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Sample records for activates host defense

  1. Oncolytic Activities of Host Defense Peptides

    PubMed Central

    Al-Benna, Sammy; Shai, Yechiel; Jacobsen, Frank; Steinstraesser, Lars

    2011-01-01

    Cancer continues to be a leading source of morbidity and mortality worldwide in spite of progress in oncolytic therapies. In addition, the incidence of cancers affecting the breast, kidney, prostate and skin among others continue to rise. Chemotherapeutic drugs are widely used in cancer treatment but have the serious drawback of nonspecific toxicity because these agents target any rapidly dividing cell without discriminating between healthy and malignant cells. In addition, many neoplasms eventually become resistant to conventional chemotherapy due to selection for multidrug-resistant variants. The limitations associated with existing chemotherapeutic drugs have stimulated the search for new oncolytic therapies. Host defense peptides (HDPs) may represent a novel family of oncolytic agents that can avoid the shortcomings of conventional chemotherapy because they exhibit selective cytotoxicity against a broad spectrum of malignant human cells, including multi-drug-resistant neoplastic cells. Oncolytic activity by HDPs is usually via necrosis due to cell membrane lysis, but some HDPs can trigger apoptosis in cancer cells via mitochondrial membrane disruption. In addition, certain HDPs are anti-angiogenic which may inhibit cancer progression. This paper reviews oncolytic HDP studies in order to address the suitability of selected HDPs as oncolytic therapies. PMID:22174648

  2. Modulation of host defense peptide-mediated human mast cell activation by LPS

    PubMed Central

    Gupta, Kshitij; Subramanian, Hariharan; Ali, Hydar

    2016-01-01

    Human β-defensin3 (hBD3) and the cathelicidin LL-37 are host defense peptides (HDPs) that directly kill microbes and display immunomodulatory/wound healing properties via the activation of chemokine, formylpeptide and epidermal growth factor receptors on monocytes and epithelial cells. A C-terminal 14 amino acid hBD3 peptide with all Cys residues replaced with Ser (CHRG01) and an LL-37 peptide consisting of residues 17-29 (FK-13) display antimicrobial activity but lack immunomodulatory property. Surprisingly, we found that CHRG01 and FK-13 caused Ca2+ mobilization and degranulation in human mast cells via a novel G protein coupled receptor (GPCR) known as Mas-related gene-X2 (MrgX2). At local sites of bacterial infection, the negatively charged LPS likely interacts with cationic HDPs to inhibit their activity and thus providing a mechanism for pathogens to escape the host defense mechanisms. We found that LPS caused almost complete inhibition of hBD3 and LL-37-induced Ca2+ mobilization and mast cell degranulation. In contrast, it had no effect on CHRG01 and FK-13-induced mast cell responses. These findings suggest that HDP derivatives that kill microbes, harness mast cell’s host defense and wound healing properties via the activation of MrgX2 but are resistant to inhibition by LPS could be utilized for the treatment of antibiotic-resistant microbial infections. PMID:26511058

  3. Human Macrophage SCN5A Activates an Innate Immune Signaling Pathway for Antiviral Host Defense*

    PubMed Central

    Jones, Alexis; Kainz, Danielle; Khan, Faatima; Lee, Cara; Carrithers, Michael D.

    2014-01-01

    Pattern recognition receptors contain a binding domain for pathogen-associated molecular patterns coupled to a signaling domain that regulates transcription of host immune response genes. Here, a novel mechanism that links pathogen recognition to channel activation and downstream signaling is proposed. We demonstrate that an intracellular sodium channel variant, human macrophage SCN5A, initiates signaling and transcription through a calcium-dependent isoform of adenylate cyclase, ADCY8, and the transcription factor, ATF2. Pharmacological stimulation with a channel agonist or treatment with cytoplasmic poly(I:C), a mimic of viral dsRNA, activates this pathway to regulate expression of SP100-related genes and interferon β. Electrophysiological analysis reveals that the SCN5A variant mediates nonselective outward currents and a small, but detectable, inward current. Intracellular poly(I:C) markedly augments an inward voltage-sensitive sodium current and inhibits the outward nonselective current. These results suggest human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense. It is postulated that SCN5A is a novel pathogen sensor and that this pathway represents a channel activation-dependent mechanism of transcriptional regulation. PMID:25368329

  4. Salt, chloride, bleach, and innate host defense

    PubMed Central

    Wang, Guoshun; Nauseef, William M.

    2015-01-01

    Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense. PMID:26048979

  5. Salt, chloride, bleach, and innate host defense.

    PubMed

    Wang, Guoshun; Nauseef, William M

    2015-08-01

    Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense. PMID:26048979

  6. Obligate Biotroph Pathogens of the Genus Albugo Are Better Adapted to Active Host Defense Compared to Niche Competitors.

    PubMed

    Ruhe, Jonas; Agler, Matthew T; Placzek, Aleksandra; Kramer, Katharina; Finkemeier, Iris; Kemen, Eric M

    2016-01-01

    Recent research suggested that plants behave differently under combined versus single abiotic and biotic stress conditions in controlled environments. While this work has provided a glimpse into how plants might behave under complex natural conditions, it also highlights the need for field experiments using established model systems. In nature, diverse microbes colonize the phyllosphere of Arabidopsis thaliana, including the obligate biotroph oomycete genus Albugo, causal agent of the common disease white rust. Biotrophic, as well as hemibiotrophic plant pathogens are characterized by efficient suppression of host defense responses. Lab experiments have even shown that Albugo sp. can suppress non-host resistance, thereby enabling otherwise avirulent pathogen growth. We asked how a pathogen that is vitally dependent on a living host can compete in nature for limited niche space while paradoxically enabling colonization of its host plant for competitors? To address this question, we used a proteomics approach to identify differences and similarities between lab and field samples of Albugo sp.-infected and -uninfected A. thaliana plants. We could identify highly similar apoplastic proteomic profiles in both infected and uninfected plants. In wild plants, however, a broad range of defense-related proteins were detected in the apoplast regardless of infection status, while no or low levels of defense-related proteins were detected in lab samples. These results indicate that Albugo sp. do not strongly affect immune responses and leave distinct branches of the immune signaling network intact. To validate our findings and to get mechanistic insights, we tested a panel of A. thaliana mutant plants with induced or compromised immunity for susceptibility to different biotrophic pathogens. Our findings suggest that the biotroph pathogen Albugo selectively interferes with host defense under different environmental and competitive pressures to maintain its ecological niche

  7. Obligate Biotroph Pathogens of the Genus Albugo Are Better Adapted to Active Host Defense Compared to Niche Competitors

    PubMed Central

    Ruhe, Jonas; Agler, Matthew T.; Placzek, Aleksandra; Kramer, Katharina; Finkemeier, Iris; Kemen, Eric M.

    2016-01-01

    Recent research suggested that plants behave differently under combined versus single abiotic and biotic stress conditions in controlled environments. While this work has provided a glimpse into how plants might behave under complex natural conditions, it also highlights the need for field experiments using established model systems. In nature, diverse microbes colonize the phyllosphere of Arabidopsis thaliana, including the obligate biotroph oomycete genus Albugo, causal agent of the common disease white rust. Biotrophic, as well as hemibiotrophic plant pathogens are characterized by efficient suppression of host defense responses. Lab experiments have even shown that Albugo sp. can suppress non-host resistance, thereby enabling otherwise avirulent pathogen growth. We asked how a pathogen that is vitally dependent on a living host can compete in nature for limited niche space while paradoxically enabling colonization of its host plant for competitors? To address this question, we used a proteomics approach to identify differences and similarities between lab and field samples of Albugo sp.-infected and -uninfected A. thaliana plants. We could identify highly similar apoplastic proteomic profiles in both infected and uninfected plants. In wild plants, however, a broad range of defense-related proteins were detected in the apoplast regardless of infection status, while no or low levels of defense-related proteins were detected in lab samples. These results indicate that Albugo sp. do not strongly affect immune responses and leave distinct branches of the immune signaling network intact. To validate our findings and to get mechanistic insights, we tested a panel of A. thaliana mutant plants with induced or compromised immunity for susceptibility to different biotrophic pathogens. Our findings suggest that the biotroph pathogen Albugo selectively interferes with host defense under different environmental and competitive pressures to maintain its ecological niche

  8. Natural History of Innate Host Defense Peptides.

    PubMed

    Linde, A; Wachter, B; Höner, O P; Dib, L; Ross, C; Tamayo, A R; Blecha, F; Melgarejo, T

    2009-12-01

    Host defense peptides act on the forefront of innate immunity, thus playing a central role in the survival of animals and plants. Despite vast morphological changes in species through evolutionary history, all animals examined to date share common features in their innate immune defense strategies, hereunder expression of host defense peptides (HDPs). Most studies on HDPs have focused on humans, domestic and laboratory animals. More than a thousand different sequences have been identified, yet data on HDPs in wild-living animals are sparse. The biological functions of HDPs include broad-spectrum antimicrobial activity and immunomodulation. Natural selection and coevolutionary host-pathogen arms race theory suggest that the extent and specificity of the microbial load influences the spectrum and potency of HDPs in different species. Individuals of extant species-that have lived for an extended period in evolutionary history amid populations with intact processes of natural selection-likely possess the most powerful and well-adapted "natural antibiotics". Research on the evolutionary history of the innate defense system and the host in context of the consequences of challenges as well as the efficacy of the innate immune system under natural conditions is therefore of immediate interest. This review focuses on evolutionary aspects of immunophysiology, with emphasis on innate effector molecules. Studies on host defense in wild-living animals may significantly enhance our understanding of inborn immune mechanisms, and help identify molecules that may assist us to cope better with the increasing microbial challenges that likely follow from the continuous amplification of biodiversity levels on Earth. PMID:26783164

