; Alitheen, Noorjahan Banu Mohamed; Kaiser, Pete; Omar, Abdul Rahman

    2014-01-01

    Newcastle disease (ND) is a highly contagious avian disease and one of the major causes of economic losses in the poultry industry. The emergence of virulent NDV genotypes and repeated outbreaks of NDV in vaccinated chickens have raised the need for fundamental studies on the virus-host interactions. In this study, the profiles of B and T lymphocytes and macrophages and differential expression of 26 immune-related genes in the spleen of specific-pathogen-free (SPF) chickens, infected with either the velogenic genotype VII NDV strain IBS002 or the genotype VIII NDV strain AF2240, were evaluated. A significant reduction in T lymphocyte population and an increase in the infiltration of IgM+ B cells and KUL01+ macrophages were detected in the infected spleens at 1, 3 and 4 days post-infection (dpi) (P<0.05). The gene expression profiles showed an up-regulation of CCLi3, CXCLi1, CXCLi2 (IL-8), IFN-γ, IL-12α, IL-18, IL-1β, IL-6, iNOS, TLR7, MHCI, IL-17F and TNFSF13B (P<0.05). However, these two genotypes showed different cytokine expression patterns and viral load. IBS002 showed higher viral load than AF2240 in spleen at 3 and 4dpi and caused a more rapid up-regulation of CXCLi2, IFN-γ, IL-12α, IL-18, IL-1β, iNOS and IL-10 at 3dpi. Meanwhile, the expression levels of CCLI3, CXCLi1, IFN-γ, IL-12α, IL-1β and iNOS genes were significantly higher in AF2240 at 4dpi. In addition, the expression levels of IL-10 were significantly higher in the IBS002-infected chickens at 3 and 4dpi. Hence, infection with velogenic genotype VII and VIII NDV induced different viral load and production of cytokines and chemokines associated with inflammatory reactions.

  5. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species.

    PubMed

    Schoffelen, Teske; Illnait-Zaragozi, Maria-Teresa; Joosten, Leo A B; Netea, Mihai G; Boekhout, Teun; Meis, Jacques F; Sprong, Tom

    2013-01-01

    Understanding more about the host's immune response to different Cryptococcus spp. will provide additional insight into the pathogenesis of cryptocococcis. We hypothesized that the ability of C. gattii to cause disease in immunocompetent humans depends on a distinct innate cytokine response of the host to this emerging pathogen. In the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with 40 different well-defined heat-killed isolates of C. gattii, C. neoformans and several hybrid strains. In addition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii. Isolates of C. gattii induced higher concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6 and the Th17/22 cytokine IL-17 and IL-22 compared to C. neoformans var neoformans and C. neoformans var grubii. In addition, clinical C. gattii isolates induced higher amounts of cytokines than environmental isolates. This difference was not observed in C. neoformans var. grubii isolates. Furthermore, we demonstrated a likely contribution of TLR4 and TLR9, but no role for TLR2, in the host's cytokine response to C. gattii. In conclusion, clinical heat-killed C. gattii isolates induced a more pronounced inflammatory response compared to other Cryptococcus species and non-clinical C. gattii. This is dependent on TLR4 and TLR9 as cellular receptors.

  6. Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint.

    PubMed

    Emeny, Rebecca T; Kasten-Jolly, Jane; Mondal, Tapan; Lynes, Michael A; Lawrence, David A

    2015-11-01

    Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteine-rich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT's role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR.

  7. The effects of exercise withdrawal on mood and inflammatory cytokine responses in humans.

    PubMed

    Poole, Lydia; Hamer, Mark; Wawrzyniak, Andrew J; Steptoe, Andrew

    2011-07-01

    Mechanisms underlying the relationship between exercise and mood are not well understood. This study sought to investigate the role of pro- and anti-inflammatory cytokines and autonomic balance in determining the impact of exercise withdrawal on negative mood. Healthy men and women who regularly exercised (N = 26, mean age = 25.5 years, SD = 4.5 years) were randomised to exercise withdrawal or exercise maintenance for 2 weeks. Protocol adherence was monitored using accelerometers. Inflammatory markers from plasma (interleukin-6, IL-6; tumour necrosis factor-alpha; interleukin-10; and interleukin-1 receptor antagonist), heart-rate variability (HRV) and measures of mood (General Health Questionnaire-28 (GHQ) and the Profile of Mood States (POMS)) were assessed at study entry and at 2-week follow-up. Exercise withdrawal resulted in significant increases in negative mood over time on both the GHQ (p = 0.028) and the POMS (p = 0.005). Following the intervention, IL-6 concentration was lower in the exercise withdrawal than exercise maintenance condition (p = 0.05). No intervention effects were observed for other cytokines or HRV. The mood changes were significantly related to changes in IL-6 concentration (β = - 0.50, p = 0.011), indicating that reduction in IL-6 was related to increased negative mood. Our results are consistent with positive effects of exercise on mental health, but further research on inflammatory pathways is warranted.

  8. Influence of prenatal stress on behavioral, endocrine, and cytokine responses to adulthood bacterial endotoxin exposure.

    PubMed

    Kohman, Rachel A; Tarr, Andrew J; Day, Cameron E; McLinden, Kristina A; Boehm, Gary W

    2008-11-21

    Prior research suggests that prenatal stress, among other effects, can lead to hyper-reactivity of the offspring's hypothalamic-pituitary-adrenal (HPA) axis and alterations in immune function. These stress-induced changes have been linked to a greater propensity to develop depression or anxiety disorders. Furthermore, prenatally stressed offspring may be more susceptible to certain diseases. The immune alterations induced by prenatal stress exposure may disrupt the normal communication between the immune system, endocrine system, and central nervous system, potentially making prenatally stressed individuals more vulnerable to the negative aspects of immune activation, including cytokine-induced cognitive deficits and anxiety. The present study investigated whether prenatal stress would exaggerate these detrimental effects of peripheral immune activation. We hypothesized that prenatally stressed subjects would be hypersensitive to endotoxin administration and would therefore show exaggerated learning deficits, increased anxiety-like behavior, and increased peripheral and central interleukin-1beta (IL-1beta) levels. The observed results only partially supported our hypotheses, as prenatally stressed subjects showed evidence, albeit modest, of increased anxiety-like behavior following endotoxin administration relative to non-stressed controls. While prenatal stress exposure or lipopolysaccharide (LPS) administration independently impaired learning, the data failed to support the hypothesis that prenatally stressed subjects would show exaggerated cognitive deficits, engendered via enhanced peripheral and central IL-1beta levels, following immune activation. Collectively, the data suggest that although prenatal stress exposure led to increases in anxiety-like behavior following endotoxin exposure, it did not appear to increase susceptibility to LPS-induced cognitive decline or elevations in proinflammatory cytokine production.

  9. G1-4A, a Polysaccharide from Tinospora cordifolia Inhibits the Survival of Mycobacterium tuberculosis by Modulating Host Immune Responses in TLR4 Dependent Manner

    PubMed Central

    Gupta, Pramod Kumar; Chakraborty, Pampi; Kumar, Santosh; Singh, Prafull Kumar; Rajan, M. G. R.; Sainis, Krishna B.; Kulkarni, Savita

    2016-01-01

    Rapid emergence of drug resistance in Mycobacterium tuberculosis (MTB) is a major health concern and demands the development of novel adjunct immunotherapeutic agents capable of modulating the host immune responses in order to control the pathogen. In the present study, we sought to investigate the immunomodulatory effects of G1-4A, a polysaccharide derived from the Indian medicinal plant Tinospora cordifolia, in in-vitro and aerosol mouse models of MTB infection. G1-4A treatment of MTB infected RAW264.7 macrophages significantly induced the surface expression of MHC-II and CD-86 molecules, secretion of proinflammatory cytokines (TNF-α, IL-β, IL-6, IL-12, IFN-γ) and nitric oxide leading to reduced intracellular survival of both drug sensitive (H37Rv) as well as multi drug resistant strains (Beijing and LAM) of MTB, which was partially attributed to G1-4A induced NO production in TLR4-MyD88 dependent manner. Similarly, bacillary burden was significantly reduced in the lungs of MTB infected BALB/c mice treated with G1-4A, with simultaneous up-regulation of the expression of TNF-α, INF-γ and NOS2 in the mouse lung along with increased levels of Th1 cytokines like IFN-γ, IL-12 and decreased levels of Th2 cytokine like IL-4 in the serum. Furthermore, combination of G1-4A with Isoniazid (INH) exhibited better protection against MTB compared to that due to INH or G1-4A alone, suggesting its potential as adjunct therapy. Our results demonstrate that modulation of host immune responses by G1-4A might improve the therapeutic efficacy of existing anti-tubercular drugs and provide an attractive strategy for the development of alternative therapies to control tuberculosis. PMID:27148868

  10. Identification of Novel Inflammatory Cytokines and Contribution of Keratinocyte-Derived Chemokine to Inflammation in Response to Vibrio vulnificus Infection in Mice.

    PubMed

    Liu, Xiao-Fei; Wu, Jing; Wang, Ming-Yi; Chen, Ying-Jian; Cao, Yuan; Hu, Cheng-Jin

    2015-10-01

    Currently, only tumor necrosis factor alpha (TNF-α) and interleukin family cytokines have been found to be elicited in Vibrio vulnificus (V. vulnificus)-infected animal models and humans. However, multiple other cytokines are also involved in the immune and inflammatory responses to foreign microorganism infection. Antibody array technology, unlike traditional enzyme-linked immunosorbent assay (ELISA), is able to detect multiple cytokines at one time. Therefore, in this study, we examined the proinflammatory cytokine profile in the serum and liver homogenate samples of bacterial-infected mice using antibody array technology. We identified nine novel cytokines in response to V. vulnificus infection in mice. We found that keratinocyte-derived chemokine (KC) was the most elevated cytokine and demonstrated that KC played a very important role in the V. vulnificus infection-elicited inflammatory response in mice, as evidenced by the fact that the blocking of KC by anti-KC antibody reduced hepatic injury in vivo and that KC induced by V. vulnificus infection in AML-12 cells chemoattracted neutrophils. Our findings implicate that KC may serve as a novel diagnostic biomarker and a possible therapeutic target for V. vulnificus infection.

  11. Phytophagous insect fauna tracks host plant responses to exotic grass invasion.

    PubMed

    Almeida-Neto, Mário; Prado, Paulo I; Lewinsohn, Thomas M

    2011-04-01

    The high dependence of herbivorous insects on their host plants implies that plant invaders can affect these insects directly, by not providing a suitable habitat, or indirectly, by altering host plant availability. In this study, we sampled Asteraceae flower heads in cerrado remnants with varying levels of exotic grass invasion to evaluate whether invasive grasses have a direct effect on herbivore richness independent of the current disturbance level and host plant richness. By classifying herbivores according to the degree of host plant specialization, we also investigated whether invasive grasses reduce the uniqueness of the herbivorous assemblages. Herbivorous insect richness showed a unimodal relationship with invasive grass cover that was significantly explained only by way of the variation in host plant richness. The same result was found for polyphagous and oligophagous insects, but monophages showed a significant negative response to the intensity of the grass invasion that was independent of host plant richness. Our findings lend support to the hypothesis that the aggregate effect of invasive plants on herbivores tends to mirror the effects of invasive plants on host plants. In addition, exotic plants affect specialist insects differently from generalist insects; thus exotic plants affect not only the size but also the structural profile of herbivorous insect assemblages.

  12. Host suitability and gas exchange response of grapevines to potato leafhopper (Hemiptera: Cicadellidae).

    PubMed

    Lamp, William O; Miranda, Daniel; Culler, Lauren E; Alexander, Laurie C

    2011-08-01

    Although potato leafhopper, Empoasca fabae (Harris) (Hemiptera: Cicadellidae), is highly polyphagous, classic host studies do not recognize grapevines (Vitis spp.), as suitable hosts. Recently, injury has been reported and reproduction documented within grape vineyards, suggesting a host expansion for the leafhopper. To document this apparent expansion in host use, we determined whether grape plants were suitable hosts for potato leafhopper reproduction, measured the consequence of feeding injury on gas exchange rates of grape leaves, and compared the susceptibility to feeding injury among cultivars. We found that potato leafhopper adults survived equally well on grape (Vitis vinifera L.), alfalfa (Medicago sativa L.), and fava bean (Vicia faba L.). The total number of offspring was greater on fava bean but did not differ between alfalfa and grape. Injury to grapevines was assessed by measuring gas exchange responses of leaves in field cages and in greenhouse tests. We found marginally significant declines in photosynthesis and transpiration rates in the field (9.6 and 13.2%, respectively), and much stronger effects in greenhouse tests (ranging between 22 and 52%). Our results verify that Vitis is a suitable host, and that potato leafhopper is capable of injuring its gas exchange physiology. We discuss possible explanations for the host expansion, and its potential to damage commercial grapevines.

  13. Differential cytokine and antibody responses to adult and larval stages of Onchocerca volvulus consistent with the development of concomitant immunity.

    PubMed

    MacDonald, Angus J; Turaga, Prasad S D; Harmon-Brown, Carolyn; Tierney, Tracy J; Bennett, Kristine E; McCarthy, Maggie C; Simonek, Scott C; Enyong, Peter A; Moukatte, Daniel W; Lustigman, Sara

    2002-06-01

    The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocyte-macrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.

  14. Electroantennogram (EAG) responses of Microplitis croceipes and Cotesia marginiventris and their lepidopteran hosts to a wide array of odor stimuli: correlation between EAG response and degree of host specificity?

    PubMed

    Ngumbi, Esther; Chen, Li; Fadamiro, Henry

    2010-09-01

    In order to test whether the electroantennogram (EAG) response spectrum of an insect correlates to its degree of host specificity, we recorded EAG responses of two parasitoid species with different degrees of host specificity, Microplitis croceipes (specialist) and Cotesia marginiventris (generalist), to a wide array of odor stimuli including compounds representing green leaf volatiles (GLVs), herbivore-induced plant volatiles (HIPV), ecologically irrelevant (not used by the parasitoid species and their hosts for host location) plant volatiles, and host-specific odor stimuli (host sex pheromones, and extracts of host caterpillar body and frass). We also tested the EAG responses of female moths of the caterpillar hosts of the parasitoids, Heliothis virescens and Spodoptera exigua, to some of the odor stimuli. We hypothesized that the specialist parasitoid will have a narrower EAG response spectrum than the generalist, and that the two lepidopteran species, which are similar in their host plant use, will show similar EAG response spectra to plant volatiles. As predicted, the specialist parasitoid showed greater EAG responses than the generalist to host-specific odor and one HIPV (cis-3-hexenyl butyrate), whereas the generalist showed relatively greater EAG responses to the GLVs and unrelated plant volatiles. We detected no differences in the EAG responses of H. virescens and S. exigua to any of the tested odor.

  15. Inducible nitric oxide synthase response and associated cytokine gene expression in the spleen of mice infected with Clonorchis sinensis.

    PubMed

    Shen, Ji-Qing; Yang, Qing-Li; Xue, Yan; Cheng, Xiao-Bing; Jiang, Zhi-Hua; Yang, Yi-Chao; Chen, Ying-Dan; Zhou, Xiao-Nong

    2015-05-01

    Clonorchis sinensis is a food-borne parasite that induces a permanent increase of nitrosation in the body upon infection. The spleen is an important secondary lymphoid organ for the regulation of immune responses locally and in the whole body. However, the functions and mechanisms of the spleen in nitric oxide (NO) responses after C. sinensis infection remain unknown. In this study, BALB/c mice were infected with 20, 40, and 80 C. sinensis metacercariae to simulate mild, moderate, and severe infections, respectively. We examined the expression of inducible nitric oxide synthase (iNOS) in the spleen and the relevant cytokine transcription in splenocytes from the mice infected with different amounts of metacercariae. The iNOS of the mice infected with 80 metacercariae was expressed in the spleen as early as 10 days post-infection (dpi) and gradually increased until 90 dpi. The iNOS expression in the mice infected with 40 metacercariae was detected only at 45 and 90 dpi, but not in the mice infected with 20 metacercariae. The level of interferon (IFN)-γ messenger RNA (mRNA) transcription in splenocytes significantly increased at 10 and 20 dpi (P < 0.05) in response to mild/moderate infection but gradually decreased to normal levels after 45 dpi. The level of IL-12p35 mRNA transcription did not change at 10 and 20 dpi but significantly decreased after 45 dpi under moderate/severe infection (P < 0.05/0.01/0.001). The level of IL-18 mRNA transcription significantly increased at 10 dpi (P < 0.05/0.01) but significantly decreased after 20 dpi (P < 0.05/0.01/0.001). These results suggest that spleen is an important organ for iNOS/NO responses, which correspond to the severity of C. sinensis infection, but cannot be attributed to the expression of the Th1 cytokines.

  16. Alphavirus Infection: Host Cell Shut-Off and Inhibition of Antiviral Responses.

    PubMed

    Fros, Jelke J; Pijlman, Gorben P

    2016-06-11

    Alphaviruses cause debilitating disease in humans and animals and are transmitted by blood-feeding arthropods, typically mosquitoes. With a traditional focus on two models, Sindbis virus and Semliki Forest virus, alphavirus research has significantly intensified in the last decade partly due to the re-emergence and dramatic expansion of chikungunya virus in Asia, Europe, and the Americas. As a consequence, alphavirus-host interactions are now understood in much more molecular detail, and important novel mechanisms have been elucidated. It has become clear that alphaviruses not only cause a general host shut-off in infected vertebrate cells, but also specifically suppress different host antiviral pathways using their viral nonstructural proteins, nsP2 and nsP3. Here we review the current state of the art of alphavirus host cell shut-off of viral transcription and translation, and describe recent insights in viral subversion of interferon induction and signaling, the unfolded protein response, and stress granule assembly.