  9. Membrane-active host defense peptides – Challenges and perspectives for the development of novel anticancer drugs

    PubMed Central

    Riedl, Sabrina; Zweytick, Dagmar; Lohner, Karl

    2011-01-01

    Although much progress has been achieved in the development of cancer therapies in recent decades, problems continue to arise particularly with respect to chemotherapy due to resistance to and low specificity of currently available drugs. Host defense peptides as effector molecules of innate immunity represent a novel strategy for the development of alternative anticancer drug molecules. These cationic amphipathic peptides are able to discriminate between neoplastic and non-neoplastic cells interacting specifically with negatively charged membrane components such as phosphatidylserine (PS), sialic acid or heparan sulfate, which differ between cancer and non-cancer cells. Furthermore, an increased number of microvilli has been found on cancer cells leading to an increase in cell surface area, which may in turn enhance their susceptibility to anticancer peptides. Thus, part of this review will be devoted to the differences in membrane composition of non-cancer and cancer cells with a focus on the exposure of PS on the outer membrane. Normally, surface exposed PS triggers apoptosis, which can however be circumvented by cancer cells by various means. Host defense peptides, which selectively target differences between cancer and non-cancer cell membranes, have excellent tumor tissue penetration and can thus reach the site of both primary tumor and distant metastasis. Since these molecules kill their target cells rapidly and mainly by perturbing the integrity of the plasma membrane, resistance is less likely to occur. Hence, a chapter will also describe studies related to the molecular mechanisms of membrane damage as well as alternative non-membrane related mechanisms. In vivo studies have demonstrated that host defense peptides display anticancer activity against a number of cancers such as e.g. leukemia, prostate, ascite and ovarian tumors, yet so far none of these peptides has made it on the market. Nevertheless, optimization of host defense peptides using various

  10. Immune modulation by multifaceted cationic host defense (antimicrobial) peptides.

    PubMed

    Hilchie, Ashley L; Wuerth, Kelli; Hancock, Robert E W

    2013-12-01

    Cationic host defense (antimicrobial) peptides were originally studied for their direct antimicrobial activities. They have since been found to exhibit multifaceted immunomodulatory activities, including profound anti-infective and selective anti-inflammatory properties, as well as adjuvant and wound-healing activities in animal models. These biological properties suggest that host defense peptides, and synthetic derivatives thereof, possess clinical potential beyond the treatment of antibiotic-resistant infections. In this Review, we provide an overview of the biological activities of host defense and synthetic peptides, their mechanism(s) of action and new therapeutic applications and challenges that are associated with their clinical use. PMID:24231617

  11. Systemic Activation of TLR3-Dependent TRIF Signaling Confers Host Defense against Gram-Negative Bacteria in the Intestine

    PubMed Central

    Ruiz, Jose; Kanagavelu, Saravana; Flores, Claudia; Romero, Laura; Riveron, Reldy; Shih, David Q.; Fukata, Masayuki

    2016-01-01

    Recognition of Gram-negative bacteria by toll-like receptor (TLR)4 induces MyD88 and TRIF mediated responses. We have shown that TRIF-dependent responses play an important role in intestinal defense against Gram-negative enteropathogens. In the current study, we examined underlying mechanisms of how systemic TRIF activation enhances intestinal immune defense against Gram-negative bacteria. First we confirmed that the protective effect of poly I:C against enteric infection of mice with Yersinia enterocolitica was dependent on TLR3-mediated TRIF signaling by using TLR3-deficient mice. This protection was unique in TRIF-dependent TLR signaling because systemic stimulation of mice with agonists for TLR2 (Pam3CSK4) or TLR5 (flagellin) did not reduce mortality on Y. enterocolitica infection. Systemic administration of poly I:C mobilized CD11c+, F4/80+, and Gr−1hi cells from lamina propria and activated NK cells in the mesenteric lymph nodes (MLN) within 24 h. This innate immune cell rearrangement was type I IFN dependent and mediated through upregulation of TLR4 followed by CCR7 expression in these innate immune cells found in the intestinal mucosa. Poly I:C induced IFN-γ expression by NK cells in the MLN, which was mediated through type I IFNs and IL-12p40 from antigen presenting cells and consequent activation of STAT1 and STAT4 in NK cells. This formation of innate immunity significantly contributed to the elimination of bacteria in the MLN. Our results demonstrated an innate immune network in the intestine that can be established by systemic stimulation of TRIF, which provides a strong host defense against Gram-negative pathogens. The mechanism underlying TRIF-mediated protective immunity may be useful to develop novel therapies for enteric bacterial infection. PMID:26793623

  12. Host defenses trigger salmonella's arsenal.

    PubMed

    Keestra, A Marijke; Bäumler, Andreas J

    2011-03-17

    Salmonella survives in macrophages by using a molecular syringe to deliver proteins into the host-cell cytosol where they manipulate phagocyte physiology. Arpaia and colleagues (Arpaia et al., 2011) show that deployment of this virulence factor is triggered by the very responses that are intended to confer host resistance. PMID:21402352

  13. Host Immune Defense Peptide LL-37 Activates Caspase-Independent Apoptosis and Suppresses Colon Cancer

    PubMed Central

    Ren, Shun X.; Cheng, Alfred S.L.; To, Ka F.; Tong, Joanna H.M.; Li, May S.; Shen, Jin; Wong, Clover C.M.; Zhang, Lin; Chan, Ruby L.Y.; Wang, Xiao J.; Ng, Simon S.M.; Chiu, Lawrence C.M.; Marquez, Victor E.; Gallo, Richard L.; Chan, Francis K.L.; Yu, Jun; Sung, Joseph J.Y.; Wu, William K.K.; Cho, Chi H.

    2014-01-01

    Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin–sensitive G-protein–coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG–mediated apoptosis in colon cancer cells. PMID:23100468

  14. Hepcidin and Host Defense against Infectious Diseases

    PubMed Central

    Michels, Kathryn; Nemeth, Elizabeta; Ganz, Tomas; Mehrad, Borna

    2015-01-01

    Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses. PMID:26291319

  15. Hepcidin and Host Defense against Infectious Diseases.

    PubMed

    Michels, Kathryn; Nemeth, Elizabeta; Ganz, Tomas; Mehrad, Borna

    2015-08-01

    Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses. PMID:26291319

  16. Soluble Host Defense Lectins in Innate Immunity to Influenza Virus

    PubMed Central

    Ng, Wy Ching; Tate, Michelle D.; Brooks, Andrew G.; Reading, Patrick C.

    2012-01-01

    Host defenses against viral infections depend on a complex interplay of innate (nonspecific) and adaptive (specific) components. In the early stages of infection, innate mechanisms represent the main line of host defense, acting to limit the spread of virus in host tissues prior to the induction of the adaptive immune response. Serum and lung fluids contain a range of lectins capable of recognizing and destroying influenza A viruses (IAV). Herein, we review the mechanisms by which soluble endogenous lectins mediate anti-IAV activity, including their role in modulating IAV-induced inflammation and disease and their potential as prophylactic and/or therapeutic treatments during severe IAV-induced disease. PMID:22665991

  17. Interferon-γ Is a Crucial Activator of Early Host Immune Defense against Mycobacterium ulcerans Infection in Mice

    PubMed Central

    Bieri, Raphael; Bolz, Miriam; Ruf, Marie-Thérèse; Pluschke, Gerd

    2016-01-01

    Buruli ulcer (BU), caused by infection with Mycobacterium ulcerans, is a chronic necrotizing human skin disease associated with the production of the cytotoxic macrolide exotoxin mycolactone. Despite extensive research, the type of immune responses elicited against this pathogen and the effector functions conferring protection against BU are not yet fully understood. While histopathological analyses of advanced BU lesions have demonstrated a mainly extracellular localization of the toxin producing acid fast bacilli, there is growing evidence for an early intra-macrophage growth phase of M. ulcerans. This has led us to investigate whether interferon-γ might play an important role in containing M. ulcerans infections. In an experimental Buruli ulcer mouse model we found that interferon-γ is indeed a critical regulator of early host immune defense against M. ulcerans infections. Interferon-γ knockout mice displayed a faster progression of the infection compared to wild-type mice. This accelerated progression was reflected in faster and more extensive tissue necrosis and oedema formation, as well as in a significantly higher bacterial burden after five weeks of infection, indicating that mice lacking interferon-γ have a reduced capacity to kill intracellular bacilli during the early intra-macrophage growth phase of M. ulcerans. This data demonstrates a prominent role of interferon-γ in early defense against M. ulcerans infection and supports the view that concepts for vaccine development against tuberculosis may also be valid for BU. PMID:26863011

  18. A Diverse Family of Host-Defense Peptides (Piscidins) Exhibit Specialized Anti-Bacterial and Anti-Protozoal Activities in Fishes.

    PubMed

    Salger, Scott A; Cassady, Katherine R; Reading, Benjamin J; Noga, Edward J

    2016-01-01

    Conventional antibiotics and other chemical-based drugs are currently one of the most common methods used to control disease-related mortality in animal agriculture. Use of the innate immune system to decrease disease related mortalities is a novel alternative to conventional drugs. One component of the innate immune system is the host-defense peptides, also known as antimicrobial peptides. Host-defense peptides are typically small, amphipathic, α-helical peptides with a broad-spectrum of action against viral, bacterial, fungal, and/or protozoal pathogens. Piscidins are host-defense peptides first discovered in the hybrid striped bass (white bass, Morone chrysops, x striped bass, M. saxatilis). In this paper we identify four new piscidin isoforms in the hybrid striped bass and describe their tissue distributions. We also determine the progenitor species of origin of each piscidin (orthology) and propose a revised nomenclature for this newly described piscidin family based on a three class system. The Class I piscidins (22 amino acids in length; striped bass and white bass piscidin 1 and piscidin 3) show broad-spectrum activity against bacteria and ciliated protozoans, while the Class III piscidins (55 amino acids in length; striped bass and white bass piscidin 6 and striped bass piscidin 7) primarily show anti-protozoal activity. The Class II piscidins (44-46 amino acids in length; striped bass and white bass piscidin 4 and white bass piscidin 5) have a level of activity against bacteria and protozoans intermediate to Classes I and III. Knowledge of piscidin function and activity may help in the future development of disease-resistant lines of striped bass and white bass that could be used to produce superior hybrids for aquaculture. PMID:27552222

  19. A Diverse Family of Host-Defense Peptides (Piscidins) Exhibit Specialized Anti-Bacterial and Anti-Protozoal Activities in Fishes

    PubMed Central

    Cassady, Katherine R.; Noga, Edward J.