  17. Modulation of host immune responses to Toxoplasma gondii by microRNAs.

    PubMed

    Cai, Yihong; Shen, Jilong

    2017-02-07

    To survive successfully, Toxoplasma counteracts the strictly regulated host innate response to downregulate inflammation that could be deleterious for the parasite. MicroRNAs are vital regulators of both innate and adaptive immunity, controlling the maintenance and development of immune progenitors as well as the differentiation and the functions of host mature immune cells. Thus the complexity of mechanisms underlying the connection between Toxoplasma and host immunity has led to investigations of miRNAs as additional key molecular players. The knowledge acquired from these studies will be useful for aiding the discovery of new targets for diagnosis or therapeutic approaches for toxoplasmosis and insight into the interaction between host and parasite. This article is protected by copyright. All rights reserved.

  18. The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines.

    PubMed

    Smiljanovic, Biljana; Grün, Joachim R; Biesen, Robert; Schulte-Wrede, Ursula; Baumgrass, Ria; Stuhlmüller, Bruno; Maslinski, Wlodzimierz; Hiepe, Falk; Burmester, Gerd-R; Radbruch, Andreas; Häupl, Thomas; Grützkau, Andreas

    2012-11-01

    Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as tumor necrosis factor (TNF)-α in rheumatoid arthritis (RA) and interferon (IFN)-α/γ in systemic lupus erythematosus (SLE). To relate the transcriptional imprinting of cytokines in a cell type- and disease-specific manner, we generated gene expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNF-α, IFN-α2a, and IFN-γ. Monocytes from SLE and RA patients revealed disease-specific gene expression profiles. In vitro-generated signatures induced by IFN-α2a and IFN-γ showed similar profiles that only partially overlapped with those induced by TNF-α. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNF-α regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNF-α that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene expression profiles, which can be molecularly dissected when compared with in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention.

  19. Pathogen Cell-to-cell Variability Drives Heterogeneity In Host Immune Responses

    PubMed Central

    Avraham, Roi; Haseley, Nathan; Brown, Douglas; Penaranda, Cristina; Jijon, Humberto B; Trombetta, John J; Satija, Rahul; Shalek, Alex K; Xavier, Ramnik; Regev, Aviv; Hung, Deborah T

    2015-01-01

    Summary Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation that may be important for infection outcome. To characterize gene expression variation that underlies distinct infection outcomes, we developed an experimental system that combines single-cell RNA-seq with fluorescent markers, monitoring infection phenotypes. Probing the responses of individual macrophages to invading Salmonella, we find that variation between individual infected host cells is determined by the heterogeneous activity of bacterial factors in individual infecting bacteria. We illustrate how variable PhoPQ activity in the population of invading bacteria drives variable host Type I IFN responses by modifying LPS in a subset of bacteria. This work demonstrates a causative link between host and bacterial variability, with cell-to-cell variation between different bacteria being sufficient to drive radically different host immune responses. This co-variation has implications for host-pathogen dynamics in vivo. PMID:26343579

  20. Multispecies Biofilms and Host Responses: “Discriminating the Trees from the Forest”

    PubMed Central

    Peyyala, R.; Ebersole, J.L.

    2014-01-01

    Periodontal diseases reflect a tissue destructive process of the hard and soft tissues of the periodontium that are initiated by the accumulation of multispecies bacterial biofilms in the subgingival sulcus. This accumulation, in both quantity and quality of bacteria, results in a chronic immunoinflammatory response of the host to control this noxious challenge, leading to collateral damage of the tissues. As knowledge of the characteristics of the host-bacterial interactions in the oral cavity has expanded, new knowledge has become available on the complexity of the microbial challenge and the repertoire of host responses to this challenge. Recent results from the Human Microbiome Project continue to extend the array of taxa, genera, and species of bacteria that inhabit the multiple niches in the oral cavity; however, there is rather sparse information regarding variations in how host cells discriminate commensal from pathogenic species, as well as how the host response is affected by the 3-dimensional architecture and interbacterial interactions that occur in the oral biofilms. This review provides some insights into thes- processes by including existing literature on the biology of nonoral bacterial biofilms, and the more recent literature just beginning to document how the oral cavity responds to multispecies biofilms. PMID:23141757

  1. Shigella flexneri Infection in Caenorhabditis elegans: Cytopathological Examination and Identification of Host Responses

    PubMed Central

    George, Divya T.; Behm, Carolyn A.; Hall, David H.; Mathesius, Ulrike; Rug, Melanie; Nguyen, Ken C. Q.; Verma, Naresh K.

    2014-01-01

    The Gram-negative bacterium Shigella flexneri is the causative agent of shigellosis, a diarrhoeal disease also known as bacillary dysentery. S. flexneri infects the colonic and rectal epithelia of its primate host and induces a cascade of inflammatory responses that culminates in the destruction of the host intestinal lining. Molecular characterization of host-pathogen interactions in this infection has been challenging due to the host specificity of S. flexneri strains, as it strictly infects humans and non-human primates. Recent studies have shown that S. flexneri infects the soil dwelling nematode Caenorhabditis elegans, however, the interactions between S. flexneri and C. elegans at the cellular level and the cause of nematode death are unknown. Here we attempt to gain insight into the complex host-pathogen interactions between S. flexneri and C. elegans. Using transmission electron microscopy, we show that live S. flexneri cells accumulate in the nematode intestinal lumen, produce outer membrane vesicles and invade nematode intestinal cells. Using two-dimensional differential in-gel electrophoresis we identified host proteins that are differentially expressed in response to S. flexneri infection. Four of the identified genes, aco-1, cct-2, daf-19 and hsp-60, were knocked down using RNAi and ACO-1, CCT-2 and DAF-19, which were identified as up-regulated in response to S. flexneri infection, were found to be involved in the infection process. aco-1 RNAi worms were more resistant to S. flexneri infection, suggesting S. flexneri-mediated disruption of host iron homeostasis. cct-2 and daf-19 RNAi worms were more susceptible to infection, suggesting that these genes are induced as a protective mechanism by C. elegans. These observations further our understanding of the processes involved in S. flexneri infection of C. elegans, which is immensely beneficial to the routine use of this new in vivo model to study S. flexneri pathogenesis. PMID:25187942

  2. Modulation in vitro of human natural cytotoxicity, lymphocyte proliferative response to mitogens and cytokine production by essential fatty acids.

    PubMed Central

    Purasiri, P; Mckechnie, A; Heys, S D; Eremin, O

    1997-01-01

    Essential fatty acids (EFA) have been shown in animal studies to have a differential effect on various aspects of immune reactivity. However, there have been few studies in humans. Therefore, we elected to investigate the effects of a variety of EFA [gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in vitro on human blood lymphocyte reactivity, cytokine secretion and natural cytotoxicity. The proliferative response to polyclonal mitogens (phytohaemagglutinin, pokeweed mitogen, concanavalin A), as measured by [3H]thymidine incorporation into newly synthesized lymphocytes, was inhibited (P < 0.05) by all EFAs tested, in a dose-dependent manner (3-15 micrograms/ml). The greatest inhibition of proliferation was caused by EPA and DHA. Similarly, EPA, DHA and GLA significantly reduced cytotoxic activity [expressed as lytic units, using 51 chromium-release assays natural killer (NK) (K562 cells) and lymphokine-activated (LAK) (Daudi cells) cells] (P < 0.05) in a concentration-dependent manner (5-50 micrograms/ml), without affecting cell viability. EPA and DHA exhibited greater suppression than GLA. Furthermore, the inhibition of cell proliferation and suppression of natural cytotoxicity was associated with marked decrease in cytokine [interleukin-1 (IL-1), IL-2, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] production in vitro. Our findings demonstrate that EFAs (GLA, EPA, DHA) have the potential to inhibit significantly various aspects of human lymphocyte cell-mediated and humoral immune reactivities. PMID:9415022

  3. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

    PubMed Central

    Tyner, Jeffrey W.; Bumm, Thomas G.; Deininger, Jutta; Wood, Lisa; Aichberger, Karl J.; Loriaux, Marc M.; Druker, Brian J.; Burns, Christopher J.; Fantino, Emmanuelle

    2010-01-01

    Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5μM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells. PMID:20385788

  4. Transient early neurotrophin release and delayed inflammatory cytokine release by microglia in response to PAR-2 stimulation.

    PubMed

    Chen, Chen-Wen; Chen, Qian-Bo; Ouyang, Qing; Sun, Ji-Hu; Liu, Fang-Ting; Song, Dian-Wen; Yuan, Hong-Bin

    2012-06-25

    Activated microglia exerts both beneficial and deleterious effects on neurons, but the signaling mechanism controlling these distinct responses remain unclear. We demonstrated that treatment of microglial cultures with the PAR-2 agonist, 2-Furoyl-LIGRLO-NH2, evoked early transient release of BDNF, while sustained PAR-2 stimulation evoked the delayed release of inflammatory cytokines (IL-1 β and TNF-α) and nitric oxide. Culture medium harvested during the early phase (at 1 h) of microglial activation induced by 2-Furoyl-LIGRLO-NH2 (microglial conditioned medium, MCM) had no deleterious effects on cultured neurons, while MCM harvested during the late phase (at 72 h) promoted DNA fragmentation and apoptosis as indicated by TUNEL and annexin/PI staining. Blockade of PAR-1 during the early phase of PAR-2 stimulation enhanced BDNF release (by 11%, small but significant) while a PAR-1 agonist added during the late phase (24 h after 2-Furoyl-LIGRLO-NH2 addition) suppressed the release of cytokines and NO. The neuroprotective and neurotoxic effects of activated microglial exhibit distinct temporal profiles that are regulated by PAR-1 and PAR-2 stimulation. It may be possible to facilitate neuronal recovery and repair by appropriately timed stimulation and inhibition of microglial PAR-1 and PAR-2 receptors.