    2016-01-01

    Conventional antibiotics and other chemical-based drugs are currently one of the most common methods used to control disease-related mortality in animal agriculture. Use of the innate immune system to decrease disease related mortalities is a novel alternative to conventional drugs. One component of the innate immune system is the host-defense peptides, also known as antimicrobial peptides. Host-defense peptides are typically small, amphipathic, α-helical peptides with a broad-spectrum of action against viral, bacterial, fungal, and/or protozoal pathogens. Piscidins are host-defense peptides first discovered in the hybrid striped bass (white bass, Morone chrysops, x striped bass, M. saxatilis). In this paper we identify four new piscidin isoforms in the hybrid striped bass and describe their tissue distributions. We also determine the progenitor species of origin of each piscidin (orthology) and propose a revised nomenclature for this newly described piscidin family based on a three class system. The Class I piscidins (22 amino acids in length; striped bass and white bass piscidin 1 and piscidin 3) show broad-spectrum activity against bacteria and ciliated protozoans, while the Class III piscidins (55 amino acids in length; striped bass and white bass piscidin 6 and striped bass piscidin 7) primarily show anti-protozoal activity. The Class II piscidins (44–46 amino acids in length; striped bass and white bass piscidin 4 and white bass piscidin 5) have a level of activity against bacteria and protozoans intermediate to Classes I and III. Knowledge of piscidin function and activity may help in the future development of disease-resistant lines of striped bass and white bass that could be used to produce superior hybrids for aquaculture. PMID:27552222

  20. Dietary antioxidants: immunity and host defense.

    PubMed

    Puertollano, María A; Puertollano, Elena; de Cienfuegos, Gerardo Álvarez; de Pablo, Manuel A

    2011-01-01

    Natural antioxidants may be defined as molecules that prevent cell damage against free radicals and are critical for maintaining optimum health in both animals and humans. In all living systems, cells require adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of reactive oxygen species (ROS) and to prevent damage to the immune cells. During the inflammatory processes, the activation of phagocytes and/or the action of bacterial products with specific receptors are capable of promoting the assembly of the multicomponent flavoprotein NADPH oxidase, which catalyzes the production of high amounts of the superoxide anion radical (O(2)(-)). Under these particular circumstances, neutrophils and macrophages are recognized to produce superoxide free radicals and H(2)O(2), which are essential for defence against phagocytized or invading microbes. In this state, antioxidants are absolutely necessary to regulate the reactions that release free radicals. Antioxidant nutrients commonly included in the diet such as vitamin E, vitamin C, β-carotene, selenium, copper, iron and zinc improve different immune function exhibiting an important protective role in infections caused by bacteria, viruses or parasites. As a result, dietary antioxidants have been related to modulate the host susceptibility or resistance to infectious pathogens. Overall, numerous studies have suggested that the development of tolerance, and control of inflammation are strongly correlated with specific immune mechanisms that may be altered by an inadequate supply of either macronutrients or micronutrients. Therefore, the present paper will review the effects of dietary antioxidants on immune cell function and the impact on protection against infectious microorganisms. PMID:21506934

  1. Human Immunodeficiency Virus Infection and Host Defense in the Lungs.

    PubMed

    Charles, Tysheena P; Shellito, Judd E

    2016-04-01

    Immunosuppression associated with human immunodeficiency virus (HIV) infection impacts all components of host defense against pulmonary infection. Cells within the lung have altered immune function and are important reservoirs for HIV infection. The host immune response to infected lung cells further compromises responses to a secondary pathogenic insult. In the upper respiratory tract, mucociliary function is impaired and there are decreased levels of salivary immunoglobulin A. Host defenses in the lower respiratory tract are controlled by alveolar macrophages, lymphocytes, and polymorphonuclear leukocytes. As HIV infection progresses, lung CD4 T cells are reduced in number causing a lack of activation signals from CD4 T cells and impaired defense by macrophages. CD8 T cells, on the other hand, are increased in number and cause lymphocytic alveolitis. Specific antibody responses by B-lymphocytes are decreased and opsonization of microorganisms is impaired. These observed defects in host defense of the respiratory tract explain the susceptibility of HIV-infected persons for oropharyngeal candidiasis, bacterial pneumonia, Pneumocystis pneumonia, and other opportunistic infections. PMID:26974294

  2. Pharmacodynamic activity of a cephalosporin, Ro 40-6890, in human skin blister fluid: antibiotic activity in concert with host defense mechanisms.

    PubMed Central

    Hoogkamer, J F; Hesse, W H; Sansano, S; Zimmerli, W

    1993-01-01

    The pharmacokinetics of an antimicrobial drug in human plasma and in vitro susceptibility testing of an antimicrobial drug do not necessarily predict its efficacy in vivo. Therefore, the combined activity of an antimicrobial drug and blood-derived polymorphonuclear leukocytes (PMN) against Staphylococcus aureus were investigated in vitro. In addition, a pharmacological model allowing analysis of the bactericidal activity of a drug-containing exudate against S. aureus ex vivo was developed. For this purpose, a phagocytic-bactericidal assay was miniaturized to a volume of 100 microliters in order to test the bactericidal activities of an antimicrobial drug with blood PMN in vitro and with skin blister fluid (CBF) ex vivo. Ro 40-6890, the active metabolite of the ester prodrug Ro 41-3399, was used as the test drug. Killing of S. aureus was clearly enhanced when Ro 41-6890 was combined in vitro with a suboptimal number of blood-derived PMN. In eight healthy volunteers, skin blisters were provoked by plasters containing cantharidin. Following a single oral dose of Ro 41-3399, CBF containing PMN was sampled at regular intervals and incubated ex vivo with S. aureus (5 x 10(5) CFU/ml) for 2, 4, 6, and 24 h at 37 degrees C. Concentrations of Ro 40-6890 were measured in CBF (CCBF) and plasma. Ro 40-6890 distributed well from plasma into CBF. When CCBF was below the MIC, an enhanced effect of Ro 40-6890 and host defense factors present in CBF against S. aureus was observed. In conclusion, the present model can provide additional information on human plasma drug concentrations and MICs established in vitro. PMID:8109926

  3. Dispersal of a defensive symbiont depends on contact between hosts, host health, and host size.

    PubMed

    Hopkins, Skylar R; Boyle, Lindsey J; Belden, Lisa K; Wojdak, Jeremy M

    2015-10-01

    Symbiont dispersal is necessary for the maintenance of defense mutualisms in space and time, and the distribution of symbionts among hosts should be intricately tied to symbiont dispersal behaviors. However, we know surprisingly little about how most defensive symbionts find and choose advantageous hosts or what cues trigger symbionts to disperse from their current hosts. In a series of six experiments, we explored the dispersal ecology of an oligochaete worm (Chaetogaster limnaei) that protects snail hosts from infection by larval trematode parasites. Specifically, we determined the factors that affected net symbiont dispersal from a current "donor" host to a new "receiver" host. Symbionts rarely dispersed unless hosts directly came in contact with one another. However, symbionts overcame their reluctance to disperse across the open environment if the donor host died. When hosts came in direct contact, net symbiont dispersal varied with both host size and trematode infection status, whereas symbiont density did not influence the probability of symbiont dispersal. Together, these experiments show that symbiont dispersal is not a constant, random process, as is often assumed in symbiont dispersal models, but rather the probability of dispersal varies with ecological conditions and among individual hosts. The observed heterogeneity in dispersal rates among hosts may help to explain symbiont aggregation among snail hosts in nature. PMID:25964062

  4. Evolution of Host Defense against Multiple Enemy Populations.

    PubMed

    Toor, Jaspreet; Best, Alex

    2016-03-01

    Natural and managed populations are embedded within complex ecological communities, where they face multiple enemies. Experimental studies have shown that the evolution of host defense mechanisms to a focal enemy is impacted by the surrounding enemy community. Theoretically, the evolution of host defenses against a single enemy population, typically parasites, has been widely studied, but only recently has the impact of community interactions on host-parasite evolution been looked at. In this article, we theoretically examine the evolutionary behavior of a host population that must allocate defenses between two enemy populations, parasites and predators, with defense against one enemy constraining defense against the other. We show that in simpler models the composition of the enemy community plays the key role in determining the defense strategy of the hosts, with the hosts building up defenses against the enemy population posing a larger threat. However, this simple driver is shown to break down when there is significant recovery and reproduction from infected hosts. Additionally, we find that most host diversity is likely to occur when there is a combined high risk of infection and predation, in common with experimental studies. Our results therefore provide vital insight into the ecological feedbacks that drive the evolution of host defense against multiple enemy populations. PMID:26913944

  5. [Role of myeloperoxidase in the host defense against fungal infection].

    PubMed

    Aratani, Yasuaki

    2006-01-01

    Neutrophils are believed to be the first line of defense against invading microorganisms, but in vivo roles of reactive oxygens produced by neutrophils are not well known. Myeloperoxidase (MPO) catalyzes reaction of hydrogen peroxide with chloride ion to produce hypochlorous acid that is used for microbial killing by phagocytic cells. To define the in vivo role of MPO, we generated mice having no peroxidase activity in their neutrophils or monocytes. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for host defense against fungi. However, the significance of MPO compared to the NADPH-oxidase is still unclear because individuals with MPO deficiency are usually healthy in contrast to patients with chronic granulomatous disease (CGD) who present clinical symptoms early in life. To better understand the contributions of MPO and NADPH-oxidase to antifungal defense mechanisms, we compared the susceptibility of MPO-KO mice and CGD mice to infections by C. albicans. Interestingly, at the highest dose, the mortality of MPO-KO mice was comparable to CGD mice, but was the same as normal mice at the lowest dose. These results suggest that MPO and NADPH-oxidase are equally important for early host defense against a large inocula of Candida. Our present results suggest that MPO-deficient individuals could exhibit similar problems as CGD patients if exposed to a large number of microorganisms. PMID:16940954

  6. Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

    PubMed Central

    Wang, Xing; Li, Yun; Liu, Shan; Yu, Xiaoliang; Li, Lin; Shi, Cuilin; He, Wenhui; Li, Jun; Xu, Lei; Hu, Zhilin; Yu, Lu; Yang, Zhongxu; Chen, Qin; Ge, Lin; Zhang, Zili; Zhou, Biqi; Jiang, Xuejun; Chen, She; He, Sudan

    2014-01-01

    The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6–RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1–infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism. PMID:25316792

  7. Necroptosis: The Trojan horse in cell autonomous antiviral host defense.

    PubMed

    Mocarski, Edward S; Guo, Hongyan; Kaiser, William J

    2015-05-01

    Herpesviruses suppress cell death to assure sustained infection in their natural hosts. Murine cytomegalovirus (MCMV) encodes suppressors of apoptosis as well as M45-encoded viral inhibitor of RIP activation (vIRA) to block RIP homotypic interaction motif (RHIM)-signaling and recruitment of RIP3 (also called RIPK3), to prevent necroptosis. MCMV and human cytomegalovirus encode a viral inhibitor of caspase (Casp)8 activation to block apoptosis, an activity that unleashes necroptosis. Herpes simplex virus (HSV)1 and HSV2 incorporate both RHIM and Casp8 suppression strategies within UL39-encoded ICP6 and ICP10, respectively, which are herpesvirus-conserved homologs of MCMV M45. Both HSV proteins sensitize human cells to necroptosis by blocking Casp8 activity while preventing RHIM-dependent RIP3 activation and death. In mouse cells, HSV1 ICP6 interacts with RIP3 and, surprisingly, drives necroptosis. Thus, herpesviruses have illuminated the contribution of necoptosis to host defense in the natural host as well as its potential to restrict cross-species infections in nonnatural hosts. PMID:25819165

  8. The Roles of Antimicrobial Peptides in Innate Host Defense

    PubMed Central

    Diamond, Gill; Beckloff, Nicholas; Weinberg, Aaron; Kisich, Kevin O.

    2009-01-01

    Antimicrobial peptides (AMPs) are multi-functional peptides whose fundamental biological role in vivo has been proposed to be the elimination of pathogenic microorganisms, including Gram-positive and -negative bacteria, fungi, and viruses. Genes encoding these peptides are expressed in a variety of cells in the host, including circulating phagocytic cells and mucosal epithelial cells, demonstrating a wide range of utility in the innate immune system. Expression of these genes is tightly regulated; they are induced by pathogens and cytokines as part of the host defense response, and they can be suppressed by bacterial virulence factors and environmental factors which can lead to increased susceptibility to infection. New research has also cast light on alternative functionalities, including immunomodulatory activities, which are related to their unique structural characteristics. These peptides represent not only an important component of innate host defense against microbial colonization and a link between innate and adaptive immunity, but also form a foundation for the development of new therapeutic agents. PMID:19601838

  9. Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses.

    PubMed

    El-Benna, Jamel; Dang, Pham My-Chan; Gougerot-Pocidalo, Marie-Anne; Elbim, Carole

    2005-01-01

    Phagocytes such as neutrophils and monocytes play an essential role in host defenses against microbial pathogens. Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, the hydroxyl radical, and hypochlorous acid, together with microbicidal peptides and proteases, constitute their antimicrobial arsenal. The enzyme responsible for superoxide anion production and, consequently, ROS generation, is called NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of cytosolic proteins (p47phox, p67phox, p40phox, and rac1/2) and membrane proteins (p22phox and gp91phox, which form cytochrome b558) which assemble at membrane sites upon cell activation. The importance of this enzyme in host defenses is illustrated by a life-threatening genetic disorder called chronic granulomatous disease in which the phagocyte enzyme is dysfunctional, leading to life-threatening bacterial and fungal infections. Also, because ROS can damage surrounding tissues, their production, and thus NADPH oxidase activation, must be tightly regulated. This review describes the structure and activation of the neutrophil NADPH enzyme complex. PMID:15995580

  10. Avian Antimicrobial Host Defense Peptides: From Biology to Therapeutic Applications

    PubMed Central

    Zhang, Guolong; Sunkara, Lakshmi T.

    2014-01-01

    Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomoduatory properties. Because they act on the microbial membranes or host immune cells, HDPs pose a low risk of triggering microbial resistance and therefore, are being actively investigated as a novel class of antimicrobials and vaccine adjuvants. Cathelicidins and β-defensins are two major families of HDPs in avian species. More than a dozen HDPs exist in birds, with the genes in each HDP family clustered in a single chromosomal segment, apparently as a result of gene duplication and diversification. In contrast to their mammalian counterparts that adopt various spatial conformations, mature avian cathelicidins are mostly α-helical. Avian β-defensins, on the other hand, adopt triple-stranded β-sheet structures similar to their mammalian relatives. Besides classical β-defensins, a group of avian-specific β-defensin-related peptides, namely ovodefensins, exist with a different six-cysteine motif. Like their mammalian counterparts, avian cathelicidins and defensins are derived from either myeloid or epithelial origin expressed in a majority of tissues with broad-spectrum antibacterial and immune regulatory activities. Structure-function relationship studies with several avian HDPs have led to identification of the peptide analogs with potential for use as antimicrobials and vaccine adjuvants. Dietary modulation of endogenous HDP synthesis has also emerged as a promising alternative approach to disease control and prevention in chickens. PMID:24583933

  11. Microbial pathogenesis and host defense in the nematode C. elegans

    PubMed Central

    Cohen, Lianne B.; Troemel, Emily R.

    2014-01-01

    Epithelial cells line the surfaces of the body, and are on the front lines of defense against microbial infection. Like many other metazoans, the nematode C. elegans lacks known professional immune cells and relies heavily on defense mediated by epithelial cells. New results indicate that epithelial defense in C. elegans can be triggered through detection of pathogen-induced perturbation of core physiology within host cells and through autophagic defense against intracellular and extracellular pathogens. Recent studies have also illuminated a diverse array of pathogenic attack strategies used against C. elegans. These findings are providing insight into the underpinnings of host/pathogen interactions in a simple animal host that can inform studies of infectious diseases in humans. PMID:25461579

  12. Pattern Recognition Receptors in Innate Immunity, Host Defense, and Immunopathology

    ERIC Educational Resources Information Center

    Suresh, Rahul; Mosser, David M.

    2013-01-01

    Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue.…

  13. Social transmission of a host defense against cuckoo parasitism.

    PubMed

    Davies, Nicholas B; Welbergen, Justin A

    2009-06-01

    Coevolutionary arms races between brood parasites and hosts involve genetic adaptations and counter-adaptations. However, hosts sometimes acquire defenses too rapidly to reflect genetic change. Our field experiments show that observation of cuckoo (Cuculus canorus) mobbing by neighbors on adjacent territories induced reed warblers (Acrocephalus scirpaceus) to increase the mobbing of cuckoos but not of parrots (a harmless control) on their own territory. In contrast, observation of neighbors mobbing parrots had no effect on reed warblers' responses to either cuckoos or parrots. These results indicate that social learning provides a mechanism by which hosts rapidly increase their nest defense against brood parasites. Such enemy-specific social transmission enables hosts to track fine-scale spatiotemporal variation in parasitism and may influence the coevolutionary trajectories and population dynamics of brood parasites and hosts. PMID:19498167

  14. CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense.

    PubMed

    Carevic, M; Öz, H; Fuchs, K; Laval, J; Schroth, C; Frey, N; Hector, A; Bilich, T; Haug, M; Schmidt, A; Autenrieth, S E; Bucher, K; Beer-Hammer, S; Gaggar, A; Kneilling, M; Benarafa, C; Gao, J L; Murphy, P M; Schwarz, S; Moepps, B; Hartl, D

    2016-01-01

    Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases. PMID:26950764

  15. Regulation of the Intestinal Barrier Function by Host Defense Peptides

    PubMed Central

    Robinson, Kelsy; Deng, Zhuo; Hou, Yongqing; Zhang, Guolong

    2015-01-01

    Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity. PMID:26664984

  16. Epidermal EGFR controls cutaneous host defense and prevents inflammation.

    PubMed

    Lichtenberger, Beate M; Gerber, Peter A; Holcmann, Martin; Buhren, Bettina A; Amberg, Nicole; Smolle, Viktoria; Schrumpf, Holger; Boelke, Edwin; Ansari, Parinaz; Mackenzie, Colin; Wollenberg, Andreas; Kislat, Andreas; Fischer, Jens W; Röck, Katharina; Harder, Jürgen; Schröder, Jens M; Homey, Bernhard; Sibilia, Maria

    2013-08-21

    The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Δep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies. PMID:23966300

  17. FGF23 signaling impairs neutrophil recruitment and host defense during CKD

    PubMed Central

    Rossaint, Jan; Oehmichen, Jessica; Van Aken, Hugo; Reuter, Stefan; Pavenstädt, Hermann J.; Meersch, Melanie; Unruh, Mark

    2016-01-01

    Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine-activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered β2 integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation. PMID:26878171

  18. Host plant defense signaling in response to a coevolved herbivore combats introduced herbivore attack

    PubMed Central

    Woodard, Anastasia M; Ervin, Gary N; Marsico, Travis D

    2012-01-01

    Defense-free space resulting from coevolutionarily naïve host plants recently has been implicated as a factor facilitating invasion success of some insect species. Host plants, however, may not be entirely defenseless against novel herbivore threats. Volatile chemical-mediated defense signaling, which allows plants to mount specific, rapid, and intense responses, may play a role in systems experiencing novel threats. Here we investigate defense responses of host plants to a native and exotic herbivore and show that (1) host plants defend more effectively against the coevolved herbivore, (2) plants can be induced to defend against a newly-associated herbivore when in proximity to plants actively defending against the coevolved species, and (3) these defenses affect larval performance. These findings highlight the importance of coevolved herbivore-specific defenses and suggest that naïveté or defense limitations can be overcome via defense signaling. Determining how these findings apply across various host–herbivore systems is critical to understand mechanisms of successful herbivore invasion. PMID:22837849