  5. Global sensitivity analysis of a mathematical model of acute inflammation identifies nonlinear dependence of cumulative tissue damage on host interleukin-6 responses.

    PubMed

    Mathew, Shibin; Bartels, John; Banerjee, Ipsita; Vodovotz, Yoram

    2014-10-07

    The precise inflammatory role of the cytokine interleukin (IL)-6 and its utility as a biomarker or therapeutic target have been the source of much debate, presumably due to the complex pro- and anti-inflammatory effects of this cytokine. We previously developed a nonlinear ordinary differential equation (ODE) model to explain the dynamics of endotoxin (lipopolysaccharide; LPS)-induced acute inflammation and associated whole-animal damage/dysfunction (a proxy for the health of the organism), along with the inflammatory mediators tumor necrosis factor (TNF)-α, IL-6, IL-10, and nitric oxide (NO). The model was partially calibrated using data from endotoxemic C57Bl/6 mice. Herein, we investigated the sensitivity of the area under the damage curve (AUCD) to the 51 rate parameters of the ODE model for different levels of simulated LPS challenges using a global sensitivity approach called Random Sampling High Dimensional Model Representation (RS-HDMR). We explored sufficient parametric Monte Carlo samples to generate the variance-based Sobol' global sensitivity indices, and found that inflammatory damage was highly sensitive to the parameters affecting the activity of IL-6 during the different stages of acute inflammation. The AUCIL6 showed a bimodal distribution, with the lower peak representing healthy response and the higher peak representing sustained inflammation. Damage was minimal at low AUCIL6, giving rise to a healthy response. In contrast, intermediate levels of AUCIL6 resulted in high damage, and this was due to the insufficiency of damage recovery driven by anti-inflammatory responses from IL-10 and the activation of positive feedback sustained by IL-6. At high AUCIL6, damage recovery was interestingly restored in some population of simulated animals due to the NO-mediated anti-inflammatory responses. These observations suggest that the host's health status during acute inflammation depends in a nonlinear fashion on the magnitude of the inflammatory stimulus

  6. Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

    PubMed Central

    Zhou, Xikun; Ye, Yan; Sun, Yuyang; Li, Xuefeng; Wang, Wenxue; Privratsky, Breanna; Tan, Shirui; Zhou, Zongguang; Huang, Canhua; Wei, Yu-Quan; Birnbaumer, Lutz

    2015-01-01

    Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1−/− mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca2+ entry and triggered protein kinase Cα (PKCα) activity to facilitate nuclear translocation of NF-κB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCα signaling circuit. PMID:26031335

  7. Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice.

    PubMed

    Sadighi Akha, Amir A; McDermott, Andrew J; Theriot, Casey M; Carlson, Paul E; Frank, Charles R; McDonald, Roderick A; Falkowski, Nicole R; Bergin, Ingrid L; Young, Vincent B; Huffnagle, Gary B

    2015-04-01

    Our previous work has shown the significant up-regulation of Il22 and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) as part of the mucosal inflammatory response to Clostridium difficile infection in mice. Others have shown that phosphorylation of STAT3 at mucosal surfaces includes interleukin-22 (IL-22) and CD160-mediated components. The current study sought to determine the potential role(s) of IL-22 and/or CD160 in the mucosal response to C. difficile infection. Clostridium difficile-infected mice treated with anti-IL-22, anti-CD160 or a combination of the two showed significantly reduced STAT3 phosphorylation in comparison to C. difficile-infected mice that had not received either antibody. In addition, C. difficile-infected mice treated with anti-IL-22/CD160 induced a smaller set of genes, and at significantly lower levels than the untreated C. difficile-infected mice. The affected genes included pro-inflammatory chemokines and cytokines, and anti-microbial peptides. Furthermore, histopathological and flow cytometric assessments both showed a significantly reduced influx of neutrophils in C. difficile-infected mice treated with anti-IL-22/CD160. These data demonstrate that IL-22 and CD160 are together responsible for a significant fraction of the colonic STAT3 phosphorylation in C. difficile infection. They also underscore the additive effects of IL-22 and CD160 in mediating both the pro-inflammatory and pro-survival aspects of the host mucosal response in this infection.

  8. Stimuli-responsive host-guest systems based on the recognition of cryptands by organic guests.

    PubMed

    Zhang, Mingming; Yan, Xuzhou; Huang, Feihe; Niu, Zhenbin; Gibson, Harry W

    2014-07-15

    CONSPECTUS: As the star compounds in host-guest chemistry, the syntheses of crown ethers proclaimed the birth of supramolecular chemistry. Crown ether-based host-guest systems have attracted great attention in self-assembly processes because of their good selectivity, high efficiency, and convenient responsiveness, enabling their facile application to the "bottom-up" approach for construction of functional molecular aggregates, such as artificial molecular machines, drug delivery materials, and supramolecular polymers. Cryptands, as preorganized derivatives of crown ethers, not only possess the above-mentioned properties but also have three-dimensional spatial structures and higher association constants compared with crown ethers. More importantly, the introduction of the additional arms makes cryptand-based host-guest systems responsive to more stimuli, which is crucial for the construction of adaptive or smart materials. In the past decade, we designed and synthesized crown ether-based cryptands as a new type of host for small organic guests with the purpose of greatly increasing the stabilities of the host-guest complexes and preparing mechanically interlocked structures and large supramolecular systems more efficiently while retaining or increasing their stimuli-responsiveness. Organic molecules such as paraquat derivatives and secondary ammonium salts have been widely used in the fabrication of functional supramolecular aggregates. Many host molecules including crown ethers, cyclodextrins, calixarenes, cucurbiturils, pillararenes, and cryptands have been used in the preparation of self-assembled structures with these guest molecules, but among them cryptands exhibit the best stabilities with paraquat derivatives in organic solvents due to their preorganization and additional and optimized binding sites. They enable the construction of sophisticated molecules or supramolecules in high yields, affording a very efficient way to fabricate stimuli-responsive

  9. Early and Late Extensive Chronic Graft-Versus-Host Disease (cGVHD) In Children Is Characterized By Different Th1/Th2 Cytokine Profiles: Findings Of The Children’s Oncology Group Study (COG), ASCT0031

    PubMed Central

    Rozmus, Jacob; Schultz, Kirk R.; Wynne, Kristin; Kariminia, Amina; Satyanarayana, Preeti; Krailo, Mark; Grupp, Stephan A.; Gilman, Andrew L.; Goldman, Frederick D.

    2011-01-01

    Mechanisms underlying chronic graft-versus-host disease (cGVHD) are numerous, including skewing of Th1/Th2 cytokine expression. cGVHD has biological differences between early and late onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early or late onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children’s Oncology Group phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon gamma (IFN-γ) and interleukins 2, 4 and 10(IL-2, IL-4 and IL-10) from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction (Q-PCR). We found that early onset cGVHD (n=33) was characterized by decreased expression of IFN-γ and IL-2 mRNA after non-specific PMA-Ionomycin stimulation. In contrast, late onset cGVHD (n=11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti-CD3 stimulation of T cells. Receiver Operator Characteristic (ROC) curve analysis revealed that IFN-γ production could determine the absence of early cGVHD (AUC=0.77) and IL-4 (AUC=0.89) and IL-2 (AUC=0.84) the absence of late cGVHD. We did not find any correlation between cytokine expression and a specific immune cell subset. We also showed an increased expression of Foxp3 mRNA in early onset cGVHD and late controls. The different time-dependent cytokine profiles in newly-diagnosed cGVHD suggests that mechanisms underlying cGVHD are temporally regulated. While larger validation studies are needed our data suggests cytokine profiles could potentially be used as biomarkers for the diagnosis of cGVHD. PMID:21669298

  10. Effects of oat β-glucan on the macrophage cytokine response to herpes simplex virus 1 infection in vitro.

    PubMed

    Murphy, E Angela; Davis, J Mark; Brown, Adrienne S; Carmichael, Martin D; Ghaffar, Abdul; Mayer, Eugene P

    2012-08-01

    Oat β-glucan can counteract the increased risk for Herpes Simplex Virus 1 (HSV-1) infection in mice, the effects of which have, at least in part, been attributed to macrophages. However, the specific responses of macrophages to oat β-glucan treatment in this model have yet to be elucidated. We examined the effects of varying doses of oat β-glucan on the pro-inflammatory cytokine response in both peritoneal and lung macrophages with and without exposure to HSV-1 infection in vitro. Peritoneal and lung macrophages were obtained from mice and cultured with varying concentrations of oat β-glucan (0 (control), 10, 100, and 1,000 μg) for 24 h and supernatants were collected. A standardized dose of HSV-1 was added for a second 24 h incubation period after which supernatants were again collected. Samples were analyzed for interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) using enzyme linked immunosorbent assay (ELISA). In most cases, oat β-glucan resulted in a dose-dependent increase in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in lung and peritoneal macrophages with and without exposure to HSV-1 infection. When comparing across macrophage source, this response was greater for IL-1β and IL-6 in peritoneal macrophages and for TNF-α in lung macrophages. This may be a mechanism for the decreased risk for HSV-1 infection following oat β-glucan feedings in mice.