  19. Tobacco smoke. Effects on pulmonary host defense.

    PubMed

    Drath, D B; Karnovsky, M L; Huber, G L

    1979-07-01

    Tobacco smoke affected both the metabolism and function of pulmonary alveolar macrophages (PAM). Phagocytosis of viable Staphylococcus aureus and inert starch particles was minimally but consistently depressed in PAM from rats exposed to tobacco smoke for six months. Oxygen consumption, superoxide and hydrogen peroxide release, and hexose monophosphate shunt activity were elevated in cells from smokers. Oxidation of glucose, labelled in the carbon-six position, remained unchanged. All observed effects of tobacco smoke on oxygen metabolism occurred during phagocytosis and did not affect the basal metabolism of the nonstimulated cell. PMID:225267

  20. Antimicrobial peptides in echinoderm host defense.

    PubMed

    Li, Chun; Blencke, Hans-Matti; Haug, Tor; Stensvåg, Klara

    2015-03-01

    Antimicrobial peptides (AMPs) are important effector molecules in innate immunity. Here we briefly summarize characteristic traits of AMPs and their mechanisms of antimicrobial activity. Echinoderms live in a microbe-rich marine environment and are known to express a wide range of AMPs. We address two novel AMP families from coelomocytes of sea urchins: cysteine-rich AMPs (strongylocins) and heterodimeric AMPs (centrocins). These peptide families have conserved preprosequences, are present in both adults and pluteus stage larvae, have potent antimicrobial properties, and therefore appear to be important innate immune effectors. Strongylocins have a unique cysteine pattern compared to other cysteine-rich peptides, which suggests a novel AMP folding pattern. Centrocins and SdStrongylocin 2 contain brominated tryptophan residues in their native form. This review also includes AMPs isolated from other echinoderms, such as holothuroidins, fragments of beta-thymosin, and fragments of lectin (CEL-III). Echinoderm AMPs are crucial molecules for the understanding of echinoderm immunity, and their potent antimicrobial activity makes them potential precursors of novel drug leads. PMID:25445901

  1. Host defense at the ocular surface.

    PubMed

    Pearlman, Eric; Sun, Yan; Roy, Sanhita; Karmakar, Mausita; Hise, Amy G; Szczotka-Flynn, Loretta; Ghannoum, Mahmoud; Chinnery, Holly R; McMenamin, Paul G; Rietsch, Arne

    2013-02-01

    Microbial infections of the cornea frequently cause painful, blinding and debilitating disease that is often difficult to treat and may require corneal transplantation. In addition, sterile corneal infiltrates that are associated with contact lens wear cause pain, visual impairment and photophobia. In this article, we review the role of Toll-Like Receptors (TLR) in bacterial keratitis and sterile corneal infiltrates, and describe the role of MD-2 regulation in LPS responsiveness by corneal epithelial cells. We conclude that both live bacteria and bacterial products activate Toll-Like Receptors in the cornea, which leads to chemokine production and neutrophil recruitment to the corneal stroma. While neutrophils are essential for bacterial killing, they also cause tissue damage that results in loss of corneal clarity. These disparate outcomes, therefore, represent a spectrum of disease severity based on this pathway, and further indicate that targeting the TLR pathway is a feasible approach to treating inflammation caused by live bacteria and microbial products. Further, as the P. aeruginosa type III secretion system (T3SS) also plays a critical role in disease pathogenesis by inducing neutrophil apoptosis and facilitating bacterial growth in the cornea, T3SS exotoxins are additional targets for therapy for P. aeruginosa keratitis. PMID:23360155

  2. Mast cell tryptases and chymases in inflammation and host defense

    PubMed Central

    Caughey, George H.

    2008-01-01

    Summary Tryptases and chymases are the major proteins stored and secreted by mast cells. The types, amounts and properties of these serine peptidases vary by mast cell subtype, tissue, and mammal of origin. Membrane-anchored γ-tryptases are tryptic, prostasin-like, type I peptidases that remain membrane-attached upon release and act locally. Soluble tryptases, including their close relatives, mastins, form inhibitor-resistant oligomers that act more remotely. Befitting their greater destructive potential, chymases are quickly inhibited after release, although some gain protection by associating with proteoglycans. Most chymase-like enzymes, including mast cell cathepsin G, hydrolyze chymotryptic substrates, an uncommon capability in the proteome. Some rodent chymases, however, have mutations resulting in elastolytic activity. Secreted tryptases and chymases promote inflammation, matrix destruction, and tissue remodeling by several mechanisms, including destroying pro-coagulant, matrix, growth and differentiation factors, and activating proteinase-activated receptors, urokinase, metalloproteinases, and angiotensin. They also modulate immune responses by hydrolyzing chemokines and cytokines. At least one chymase protects mice from intestinal worms. Tryptases and chymases also can oppose inflammation by inactivating allergens and neuropeptides causing inflammation and bronchoconstriction. Thus, like mast cells themselves, mast cell serine peptidases play multiple roles in host defense and any accounting of benefit versus harm is necessarily context-specific. PMID:17498057

  3. Airway acidification initiates host defense abnormalities in cystic fibrosis mice

    PubMed Central

    Shah, Viral S.; Meyerholz, David K.; Tang, Xiao Xiao; Reznikov, Leah; Alaiwa, Mahmoud Abou; Ernst, Sarah E.; Karp, Philip H.; Wohlford-Lenane, Christine L.; Heilmann, Kristopher P.; Leidinger, Mariah R.; Allen, Patrick D.; Zabner, Joseph; McCray, Paul B.; Ostedgaard, Lynda S.; Stoltz, David A.; Randak, Christoph O.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  4. Airway acidification initiates host defense abnormalities in cystic fibrosis mice.

    PubMed

    Shah, Viral S; Meyerholz, David K; Tang, Xiao Xiao; Reznikov, Leah; Abou Alaiwa, Mahmoud; Ernst, Sarah E; Karp, Philip H; Wohlford-Lenane, Christine L; Heilmann, Kristopher P; Leidinger, Mariah R; Allen, Patrick D; Zabner, Joseph; McCray, Paul B; Ostedgaard, Lynda S; Stoltz, David A; Randak, Christoph O; Welsh, Michael J

    2016-01-29

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H(+) secretion by the nongastric H(+)/K(+) adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H(+); consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  5. Interleukin 17-Mediated Host Defense against Candida albicans

    PubMed Central

    Sparber, Florian; LeibundGut-Landmann, Salomé

    2015-01-01

    Candida albicans is part of the normal microbiota in most healthy individuals. However, it can cause opportunistic infections if host defenses are breached, with symptoms ranging from superficial lesions to severe systemic disease. The study of rare congenital defects in patients with chronic mucocutaneous candidiasis led to the identification of interleukin-17 (IL-17) as a key factor in host defense against mucosal fungal infection. Experimental infections in mice confirmed the critical role of IL-17 in mucocutaneous immunity against C. albicans. Research on mouse models has also contributed importantly to our current understanding of the regulation of IL-17 production by different cellular sources and its effector functions in distinct tissues. In this review, we highlight recent findings on IL-17-mediated immunity against C. albicans in mouse and man. PMID:26274976

  6. Role of NADPH Oxidase versus Neutrophil Proteases in Antimicrobial Host Defense

    PubMed Central

    Grimm, Melissa J.; Lewandowski, David C.; Pham, Christine T. N.; Blackwell, Timothy S.; Petraitiene, Ruta; Petraitis, Vidmantas; Walsh, Thomas J.; Urban, Constantin F.; Segal, Brahm H.

    2011-01-01

    NADPH oxidase is a crucial enzyme in mediating antimicrobial host defense and in regulating inflammation. Patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates (ROIs), suffer from life-threatening bacterial and fungal infections. The mechanisms by which NADPH oxidase mediate host defense are unclear. In addition to ROI generation, neutrophil NADPH oxidase activation is linked to the release of sequestered proteases that are posited to be critical effectors of host defense. To definitively determine the contribution of NADPH oxidase versus neutrophil serine proteases, we evaluated susceptibility to fungal and bacterial infection in mice with engineered disruptions of these pathways. NADPH oxidase-deficient mice (p47phox−/−) were highly susceptible to pulmonary infection with Aspergillus fumigatus. In contrast, double knockout neutrophil elastase (NE)−/−×cathepsin G (CG)−/− mice and lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI)-deficient mice that are defective in neutrophil serine protease activation demonstrated no impairment in antifungal host defense. In separate studies of systemic Burkholderia cepacia infection, uniform fatality occurred in p47phox−/− mice, whereas NE−/−×CG−/− mice cleared infection. Together, these results show a critical role for NADPH oxidase in antimicrobial host defense against A. fumigatus and B. cepacia, whereas the proteases we evaluated were dispensable. Our results indicate that NADPH oxidase dependent pathways separate from neutrophil serine protease activation are required for host defense against specific pathogens. PMID:22163282

  7. Bioprospecting the American alligator (Alligator mississippiensis) host defense peptidome.

    PubMed

    Bishop, Barney M; Juba, Melanie L; Devine, Megan C; Barksdale, Stephanie M; Rodriguez, Carlos Alberto; Chung, Myung C; Russo, Paul S; Vliet, Kent A; Schnur, Joel M; van Hoek, Monique L

    2015-01-01

    Cationic antimicrobial peptides and their therapeutic potential have garnered growing interest because of the proliferation of bacterial resistance. However, the discovery of new antimicrobial peptides from animals has proven challenging due to the limitations associated with conventional biochemical purification and difficulties in predicting active peptides from genomic sequences, if known. As an example, no antimicrobial peptides have been identified from the American alligator, Alligator mississippiensis, although their serum is antimicrobial. We have developed a novel approach for the discovery of new antimicrobial peptides from these animals, one that capitalizes on their fundamental and conserved physico-chemical properties. This sample-agnostic process employs custom-made functionalized hydrogel microparticles to harvest cationic peptides from biological samples, followed by de novo sequencing of captured peptides, eliminating the need to isolate individual peptides. After evaluation of the peptide sequences using a combination of rational and web-based bioinformatic analyses, forty-five potential antimicrobial peptides were identified, and eight of these peptides were selected to be chemically synthesized and evaluated. The successful identification of multiple novel peptides, exhibiting antibacterial properties, from Alligator mississippiensis plasma demonstrates the potential of this innovative discovery process in identifying potential new host defense peptides. PMID:25671663

  8. CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis

    PubMed Central

    Juffermans, Nicole P.; Leemans, Jaklien C.; Florquin, Sandrine; Verbon, Annelies; Kolk, Arend H.; Speelman, Peter; van Deventer, Sander J. H.; van der Poll, Tom

    2002-01-01

    Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs activate immune cells to produce cytokines. CpG ODNs protect mice against infections with intracellular bacteria by the induction of a T helper 1 (Th1) response. To determine the effect of CpG ODNs in pulmonary tuberculosis, mice were treated with CpG ODNs or control ODNs at the time of intranasal infection. CpG ODNs reduced mycobacterial outgrowth for up to 5 weeks after Mycobacterium tuberculosis infection and were associated with a decrease in inflammation in lung tissue. CpG treatment was also associated with elevated levels of gamma interferon (IFN-γ) and decreased levels of interleukin 4 in the lungs and an increased capacity of splenocytes to secrete Th1-type cytokines. CpG ODNs given 2 weeks after infection were still able to reduce mycobacterial outgrowth and to enhance a Th1 response 5 weeks postinfection. Administration of CpG ODNs to IFN-γ-gene-deficient mice failed to reduce mycobacterial outgrowth. These data suggest that CpG ODNs improve host defense during pulmonary tuberculosis by an IFN-γ-dependent mechanism. PMID:11748176

  9. Herbivore Oral Secreted Bacteria Trigger Distinct Defense Responses in Preferred and Non-Preferred Host Plants.

    PubMed

    Wang, Jie; Chung, Seung Ho; Peiffer, Michelle; Rosa, Cristina; Hoover, Kelli; Zeng, Rensen; Felton, Gary W

    2016-06-01

    Insect symbiotic bacteria affect host physiology and mediate plant-insect interactions, yet there are few clear examples of symbiotic bacteria regulating defense responses in different host plants. We hypothesized that plants would induce distinct defense responses to herbivore- associated bacteria. We evaluated whether preferred hosts (horsenettle) or non-preferred hosts (tomato) respond similarly to oral secretions (OS) from the false potato beetle (FPB, Leptinotarsa juncta), and whether the induced defense triggered by OS was due to the presence of symbiotic bacteria in OS. Both horsenettle and tomato damaged by antibiotic (AB) treated larvae showed higher polyphenol oxidase (PPO) activity than those damaged by non-AB treated larvae. In addition, application of OS from AB treated larvae induced higher PPO activity compared with OS from non-AB treated larvae or water treatment. False potato beetles harbor bacteria that may provide abundant cues that can be recognized by plants and thus mediate corresponding defense responses. Among all tested bacterial isolates, the genera Pantoea, Acinetobacter, Enterobacter, and Serratia were found to suppress PPO activity in tomato, while only Pantoea sp. among these four isolates was observed to suppress PPO activity in horsenettle. The distinct PPO suppression caused by symbiotic bacteria in different plants was similar to the pattern of induced defense-related gene expression. Pantoea inoculated FPB suppressed JA-responsive genes and triggered a SA-responsive gene in both tomato and horsenettle. However, Enterobacter inoculated FPB eliminated JA-regulated gene expression and elevated SA-regulated gene expression in tomato, but did not show evident effects on the expression levels of horsenettle defense-related genes. These results indicate that suppression of plant defenses by the bacteria found in the oral secretions of herbivores may be a more widespread phenomenon than previously indicated. PMID:27294415

  10. Host Defense Peptides in the Oral Cavity and the Lung: Similarities and Differences

    PubMed Central

    Diamond, G.; Beckloff, N.; Ryan, L.K.

    2009-01-01

    Peptides with broad-spectrum antimicrobial activity are found in the mucosal surfaces at many sites in the body, including the airway, the oral cavity, and the digestive tract. Based on their in vitro antimicrobial and other immunomodulatory activities, these host defense peptides have been proposed to play an important role in the innate defense against pathogenic microbial colonization. The genes that encode these peptides are up-regulated by pathogens, further supporting their role in innate immune defense. However, the differences in the local microbial environments between the generally sterile airway and the highly colonized oral cavity suggest a more complex role for these peptides in innate immunity. For example, β-defensin genes are induced in the airway by all bacteria and Toll-like receptor (TLR) agonists primarily through an NF-κB-mediated pathway. In contrast, the same genes are induced in the gingival epithelium by only a subset of bacteria and TLR ligands, via different pathways. Furthermore, the environments into which the peptides are secreted—specifically saliva, gingival crevicular fluid, and airway surface fluid—differ greatly and can effect their respective activities in host defense. In this review, we examine the differences and similarities between host defense peptides in the oral cavity and the airway, to gain a better understanding of their contributions to immunity. PMID:18809744

  11. Role of Interleukin 36γ in Host Defense Against Tuberculosis.

    PubMed

    Ahsan, Fadhil; Moura-Alves, Pedro; Guhlich-Bornhof, Ute; Klemm, Marion; Kaufmann, Stefan H E; Maertzdorf, Jeroen

    2016-08-01

    Tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. The roles of the interleukin 1 (IL-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. In contrast, the regulation of interleukin 36γ (IL-36γ), a recently described member of the IL-1 family, and its immunological relevance in host defense remain largely unknown. Here we show that Mycobacterium tuberculosis infection of macrophages induces IL-36γ production in a 2-stage-regulated fashion. In the first stage, microbial ligands trigger host Toll-like receptor and MyD88-dependent pathways, leading to IL-36γ secretion. In the second stage, endogenous IL-1β and interleukin 18 further amplify IL-36γ synthesis. The relevance of this cytokine in the control of M. tuberculosis is demonstrated by IL-36γ-induced antimicrobial peptides and IL-36 receptor-dependent restriction of M. tuberculosis growth. Thus, we provide first insight into the induction and regulation of the proinflammatory cytokine IL-36γ during tuberculosis. PMID:27389350

  12. Silencing suppressors: viral weapons for countering host cell defenses.

    PubMed

    Song, Liping; Gao, Shijuan; Jiang, Wei; Chen, Shuai; Liu, Yanjun; Zhou, Ling; Huang, Wenlin

    2011-04-01

    RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21-23 nt RNA molecules. During infection, RNAi can act as an innate immune system to defend against viruses. As a counter-defensive strategy, silencing suppressors are encoded by viruses to inhibit various stages of the silencing process. These suppressors are diverse in sequence and structure and act via different mechanisms. In this review, we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses. We also review the modes of action proposed for some silencing suppressors. PMID:21528352

  13. Salivary mucins in host defense and disease prevention.

    PubMed

    Frenkel, Erica Shapiro; Ribbeck, Katharina

    2015-01-01

    Mucus forms a protective coating on wet epithelial surfaces throughout the body that houses the microbiota and plays a key role in host defense. Mucins, the primary structural components of mucus that creates its viscoelastic properties, are critical components of the gel layer that protect against invading pathogens. Altered mucin production has been implicated in diseases such as ulcerative colitis, asthma, and cystic fibrosis, which highlights the importance of mucins in maintaining homeostasis. Different types of mucins exist throughout the body in various locations such as the gastrointestinal tract, lungs, and female genital tract, but this review will focus on mucins in the oral cavity. Salivary mucin structure, localization within the oral cavity, and defense mechanisms will be discussed. These concepts will then be applied to present what is known about the protective function of mucins in oral diseases such as HIV/AIDS, oral candidiasis, and dental caries. PMID:26701274

  14. Salivary mucins in host defense and disease prevention

    PubMed Central

    Frenkel, Erica Shapiro; Ribbeck, Katharina

    2015-01-01

    Mucus forms a protective coating on wet epithelial surfaces throughout the body that houses the microbiota and plays a key role in host defense. Mucins, the primary structural components of mucus that creates its viscoelastic properties, are critical components of the gel layer that protect against invading pathogens. Altered mucin production has been implicated in diseases such as ulcerative colitis, asthma, and cystic fibrosis, which highlights the importance of mucins in maintaining homeostasis. Different types of mucins exist throughout the body in various locations such as the gastrointestinal tract, lungs, and female genital tract, but this review will focus on mucins in the oral cavity. Salivary mucin structure, localization within the oral cavity, and defense mechanisms will be discussed. These concepts will then be applied to present what is known about the protective function of mucins in oral diseases such as HIV/AIDS, oral candidiasis, and dental caries. PMID:26701274

  15. Unmasking host and microbial strategies in the Agrobacterium-plant defense tango

    PubMed Central

    Hwang, Elizabeth E.; Wang, Melinda B.; Bravo, Janis E.; Banta, Lois M.