  11. Aromatic amide and hydrazide foldamer-based responsive host-guest systems.

    PubMed

    Zhang, Dan-Wei; Zhao, Xin; Li, Zhan-Ting

    2014-07-15

    CONSPECTUS: In host-guest chemistry, a larger host molecule selectively and noncovalently binds to a smaller guest molecule or ion. Early studies of host-guest chemistry focused on the recognition of spherical metal or ammonium ions by macrocyclic hosts, such as cyclic crown ethers. In these systems, preorganization enables their binding sites to cooperatively contact and attract a guest. Although some open-chain crown ether analogues possess similar, but generally lower, binding affinities, the design of acyclic molecular recognition hosts has remained challenging. One of the most successful examples was rigid molecular tweezers, acyclic covalently bonded preorganized host molecules with open cavities that bind tightly as they stiffen. Depending on the length of the atomic backbones, hydrogen bonding-driven aromatic amide foldamers can form open or closed cavities. Through rational design of the backbones and the introduction of added functional groups, researchers can regulate the shape and size of the cavity. The directionality of hydrogen bonding and the inherent rigidity of aromatic amide units allow researchers to predict both the shape and size of the cavity of an aromatic amide foldamer. Therefore, researchers can then design guest molecules with structure that matches the cavity shape, size, and binding sites of the foldamer host. In addition, because hydrogen bonds are dynamic, researchers can design structures that can adapt to outside stimuli to produce responsive supramolecular architectures. In this Account, we discuss how aromatic amide and hydrazide foldamers induced by hydrogen bonding can produce responsive host-guest systems, based on research by our group and others. First we highlight the helical chirality induced as binding occurs in solution, which includes the induction of helicity by chiral guests in oligomeric and polymeric foldamers, the formation of diastereomeric complexes between chiral foldamer hosts and guests, and the induction of

  12. Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines.

    PubMed

    Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R; Davis, Dawn B; Corbett, John A; Mathews, Clayton E

    2015-09-01

    While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line.

  13. Early host responses to avian influenza A virus are prolonged and enhanced at transcriptional level depending on maturation of the immune system.

    PubMed

    Reemers, Sylvia S; van Leenen, Dik; Koerkamp, Marian J Groot; van Haarlem, Daphne; van de Haar, Peter; van Eden, Willem; Vervelde, Lonneke

    2010-05-01

    Newly hatched chickens are more susceptible to infectious diseases than older birds because of an immature immune system. The aim of this study was to determine to what extent host responses to avian influenza virus (AIV) inoculation are affected by age. Therefore, 1- and 4-week (wk) old birds were inoculated with H9N2 AIV or saline. The trachea and lung were sampled at 0, 8, 16 and 24h post-inoculation (h.p.i.) and gene expression profiles determined using microarray analysis. Firstly, saline controls of both groups were compared to analyse the changes in gene profiles related to development. In 1-wk-old birds, higher expression of genes related to development of the respiratory immune system and innate responses were found, whereas in 4-wk-old birds genes were up regulated that relate to the presence of higher numbers of leukocytes in the respiratory tract. After inoculation with H9N2, gene expression was most affected at 16 h.p.i. in 1-wk-old birds and at 16 and 24h.p.i. in 4-wk-old birds in the trachea and especially in the lung. In 1-wk-old birds less immune related genes including innate related genes were induced which might be due to age-dependent reduced functionality of antigen presenting cells (APC), T cells and NK cells. In contrast cytokine and chemokines gene expression was related to viral load in 1-wk-old birds and less in 4-wk-old birds. Expression of cellular host factors that block virus replication by interacting with viral factors was independent of age or tissue for most host factors. These data show that differences in development are reflected in gene expression and suggest that the strength of host responses at transcriptional level may be a key factor in age-dependent susceptibility to infection, and the cellular host factors involved in virus replication are not.

  14. Role of the leukocyte response in normal and immunocompromised host after Clostridium difficile infection.

    PubMed

    Vargas, Edwin; Apewokin, Senu; Madan, Rajat

    2017-02-20

    Clostridium difficile is the leading cause of healthcare-associated infections in the United States. Clinically, C. difficile-associated disease can present as asymptomatic colonization, self-limited diarrheal illness or severe colitis (that may result in death). This variability in disease course and outcomes suggests that host factors play an important role as key determinants of disease severity. Currently, there are several scoring indices to estimate severity of C. difficile-associated disease. Leukocytosis and renal failure are considered to be the most important predictors of C. difficile disease severity in hosts with a normal immune system. The degree of leukocytosis which is considered significant for severe disease and how it is scored vary amongst scoring indices. None of the scores have been prospectively validated, and while total WBC count is useful to estimate the magnitude of the host response in most patient populations, in immune-compromised patients like those receiving chemotherapy, solid organ transplant patients or hematopoietic stem cell transplants the WBC response can be variable or even absent making this marker of severity difficult to interpret. Other cellular subsets like neutrophils, eosinophils and lymphocytes provide important information about the host immune status and play an important role in the immune response against C. difficile infection. However, under the current scoring systems the role of these cellular subsets have been underestimated and only total white blood cell counts are taken into account. In this review we highlight the role of host leukocyte response to C. difficile challenge in the normal and immunocompromised host, and propose possible ways that would allow for a better representation of the different immune cell subsets (neutrophils, lymphocytes and eosinophils) in the current scoring indices.

  15. Septate endophyte colonization and host responses of grasses and forbs native to a tallgrass prairie.

    PubMed

    Mandyam, Keerthi; Fox, Chad; Jumpponen, Ari

    2012-02-01

    Native tallgrass prairies support distinct dark septate endophyte (DSE) communities exemplified by Periconia macrospinosa and Microdochium sp. that were recently identified as common root symbionts in this system. Since these DSE fungi were repeatedly isolated from grasses and forbs, we aimed to test their abilities to colonize different hosts. One Microdochium and three Periconia strains were screened for colonization and growth responses using five native grasses and six forbs in an in vitro system. Previously published data for an additional grass (Andropogon gerardii) were included and reanalyzed. Presence of indicative inter- and intracellular structures (melanized hyphae, microsclerotia, and chlamydospores) demonstrated that all plant species were colonized by the DSE isolates albeit to varying degrees. Microscopic observations suggested that, compared to forbs, grasses were colonized to a greater degree in vitro. Host biomass responses varied among the host species. In broad comparisons, more grass species than forbs tended to respond positively to colonization, whereas more forb species tended to be non-responsive. Based on the suspected differences in the levels of colonization, we predicted that tallgrass prairie grasses would support greater DSE colonization than forbs in the field. A survey of field-collected roots from 15 native species supported this hypothesis. Our study supports the "broad host range" of DSE fungi, although the differences in the rates of colonization in the laboratory and in the field suggest a greater compatibility between grasses and DSE fungi. Furthermore, host responses to DSE range from mutualism to parasitism, suggesting a genotype-level interplay between the fungi and their hosts that determines the outcome of this symbiosis.

  16. Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway.

    PubMed

    Zheng, Yuejuan; Yang, Yang; Li, Yuhu; Xu, Limin; Wang, Yi; Guo, Ziyi; Song, Haiyan; Yang, Muyi; Luo, Beier; Zheng, Aoxiang; Li, Ping; Zhang, Yan; Ji, Guang; Yu, Yizhi

    2013-07-01

    Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-α, IL-12 and IL-1β) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro- and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

  17. IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13-dependent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical “type 2” immune response in the gastrointestinal tract, yet the underlying mechani...

  18. A new method to measure air-borne pyrogens based on human whole blood cytokine response.

    PubMed

    Kindinger, Ilona; Daneshian, Mardas; Baur, Hans; Gabrio, Thomas; Hofmann, Andreas; Fennrich, Stefan; von Aulock, Sonja; Hartung, Thomas

    2005-03-01

    Air-borne microorganisms, as well as their fragments and components, are increasingly recognized to be associated with pulmonary diseases, e.g. organic dust toxic syndrome, humidifier lung, building-related illness, "Monday sickness." We have previously described and validated a new method for the detection of pyrogenic (fever-inducing) microbial contaminations in injectable drugs, based on the inflammatory reaction of human blood to pyrogens. We have now adapted this test to evaluate the total inflammatory capacity of air samples. Air was drawn onto PTFE membrane filters, which were incubated with human whole blood from healthy volunteers inside the collection device. Cytokine release was measured by ELISA. The test detects endotoxins and non-endotoxins, such as fungal spores, Gram-positive bacteria and their lipoteichoic acid moiety and pyrogenic dust particles with high sensitivity, thus reflecting the total inflammatory capacity of a sample. When air from different surroundings such as working environments and animal housing was assayed, the method yielded reproducible data which correlated with other parameters of microbial burden tested. We further developed a standard material for quantification and showed that this assay can be performed with cryopreserved as well as fresh blood. The method offers a test to measure the integral inflammatory capacity of air-borne microbial contaminations relevant to humans. It could thus be employed to assess air quality in different living and work environments.