    2015-01-01

    Coevolutionary forces drive adaptation of both plant-associated microbes and their hosts. Eloquently captured in the Red Queen Hypothesis, the complexity of each plant–pathogen relationship reflects escalating adversarial strategies, but also external biotic and abiotic pressures on both partners. Innate immune responses are triggered by highly conserved pathogen-associated molecular patterns, or PAMPs, that are harbingers of microbial presence. Upon cell surface receptor-mediated recognition of these pathogen-derived molecules, host plants mount a variety of physiological responses to limit pathogen survival and/or invasion. Successful pathogens often rely on secretion systems to translocate host-modulating effectors that subvert plant defenses, thereby increasing virulence. Host plants, in turn, have evolved to recognize these effectors, activating what has typically been characterized as a pathogen-specific form of immunity. Recent data support the notion that PAMP-triggered and effector-triggered defenses are complementary facets of a convergent, albeit differentially regulated, set of immune responses. This review highlights the key players in the plant’s recognition and signal transduction pathways, with a focus on the aspects that may limit Agrobacterium tumefaciens infection and the ways it might overcome those defenses. Recent advances in the field include a growing appreciation for the contributions of cytoskeletal dynamics and membrane trafficking to the regulation of these exquisitely tuned defenses. Pathogen counter-defenses frequently manipulate the interwoven hormonal pathways that mediate host responses. Emerging systems-level analyses include host physiological factors such as circadian cycling. The existing literature indicates that varying or even conflicting results from different labs may well be attributable to environmental factors including time of day of infection, temperature, and/or developmental stage of the host plant. PMID:25873923

  16. Unmasking host and microbial strategies in the Agrobacterium-plant defense tango.

    PubMed

    Hwang, Elizabeth E; Wang, Melinda B; Bravo, Janis E; Banta, Lois M

    2015-01-01

    Coevolutionary forces drive adaptation of both plant-associated microbes and their hosts. Eloquently captured in the Red Queen Hypothesis, the complexity of each plant-pathogen relationship reflects escalating adversarial strategies, but also external biotic and abiotic pressures on both partners. Innate immune responses are triggered by highly conserved pathogen-associated molecular patterns, or PAMPs, that are harbingers of microbial presence. Upon cell surface receptor-mediated recognition of these pathogen-derived molecules, host plants mount a variety of physiological responses to limit pathogen survival and/or invasion. Successful pathogens often rely on secretion systems to translocate host-modulating effectors that subvert plant defenses, thereby increasing virulence. Host plants, in turn, have evolved to recognize these effectors, activating what has typically been characterized as a pathogen-specific form of immunity. Recent data support the notion that PAMP-triggered and effector-triggered defenses are complementary facets of a convergent, albeit differentially regulated, set of immune responses. This review highlights the key players in the plant's recognition and signal transduction pathways, with a focus on the aspects that may limit Agrobacterium tumefaciens infection and the ways it might overcome those defenses. Recent advances in the field include a growing appreciation for the contributions of cytoskeletal dynamics and membrane trafficking to the regulation of these exquisitely tuned defenses. Pathogen counter-defenses frequently manipulate the interwoven hormonal pathways that mediate host responses. Emerging systems-level analyses include host physiological factors such as circadian cycling. The existing literature indicates that varying or even conflicting results from different labs may well be attributable to environmental factors including time of day of infection, temperature, and/or developmental stage of the host plant. PMID:25873923

  17. Host Defense Peptides from Asian Frogs as Potential Clinical Therapies

    PubMed Central

    Kumar, Vineeth T.V.; Holthausen, David; Jacob, Joshy; George, Sanil

    2015-01-01

    Host defense peptides (HDPs) are currently major focal points of medical research as infectious microbes are gaining resistance to existing drugs. They are effective against multi-drug resistant pathogens due to their unique primary target, biological membranes, and their peculiar mode of action. Even though HDPs from 60 Asian frog species belonging to 15 genera have been characterized, research into these peptides is at a very early stage. The purpose of this review is to showcase the status of peptide research in Asia. Here we provide a summary of HDPs from Asian frogs. PMID:27025618

  18. Fibrinogen Is at the Interface of Host Defense and Pathogen Virulence in Staphylococcus aureus Infection.

    PubMed

    Ko, Ya-Ping; Flick, Matthew J

    2016-06-01

    Fibrinogen not only plays a pivotal role in hemostasis but also serves key roles in antimicrobial host defense. As a rapidly assembled provisional matrix protein, fibrin(ogen) can function as an early line of host protection by limiting bacterial growth, suppressing dissemination of microbes to distant sites, and mediating host bacterial killing. Fibrinogen-mediated host antimicrobial activity occurs predominantly through two general mechanisms, namely, fibrin matrices functioning as a protective barrier and fibrin(ogen) directly or indirectly driving host protective immune function. The potential of fibrin to limit bacterial infection and disease has been countered by numerous bacterial species evolving and maintaining virulence factors that engage hemostatic system components within vertebrate hosts. Bacterial factors have been isolated that simply bind fibrinogen or fibrin, promote fibrin polymer formation, or promote fibrin dissolution. Staphylococcus aureus is an opportunistic gram-positive bacterium, the causative agent of a wide range of human infectious diseases, and a prime example of a pathogen exquisitely sensitive to host fibrinogen. Indeed, current data suggest fibrinogen serves as a context-dependent determinant of host defense or pathogen virulence in Staphylococcus infection whose ultimate contribution is dictated by the expression of S. aureus virulence factors, the path of infection, and the tissue microenvironment. PMID:27056151

  19. Glutathione Reductase Is Essential for Host Defense against Bacterial Infection

    PubMed Central

    Yan, Jing; Ralston, Melissa M.; Meng, Xiaomei; Bongiovanni, Kathleen D.; Jones, Amanda L.; Benndorf, Rainer; Nelin, Leif D.; Frazier, W. Joshua; Rogers, Lynette K.; Smith, Charles V.; Liu, Yusen

    2013-01-01

    Glutathione reductase (Gsr)1 catalyzes the reduction of glutathione disulfide to glutathione, a major cellular antioxidant. We have recently shown that Gsr is essential for host defense against the Gram-negative bacteria Escherichia coli in a mouse model of sepsis. While we have demonstrated that Gsr is required for sustaining the oxidative burst and the development of neutrophil extracellular traps, the role of Gsr in other phagocytic functions remains unclear. It is also unclear whether Gsr-deficient mice exhibit host defense defects against Gram-positive bacteria. In the present study, we characterized the effects of Gsr deficiency on the innate immune responses to a Gram-positive bacterium, group B Streptococcus, and to the Gram-negative bacterial cell wall component lipopolysaccharide (LPS). We found that like, E. coli, group B Streptococcus resulted in a substantially more robust cytokine response and a markedly higher morbidity and mortality in Gsr-deficient mice than in wildtype mice. The increased morbidity and mortality were associated with greater bacterial burden in the Gsr-deficient mice. Interestingly, Gsr-deficient mice did not exhibit a greater sensitivity to LPS than did wildtype mice. Analysis of the neutrophils of Gsr-deficient mice revealed impaired phagocytosis. In response to thioglycollate stimulation, Gsr-deficient mice mobilized far fewer phagocytes, including neutrophils, macrophages, and eosinophils, into their peritoneal cavities than did wildtype mice. The defective phagocyte mobilization is associated with profound oxidation and aggregation of ascitic proteins, particularly albumin. Our results indicate that the oxidative defense mechanism mediated by Gsr is required for an effective innate immune response against bacteria, likely by preventing phagocyte dysfunction due to oxidative damage. PMID:23623936

  20. DNA-sensing inflammasomes: regulation of bacterial host defense and the gut microbiota.

    PubMed

    Man, Si Ming; Karki, Rajendra; Kanneganti, Thirumala-Devi

    2016-06-01

    DNA sensors are formidable immune guardians of the host. At least 14 cytoplasmic DNA sensors have been identified in recent years, each with specialized roles in driving inflammation and/or cell death. Of these, AIM2 is a sensor of dsDNA, and forms an inflammasome complex to activate the cysteine protease caspase-1, mediates the release of the proinflammatory cytokines IL-1β and IL-18, and induces pyroptosis. The inflammasome sensor NLRP3 can also respond to DNA in the forms of oxidized mitochondrial DNA and the DNA derivative RNA:DNA hybrids produced by bacteria, whereas the putative inflammasome sensor IFI16 responds to viral DNA in the nucleus. Although inflammasomes provoke inflammation for anti-microbial host defense, they must also maintain homeostasis with commensal microbiota. Here, we outline recent advances highlighting the complex relationship between DNA-sensing inflammasomes, bacterial host defense and the gut microbiota. PMID:27056948

  1. A cupin domain-containing protein with a quercetinase activity (VdQase) regulates Verticillium dahliae's pathogenicity and contributes to counteracting host defenses

    PubMed Central

    El Hadrami, Abdelbasset; Islam, Md. Rashidul; Adam, Lorne R.; Daayf, Fouad

    2015-01-01

    We previously identified rutin as part of potato root responses to its pathogen Verticillium dahliae. Rutin was directly toxic to the pathogen at doses greater than 160 μM, a threshold below which many V. dahliae pathogenicity-related genes were up-regulated. We identified and characterized a cupin domain-containing protein (VdQase) with a dioxygenase activity and a potential role in V. dahliae-potato interactions. The pathogenicity of VdQase knock-out mutants generated through Agrobacterium tumefasciens-mediated transformation was significantly reduced on susceptible potato cultivar Kennebec compared to wild type isolates. Fluorescence microscopy revealed a higher accumulation of flavonols in the stems of infected potatoes and a higher concentration of rutin in the leaves in response to the VdQase mutants as compared to wild type isolates. This, along with the HPLC characterization of high residual and non-utilized quercetin in presence of the knockout mutants, indicates the involvement of VdQase in the catabolism of quercetin and possibly other flavonols in planta. Quantification of Salicylic and Jasmonic Acids (SA, JA) in response to the mutants vs. wild type isolates revealed involvement of VdQase in the interference with signaling, suggesting a role in pathogenicity. It is hypothesized that the by-product of dioxygenation 2-protocatechuoylphloroglucinolcarboxylic acid, after dissociating into phloroglucinol and protocatechuoyl moieties, becomes a starting point for benzoic acid and SA, thereby interfering with the JA pathway and affecting the interaction outcome. These events may be key factors for V. dahliae in countering potato defenses and becoming notorious in the rhizosphere. PMID:26113857

  2. Murine models of Aspergillosis: Role of collectins in host defense.

    PubMed

    Singh, Mamta; Mahajan, Lakshna; Chaudhary, Neelkamal; Kaur, Savneet; Madan, Taruna; Sarma, P Usha