  19. IL-36α: a novel cytokine involved in the catabolic and inflammatory response in chondrocytes

    PubMed Central

    Conde, Javier; Scotece, Morena; Abella, Vanessa; Lois, Ana; López, Verónica; García-Caballero, Tomás; Pino, Jesús; Gómez-Reino, Juan Jesús; Gómez, Rodolfo; Lago, Francisca; Gualillo, Oreste

    2015-01-01

    Recent studies confer to IL-36α pro-inflammatory properties. However, little is known about the expression and function of IL-36α in cartilage. This study sought to analyze the expression of IL-36α in healthy and OA cartilage. Next, we determined the effects of recombinant IL-36α on catabolism and inflammation in chondrocytes. For completeness, part of the signaling pathway elicited by IL-36α was also explored. IL-36α expression was evaluated by immunohistochemistry and RT-qPCR. Expression of MMP-13, NOS2 and COX-2 was also determined in OA articular chondrocytes treated with recombinant IL-36α. IκB-α and P-p38 was explored by western blot. We observed a low constitutive expression of IL-36α in healthy human chondrocytes. However, OA chondrocytes likely expressed more IL-36α than healthy chondrocytes. In addition, immune cells infiltrated into the joint and PBMCs express higher levels of IL-36α in comparison to chondrocytes. OA chondrocytes, treated with IL-36α, showed significant increase in the expression of MMP-13, NOS2 and COX-2. Finally, IL-36α stimulated cells showed NFκB and p38 MAPK activated pathways. IL-36α acts as a pro-inflammatory cytokine at cartilage level, by increasing the expression of markers of inflammation and cartilage catabolism. Like other members of IL-1 family, IL-36α acts through the activation of NFκB and p38 MAPK pathway. PMID:26560022

  20. Systematic Analysis of the Cytokine and Anhedonia Response to Peripheral Lipopolysaccharide Administration in Rats.

    PubMed

    Biesmans, Steven; Matthews, Liam J R; Bouwknecht, Jan A; De Haes, Patrick; Hellings, Niels; Meert, Theo F; Nuydens, Rony; Ver Donck, Luc

    2016-01-01

    Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans.

  1. Systematic Analysis of the Cytokine and Anhedonia Response to Peripheral Lipopolysaccharide Administration in Rats

    PubMed Central

    Bouwknecht, Jan A.; De Haes, Patrick; Hellings, Niels; Meert, Theo F.

    2016-01-01

    Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans. PMID:27504457

  2. Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation

    PubMed Central

    Lévêque, Xavier; Mathieux, Elodie; Nerrière-Daguin, Véronique; Thinard, Reynald; Kermarrec, Laetitia; Durand, Tony; Haudebourg, Thomas; Vanhove, Bernard; Lescaudron, Laurent; Neveu, Isabelle; Naveilhan, Philippe

    2015-01-01

    Foetal pig neuroblasts are interesting candidates as a cell source for transplantation, but xenotransplantation in the brain requires the development of adapted immunosuppressive treatments. As systemic administration of high doses of cyclosporine A has side effects and does not protect xenotransplants forever, we focused our work on local control of the host immune responses. We studied the advantage of cotransplanting syngenic mesenchymal stem cells (MSC) with porcine neuroblasts (pNb) in immunocompetent rat striata. Two groups of animals were transplanted, either with pNb alone or with both MSC and pNb. At day 63, no porcine neurons were detected in the striata that received only pNb, while four of six rats transplanted with both pNb and MSC exhibited healthy porcine neurons. Interestingly, 50% of the cotransplanted rats displayed healthy grafts with pNF70+ and TH+ neurons at 120 days post-transplantation. qPCR analyses revealed a general dwindling of pro- and anti-inflammatory cytokines in the striata that received the cotransplants. Motor recovery was also observed following the transplantation of pNb and MSC in a rat model of Parkinson's disease. Taken together, the present data indicate that the immunosuppressive properties of MSC are of great interest for the long-term survival of xenogeneic neurons in the brain. PMID:25310920

  3. The fibroblast growth factor-2 arrests Mycobacterium avium sp. paratuberculosis growth and immunomodulates host response in macrophages.

    PubMed

    Wang, Jianjun; Wang, Zeyou; Yao, Yongliang; Wu, Jianhong; Tang, Xin; Gu, Tao; Li, Guangxin

    2015-07-01

    Mycobacterium tuberculosisis (M. tb) epidemic is one of the most severe health problem worldwide, while mechanisms underlying its pathogenesis and host immune responses remain unclear. Mycobacterium avium (M. avium), a mycobacterial species related to M. tb, shares similarities with M. tb in many ways. In this study, using M. avium infection of macrophages as a model, we systematically studied the effect of fibroblast growth factor-2 (FGF-2) on M. avium infection of macrophages. Our results showed that M. avium infection could increase FGF-2 expression on both mRNA and protein levels. M. avium infection elevated TNF-α and IFN-γ production while the addition of FGF-2 could further increase TNF-α but not IFN-γ level. M. avium infection could increase the expression of oxygen/nitrogen metabolism proteins iNOS and SOD-1, and FGF-2 had additive effect on the expression of these two proteins. M. avium infection had inhibitive effect on actin expression while FGF-2 could partly counteract such inhibition. Moreover, FGF-2 could inhibit M. avium proliferation in macrophages. Our results together indicate that macrophage-secreted FGF-2 upon M. avium infection could suppress M. avium proliferation through various ways including cytokine production, enhancement of phagocytosis as well as oxygen/nitrogen metabolism.

  4. Ginseng Diminishes Lung Disease in Mice Immunized with Formalin-Inactivated Respiratory Syncytial Virus After Challenge by Modulating Host Immune Responses

    PubMed Central

    Lee, Jong Seok; Cho, Min Kyoung; Hwang, Hye Suk; Ko, Eun-Ju; Lee, Yu-Na; Kwon, Young-Man; Kim, Min-Chul; Kim, Ki-Hye; Lee, Young-Tae; Jung, Yu-Jin

    2014-01-01

    Formalin-inactivated respiratory syncytial virus (FI-RSV) immunization is known to cause severe pulmonary inflammatory disease after subsequent RSV infection. Ginseng has been used in humans for thousands of years due to its potential health benefits. We investigated whether ginseng would have immune modulating effects on RSV infection in mice previously immunized with FI-RSV. Oral administration of mice with ginseng increased IgG2a isotype antibody responses to FI-RSV immunization, indicating T-helper type 1 (Th1) immune responses. Ginseng-treated mice that were nonimmunized or previously immunized with FI-RSV showed improved protection against RSV challenge compared with control mice without ginseng treatment. Ginseng-mediated improved clinical outcomes after live RSV infection were evidenced by diminished weight losses, decreased interleukin-4 cytokine production but increased interferon-γ production, modulation of CD3 T-cell populations toward a Th1 response, and reduced inflammatory response. Ginseng-mediated protective host immune modulation against RSV pulmonary inflammation was observed in different strains of wild-type and mutant mice. These results indicate that ginseng can modulate host immune responses to FI-RSV immunization and RSV infection, resulting in protective effects against pulmonary inflammatory disease. PMID:25051168

  5. Host responses in the bursa of Fabricius of chickens infected with virulent Marek's disease virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Host responses associated with very virulent Marek’s disease virus (MDV) infection in the bursa of Fabricius of chicken was investigated. The expression of MDV pp38 antigen and MDV gB transcripts were higher at 4 days post-infection (dpi) and then showed a declining trend. On the contrary, the expre...

  6. Viral Proteins That Bind Double-Stranded RNA: Countermeasures Against Host Antiviral Responses

    PubMed Central

    2014-01-01

    Several animal viruses encode proteins that bind double-stranded RNA (dsRNA) to counteract host dsRNA-dependent antiviral responses. This article discusses the structure and function of the dsRNA-binding proteins of influenza A virus and Ebola viruses (EBOVs). PMID:24905203

  7. Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epitehlial cells and in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Host DNA damage and DNA repair response to bacterial infections and its significance are not fully understood. Here, we demonstrate that infection by Gram-negative bacterium P. aeruginosa significantly altered the expression and enzymatic activity of base excision DNA repair protein OGG1 in lung epi...

  8. Effects of dietary selenium on host response to necrotic enteritis in young broilers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of dietary supplementation of young broiler chickens with a new organic selenium (Se) formulation, B-Traxim Se, on the host response to experimental necrotic enteritis (NE) were studied. Broiler chickens treated with three Se doses (0.25, 0.50, 1.00 mg/kg) from hatch were orally challeng...

  9. Reflections on the Histopathology of Tumor-infiltrating Lymphocytes in Melanoma and the Host Immune Response

    PubMed Central

    Mihm, Martin C.; Mulé, James J.

    2015-01-01

    In the last five decades the role for lymphocytes in host immune response to tumors has been shown, at least in some patients, to be a critical component in disease prognosis. Also, the heterogeneity of lymphocytes has been documented including the existence of regulatory T cells that suppress the immune response. As the functions of lymphocytes have become better defined in terms of antitumor immunity, specific targets on lymphocytes have been uncovered. The appreciation of the role of immune-checkpoints has also led to therapeutic approaches that illustrate the effectiveness of blocking negative regulators of the antitumor immune response. In this Masters of Immunology article, we trace the evolution of our understanding of tumor-infiltrating lymphocytes and discuss their role in melanoma prognosis from the very basic observation of their existence to the latest manipulation of their functions with the result of improvement of the host response against the tumor. PMID:26242760

  10. Biological stimuli-responsive cyclodextrin-based host-guest nanosystems for cancer therapy.

    PubMed

    Dan, Zhaoling; Cao, Haiqiang; He, Xinyu; Zeng, Lijuan; Zou, Lili; Shen, Qi; Zhang, Zhiwen

    2015-04-10

    Stimuli-responsive nanosystems are of particular interest in cancer therapy, owing to their impressive capability to enable the on-demand drug release in response to specific biological stimuli in tumor microenvironments (such as pH, redox and enzyme, etc.). Cyclodextrin (CD)-based host-guest interactions provide a flexible and powerful platform for the development of multifunctional nanosystems. This article highlights the current progress of CD-based host-guest nanosystems (CHNs) with biological stimuli-responsive properties in cancer therapy. We summarize the composition, structure and design of various CHNs in response to specific stimuli in tumor, and focus on their performance in controlled drug delivery and cancer therapy. These recent advances make it a promising and intelligent drug delivery system to improve the anticancer efficacy.

  11. Engineering responsive polymer building blocks with host-guest molecular recognition for functional applications.

    PubMed

    Hu, Jinming; Liu, Shiyong

    2014-07-15

    CONSPECTUS: All living organisms and soft matter are intrinsically responsive and adaptive to external stimuli. Inspired by this fact, tremendous effort aiming to emulate subtle responsive features exhibited by nature has spurred the invention of a diverse range of responsive polymeric materials. Conventional stimuli-responsive polymers are constructed via covalent bonds and can undergo reversible or irreversible changes in chemical structures, physicochemical properties, or both in response to a variety of external stimuli. They have been imparted with a variety of emerging applications including drug and gene delivery, optical sensing and imaging, diagnostics and therapies, smart coatings and textiles, and tissue engineering. On the other hand, in comparison with molecular chemistry held by covalent bonds, supramolecular chemistry built on weak and reversible noncovalent interactions has emerged as a powerful and versatile strategy for materials fabrication due to its facile accessibility, extraordinary reversibility and adaptivity, and potent applications in diverse fields. Typically involving more than one type of noncovalent interactions (e.g., hydrogen bonding, metal coordination, hydrophobic association, electrostatic interactions, van der Waals forces, and π-π stacking), host-guest recognition refers to the formation of supramolecular inclusion complexes between two or more entities connected together in a highly controlled and cooperative manner. The inherently reversible and adaptive nature of host-guest molecular recognition chemistry, stemming from multiple noncovalent interactions, has opened up a new platform to construct novel types of stimuli-responsive materials. The introduction of host-guest chemistry not only enriches the realm of responsive materials but also confers them with promising new applications. Most intriguingly, the integration of responsive polymer building blocks with host-guest recognition motifs will endow the former with

  12. Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis

    DTIC Science & Technology

    2011-12-01

    Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis Jill K. Terra1, Bryan France1...of America Abstract Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by...Inflammatory Responses and Resistance to Bacillus anthracis. PLoS Pathog 7(12): e1002469. doi:10.1371/journal.ppat.1002469 Editor: Theresa M. Koehler, The

  13. A molecular arms race between host innate antiviral response and emerging human coronaviruses.

    PubMed

    Wong, Lok-Yin Roy; Lui, Pak-Yin; Jin, Dong-Yan

    2016-02-01

    Coronaviruses have been closely related with mankind for thousands of years. Community-acquired human coronaviruses have long been recognized to cause common cold. However, zoonotic coronaviruses are now becoming more a global concern with the discovery of highly pathogenic severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses causing severe respiratory diseases. Infections by these emerging human coronaviruses are characterized by less robust interferon production. Treatment of patients with recombinant interferon regimen promises beneficial outcomes, suggesting that compromised interferon expression might contribute at least partially to the severity of disease. The mechanisms by which coronaviruses evade host innate antiviral response are under intense investigations. This review focuses on the fierce arms race between host innate antiviral immunity and emerging human coronaviruses. Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. On the other hand, the counter-measures evolved by SARS and MERS coronaviruses to circumvent host defense are also dissected. With a better understanding of the dynamic interaction between host and coronaviruses, it is hoped that insights on the pathogenesis of newly-identified highly pathogenic human coronaviruses and new strategies in antiviral development can be derived.

  14. Genomic regions of pufferfishes responsible for host specificity of a monogenean parasite, Heterobothrium okamotoi.

    PubMed

    Hosoya, Sho; Kido, Shinichi; Hirabayashi, Yo; Kai, Wataru; Kinami, Ryuhei; Yoshinaga, Tomoyoshi; Ogawa, Kazuo; Suetake, Hiroaki; Kikuchi, Kiyoshi; Suzuki, Yuzuru

    2013-10-01

    The genetic mechanisms underlying host specificity of parasitic infections are largely unknown. After hatching, the larvae of the monogenean parasite, Heterobothrium okamotoi, attach to the gill filaments of hosts and the post-larval worms develop there by consuming nutrients from the host. The susceptibility to H. okamotoi infection differs markedly among fish species. While this parasite can grow on tiger pufferfish (also called fugu), Takifugu rubripes, it appears to be rejected by a close congener, grass pufferfish, Takifugu niphobles, after initial attachment to the gills. To determine the genetic architecture of the pufferfish responsible for this host specificity, we performed genome-wide quantitative trait loci analysis. We raised second generation (F2) hybrids of the two pufferfish species and experimentally infected them with the monogenean in vivo. To assess possible differences in host mechanisms between early and later periods of infection, we sampled fish three h and 21days after exposure. Genome scanning of fish from the 3h infection trial revealed suggestive quantitative trait loci on linkage groups 2 and 14, which affected the number of parasites on the gill. However, analysis of fish 21days p.i. detected a significant quantitative trait locus on linkage group 9 and three other suggestive quantitative trait loci on linkage groups 7, 18 and 22. These results indicated the polygenic nature of the host mechanisms involved in the infection/rejection of H. okamotoi. Moreover the analyses suggested that host factors may play a more important role during the growth period of the parasite than during initial host recognition at the time of attachment. Within the 95% confidence interval of the linkage group 9 quantitative trait locus in the fugu genome, there were 214 annotated protein-coding genes, including immunity-related genes such as Irak4, Muc2 and Muc5ac.

  15. Host Responses and Regulation by NFκB Signaling in the Liver and Liver Epithelial Cells Infected with A Novel Tick-borne Bunyavirus

    PubMed Central

    Sun, Qiyu; Jin, Cong; Zhu, Lili; Liang, Mifang; Li, Chuan; Cardona, Carol J.; Li, Dexin; Xing, Zheng

    2015-01-01

    Infection in humans by severe fever with thrombocytopenia syndrome virus (SFTSV), a novel bunyavirus transmitted by ticks, is often associated with pronounced liver damage, especially in fatal cases. Little has been known, however, about how liver cells respond to SFTSV and how the response is regulated. In this study we report that proinflammatory cytokines were induced in liver tissues of C57/BL6 mice infected with SFTSV, which may cause tissue necrosis in mice. Human liver epithelial cells were susceptible to SFTSV and antiviral interferon (IFN) and IFN-inducible proteins were induced upon infection. We observed that infection of liver epithelial cells led to significant increases in proinflammatory cytokines and chemokines, including IL-6, RANTES, IP-10, and MIP-3a, which were regulated by NFκB signaling, and the activation of NFκB signaling during infection promoted viral replication in liver epithelial cells. Viral nonstructural protein NSs was inhibitory to the induction of IFN-β, but interestingly, NFκB activation was enhanced in the presence of NSs. Therefore, NSs plays dual roles in the suppression of antiviral IFN-β induction as well as the promotion of proinflammatory responses. Our findings provide the first evidence for elucidating host responses and regulation in liver epithelial cells infected by an emerging bunyavirus. PMID:26134299

  16. Dietary sodium selenite affects host intestinal and systemic immune response and disease susceptibility to necrotic enteritis in commercial broilers.

    PubMed

    Xu, S Z; Lee, S H; Lillehoj, H S; Bravo, D

    2015-01-01

    1. This study was to evaluate the effects of supplementary dietary selenium (Se) given as sodium selenite on host immune response against necrotic enteritis (NE) in commercial broiler chickens. 2. Chicks were fed from hatching on a non-supplemented diet or diets supplemented with different levels of Se (0.25, 0.50, and 1.00 Se mg/kg). To induce NE, broiler chickens were orally infected with Eimeria maxima at 14 d of age and then with Clostridium perfringens 4 d later using our previously established NE disease model. 3. NE-associated clinical signs and host protective immunity were determined by body weight changes, intestinal lesion scores, and serum antibodies against α-toxin and necrotic enteritis B (NetB) toxin. The effects of dietary Se on the gene expression of pro-inflammatory cytokines e.g., interleukin (IL)-1β, IL-6, IL-8LITAF (lipopolysaccharide-induced TNFα-factor), tumour necrosis factor (TNF) SF15, and inducible nitric oxide synthase (iNOS), glutathione peroxidase 7 (GPx7), and avian β-defensins (AvBD) 6, 8, and 13 (following NE infection) were analysed in the intestine and spleen. 4. The results showed that dietary supplementation of newly hatched broiler chicks with 0.25 Se mg/kg from hatch significantly reduced NE-induced gut lesions compared with infected birds given a non-supplemented diet. The levels of serum antibody against the NetB toxin in the chicks fed with 0.25 and 0.50 mg/kg Se were significantly higher than the non-supplemented control group. The transcripts for IL-1β, IL-6, IL-8, iNOS, LITAF, and GPx7, as well as AvBD6, 8, and 13 were increased in the intestine and spleen of Se-supplemented groups, whereas transcript for TNFSF15 was decreased in the intestine. 5. It was concluded that dietary supplementation with optimum levels of Se exerted beneficial effects on host immune response to NE and reduced negative consequence of NE-induced immunopathology.

  17. Cytokine Responses to Novel Antigens in an Indian Population Living in an Area Endemic for Visceral Leishmaniasis

    PubMed Central

    Singh, Om Prakash; Stober, Carmel B.; Singh, Abhishek Kr.

    2012-01-01

    Background There are no effective vaccines for visceral leishmaniasis (VL), a neglected parasitic disease second only to malaria in global mortality. We previously identified 14 protective candidates in a screen of 100 Leishmania antigens as DNA vaccines in mice. Here we employ whole blood assays to evaluate human cytokine responses to 11 of these antigens, in comparison to known defined and crude antigen preparations. Methods Whole blood assays were employed to measure IFN-γ, TNF-α and IL-10 responses to peptide pools of the novel antigens R71, Q51, L37, N52, L302.06, J89, M18, J41, M22, M63, M57, as well as to recombinant proteins of tryparedoxin peroxidase (TRYP), Leishmania homolog of the receptor for activated C kinase (LACK) and to crude soluble Leishmania antigen (SLA), in Indian patients with active (n = 8) or cured (n = 16) VL, and in modified Quantiferon positive (EHC+ve, n = 20) or modified Quantiferon negative (EHC−ve, n = 9) endemic healthy controls (EHC). Results Active VL, cured VL and EHC+ve groups showed elevated SLA-specific IFN-γ, but only active VL patients produced IL-10 and EHC+ve did not make TNF-α. IFN-γ to IL-10 and TNF-α to IL-10 ratios in response to TRYP and LACK antigens were higher in cured VL and EHC+ve exposed individuals compared to active VL. Five of the eleven novel candidates (R71, L37, N52, J41, and M22) elicited IFN-γ and TNF-α, but not IL-10, responses in cured VL (55–87.5% responders) and EHC+ve (40–65% responders) subjects. Conclusions Our results are consistent with an important balance between pro-inflammatory IFNγ and TNFγ cytokine responses and anti-inflammatory IL-10 in determining outcome of VL in India, as highlighted by response to both crude and defined protein antigens. Importantly, cured VL patients and endemic Quantiferon positive individuals recognise 5 novel vaccine candidate antigens, confirming our recent data for L. chagasi in Brazil, and their potential as cross

  18. The effect of HIV infection on the host response to bacterial sepsis.

    PubMed

    Huson, Michaëla A M; Grobusch, Martin P; van der Poll, Tom

    2015-01-01

    Bacterial sepsis is an important cause of morbidity and mortality in patients with HIV. HIV causes increased susceptibility to invasive infections and affects sepsis pathogenesis caused by pre-existing activation and exhaustion of the immune system. We review the effect of HIV on different components of immune responses implicated in bacterial sepsis, and possible mechanisms underlying the increased risk of invasive bacterial infections. We focus on pattern recognition receptors and innate cellular responses, cytokines, lymphocytes, coagulation, and the complement system. A combination of factors causes increased susceptibility to infection and can contribute to a disturbed immune response during a septic event in patients with HIV. HIV-induced perturbations of the immune system depend on stage of infection and are only in part restored by combination antiretroviral therapy. Immunomodulatory treatments currently under development for sepsis might be particularly beneficial to patients with HIV co-infection because many pathogenic mechanisms in HIV and sepsis overlap.

  19. Immune Response to Snake Envenoming and Treatment with Antivenom; Complement Activation, Cytokine Production and Mast Cell Degranulation

    PubMed Central

    Stone, Shelley F.; Isbister, Geoffrey K.; Shahmy, Seyed; Mohamed, Fahim; Abeysinghe, Chandana; Karunathilake, Harendra; Ariaratnam, Ariaranee; Jacoby-Alner, Tamara E.; Cotterell, Claire L.; Brown, Simon G. A.

    2013-01-01

    Background Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment. Methodology/Principal Findings Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor α (TNFα), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. Conclusions/Significance We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast

  20. Host inflammatory response governs fitness in an avian ectoparasite, the northern fowl mite (Ornithonyssus sylviarum).

    PubMed

    Owen, Jeb P; Delany, Mary E; Cardona, Carol J; Bickford, Arthur A; Mullens, Bradley A

    2009-06-01

    Vertebrate immune responses to ectoparasites influence pathogen transmission and host fitness costs. Few studies have characterized natural immune responses to ectoparasites and resultant fitness effects on the ectoparasite. These are critical gaps in understanding vertebrate-ectoparasite interaction, disease ecology and host-parasite co-adaptation. This study focused on an ectoparasite of birds--the northern fowl mite (NFM) (Ornithonyssus sylviarum). Based on prior evidence that chickens develop resistance to NFM, these experiments tested two hypotheses: (i) skin inflammation blocks mite access to blood,impairing development, reproduction and survival; and (ii) host immunogenetic variation influences the inflammatory response and subsequent effects on the ectoparasite. On infested hosts, histology of skin inflammation revealed increased epidermal cell number and size, immigration of leukocytes and deposition of serous exudates on the skin surface. Survival of adult mites and their offspring decreased as the area of skin inflammation increased during an infestation. Inflammation increased the distance to blood vessels beyond the length of mite mouthparts (100-160 lm) and prevented protonymphs and adults from reaching a blood source. Consequently, protonymphs could not complete development, evidenced by a significant inverse relationship between inflammation and protonymph feeding success, as well as an increasing protonymph/adult ratio. Adult females were unable to feed and reproduce, indicated by an inverse relationship between inflammation and egg production, and decreasing female/juvenile ratio. These combined impacts of host inflammation reversed NFM population growth. Intensity of inflammation was influenced by the genotype of the major histocompatibility complex(MHC), supporting previous research that linked these immunological loci with NFM resistance. Overall, these data provide a model for a mechanism of avian resistance to an ectoparasitic arthropod and

  1. Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota

    PubMed Central

    Richards, Allison L.; Burns, Michael B.; Alazizi, Adnan; Barreiro, Luis B.; Pique-Regi, Roger

    2016-01-01

    ABSTRACT Many studies have demonstrated the importance of the gut microbiota in healthy and disease states. However, establishing the causality of host-microbiota interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiota for human cells and to shed light on the molecular mechanisms underlying host-gut microbiota interactions. In primary human colonic epithelial cells, we identified over 6,000 genes whose expression changed at various time points following coculturing with the gut microbiota of a healthy individual. Among the differentially expressed genes we found a 1.8-fold enrichment of genes associated with diseases that have been previously linked to the microbiome, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host single nucleotide polymorphisms (SNPs) that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiota. Of these 12 genes, 8 have been associated with diseases linked to the gut microbiota, specifically colorectal cancer, obesity, and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiota interactions and can be used to identify putative mechanisms for the interplay between host genetics and the microbiota in health and disease. IMPORTANCE The study of host-microbiota interactions in humans is largely limited to identifying associations between microbial communities and host phenotypes. While these studies have generated important insights on the links between the microbiota and human disease, the assessment of cause-and-effect relationships has been challenging. Although this relationship can be studied in germfree mice, this system is costly, and it is difficult to accurately account for the effects of host genotypic variation and environmental effects

  2. Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.

    PubMed

    Zhao, Hong; Konishi, Aki; Fujita, Yukiko; Yagi, Masanori; Ohata, Keiichi; Aoshi, Taiki; Itagaki, Sawako; Sato, Shintaro; Narita, Hirotaka; Abdelgelil, Noha H; Inoue, Megumi; Culleton, Richard; Kaneko, Osamu; Nakagawa, Atsushi; Horii, Toshihiro; Akira, Shizuo; Ishii, Ken J; Coban, Cevayir

    2012-11-15

    Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.