    2015-11-01

    Aspergillus fumigatus, a ubiquitous fungus, causes a wide spectrum of clinical conditions ranging from allergic to invasive aspergillosis depending upon the hosts' immune status. Several animal models have been generated to mimic the human clinical conditions in allergic and invasive aspergillosis. The onset, duration and severity of the disease developed in models varied depending on the animal strain/fungal isolate, quantity and mode of administration of fungal antigens/spores, duration of the treatment, and type of immunosuppressive agent used. These models provide insight into host and pathogen factors and prove to be useful for evaluation of diagnostic markers and effective therapies. A series of studies established the protective role of collectins in murine models of Allergic Bronchopulmonary Aspergillosis and Invasive Pulmonary Aspergillosis. Collectins, namely surfactant protein A (SP-A), surfactant protein D (SP-D) and mannan binding lectin (MBL), are pattern recognition molecules regulating both innate and adaptive immune response against pathogens. In the present review, we discussed various murine models of allergic and invasive aspergillosis and the role of collectins in host defense against aspergillosis. PMID:26669011

  3. Prophenoloxidase genes and antimicrobial host defense of the model beetle, Tribolium castaneum.

    PubMed

    Yokoi, Kakeru; Hayakawa, Yuuki; Kato, Daiki; Minakuchi, Chieka; Tanaka, Toshiharu; Ochiai, Masanori; Kamiya, Katsumi; Miura, Ken

    2015-11-01

    In this study, we characterized prophenoloxidase (proPO, (PPO)) genes of Tribolium castaneum and examined their involvement in antimicrobial host defense. Amino acid sequence comparison with well-characterized PPO proteins from other insect species suggested that T. castaneum PPO genes encoded functional proenzymes, with crucial sequence motifs being conserved. Developmental kinetics of the mRNA of two PPO genes, PPO1 and PPO2 in the pupal stage were different to each other. The PPO1 mRNA levels consistently decreased during pupal development while that of PPO2 peaked at mid-pupal stage. The two mRNAs also exhibited distinct responses upon immune challenges with heat-killed model microbes. The PPO1 mRNA stayed nearly unchanged by 6h post challenge, and was somewhat elevated at 24h. In contrast, the PPO2 mRNA significantly decreased at 3, 6 and 24h post challenge. These trends exhibited by respective PPO genes were consistent irrespective of the microbial species used as elicitors. Finally, we investigated the involvement of T. castaneum PPO genes in antimicrobial host defense by utilizing RNA interference-mediated gene silencing. Survival assays demonstrated that double knockdown of PPO genes, which was accompanied by weakened hemolymph PO activities, significantly impaired the host defense against Bacillus subtilis. By contrast, the knockdown did not influence the induction of any of the T. castaneum antimicrobial peptide genes that were studied here, except for one belonging to the gene group that shows very weak or negligible microbial induction. PPO knockdown as well weakened host defense against Beauveria bassiana moderately but significantly depending on the combination of infection methods and targeted genes. Our results indicated that the PPO genes represented constituents of both antibacterial and antifungal host defense of T. castaneum. PMID:26519623

  4. An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense.

    PubMed

    Najibi, Mehran; Labed, Sid Ahmed; Visvikis, Orane; Irazoqui, Javier Elbio

    2016-05-24

    The mechanisms that tightly control the transcription of host defense genes have not been fully elucidated. We previously identified TFEB as a transcription factor important for host defense, but the mechanisms that regulate TFEB during infection remained unknown. Here, we used C. elegans to discover a pathway that activates TFEB during infection. Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus. Conversely, pharmacological activation of PKD was sufficient to activate TFEB. Furthermore, phospholipase C (PLC) gene plc-1 was also required for TFEB activation, downstream of Gαq homolog egl-30 and upstream of dkf-1. Using reverse and chemical genetics, we discovered a similar PLC-PKD-TFEB axis in Salmonella-infected mouse macrophages. In addition, PKCα was required in macrophages. These observations reveal a previously unknown host defense signaling pathway, which has been conserved across one billion years of evolution. PMID:27184844

  5. Epithelial antimicrobial peptides in host defense against infection

    PubMed Central

    Bals, Robert

    2000-01-01

    One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides. Antimicrobial peptides are classified on the basis of their structure and amino acid motifs. Peptides of the defensin, cathelicidin, and histatin classes are found in humans. In the airways, α-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils. β-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid. Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis. Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation. PMID:11667978

  6. A Review of Ribonuclease 7’s Structure, Regulation, and Contributions to Host Defense

    PubMed Central

    Becknell, Brian; Spencer, John David

    2016-01-01

    The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7’s antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases. PMID:27011175

  7. Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia.

    PubMed

    van den Boogaard, Florry E; van Gisbergen, Klaas P J M; Vernooy, Juanita H; Medema, Jan P; Roelofs, Joris J T H; van Zoelen, Marieke A D; Endeman, Henrik; Biesma, Douwe H; Boon, Louis; Van't Veer, Cornelis; de Vos, Alex F; van der Poll, Tom

    2016-08-01

    Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA(-/-)) mice by intranasal inoculation of S. pneumoniae In separate experiments, WT and GzmA(-/-) mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA(-/-) mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA(-/-) mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells. PMID:27343190

  8. Addicted? Reduced host resistance in populations with defensive symbionts.

    PubMed

    Martinez, Julien; Cogni, Rodrigo; Cao, Chuan; Smith, Sophie; Illingworth, Christopher J R; Jiggins, Francis M

    2016-06-29

    Heritable symbionts that protect their hosts from pathogens have been described in a wide range of insect species. By reducing the incidence or severity of infection, these symbionts have the potential to reduce the strength of selection on genes in the insect genome that increase resistance. Therefore, the presence of such symbionts may slow down the evolution of resistance. Here we investigated this idea by exposing Drosophila melanogaster populations to infection with the pathogenic Drosophila C virus (DCV) in the presence or absence of Wolbachia, a heritable symbiont of arthropods that confers protection against viruses. After nine generations of selection, we found that resistance to DCV had increased in all populations. However, in the presence of Wolbachia the resistant allele of pastrel-a gene that has a major effect on resistance to DCV-was at a lower frequency than in the symbiont-free populations. This finding suggests that defensive symbionts have the potential to hamper the evolution of insect resistance genes, potentially leading to a state of evolutionary addiction where the genetically susceptible insect host mostly relies on its symbiont to fight pathogens. PMID:27335421

  9. Addicted? Reduced host resistance in populations with defensive symbionts

    PubMed Central

    Cogni, Rodrigo; Cao, Chuan; Smith, Sophie; Illingworth, Christopher J. R.; Jiggins, Francis M.

    2016-01-01

    Heritable symbionts that protect their hosts from pathogens have been described in a wide range of insect species. By reducing the incidence or severity of infection, these symbionts have the potential to reduce the strength of selection on genes in the insect genome that increase resistance. Therefore, the presence of such symbionts may slow down the evolution of resistance. Here we investigated this idea by exposing Drosophila melanogaster populations to infection with the pathogenic Drosophila C virus (DCV) in the presence or absence of Wolbachia, a heritable symbiont of arthropods that confers protection against viruses. After nine generations of selection, we found that resistance to DCV had increased in all populations. However, in the presence of Wolbachia the resistant allele of pastrel—a gene that has a major effect on resistance to DCV—was at a lower frequency than in the symbiont-free populations. This finding suggests that defensive symbionts have the potential to hamper the evolution of insect resistance genes, potentially leading to a state of evolutionary addiction where the genetically susceptible insect host mostly relies on its symbiont to fight pathogens. PMID:27335421

  10. Interaction of the core fragments of the LL-37 host defense peptide with actin

    PubMed Central

    Sol, Asaf; Wang, Guangshun; Blotnick, Edna; Golla, Radha; Muhlrad, Andras

    2015-01-01

    Host defense peptides are effector molecules of the innate immunity that possess antimicrobial and health-promoting properties. Due to their potential therapeutic activities, host defense peptides are being explored as alternatives for antibiotics. The human LL-37 and its shorter, cost-effective, bactericidal core peptide derivates have been suggested for their therapeutic potential. Bacteria evade host defense peptides by proteolytic inactivation. Actin released from necrotized cells and abundant in infected sites was shown to bind and protect LL-37 from microbial proteolytic degradation, and to enable the peptide’s antimicrobial action despite the presence of the proteases. Here, we characterized the interactions of the 10–13 residues long LL-37 core peptides with actin. We show that the LL-37 core peptides associate with actin with a lower affinity than that of LL-37. Their association with actin, which is very ionic strength sensitive, is mainly based on electrostatic interactions. Likewise, the antimicrobial activity against Escherichia coli of the minimal antimicrobial peptide KR-12 but not FK-13 nor LL-37 is also very sensitive to salts. In addition, the antimicrobial activity of the FK-13 core peptide is protected by actin against the tested bacterial proteases in a similar manner to that of LL-37, supporting its potential for therapeutic use. PMID:26726303

  11. Interferon induced IFIT family genes in host antiviral defense

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IF stimulated ...

  12. Cyanogenesis Inhibits Active Defense Reactions in Plants 1

    PubMed Central

    Lieberei, Reinhard; Biehl, Böle; Giesemann, Anette; Junqueira, Nilton T. V.

    1989-01-01

    In the course of fungal attack on the cyanogenic rubber tree (Hevea brasiliensis Muell.-Arg.) HCN is liberated from infected tissue. The HCN interferes with plant host and fungal pathogen. It becomes inhibitory to active defense responses which are dependent on biosynthetic processes as far as a threshold concentration is transgressed. PMID:16666758

  13. Function of Nod-like Receptors in Microbial Recognition and Host Defense

    PubMed Central

    Franchi, Luigi; Warner, Neil; Viani, Kyle; Nuñez, Gabriel

    2009-01-01

    Summary Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are a specialized group of intracellular proteins that play a critical role in the regulation of the host innate immune response. NLRs act as scaffolding proteins that assemble signaling platforms that trigger nuclear factor-κB and mitogen-activated protein kinase signaling pathways and control the activation of inflammatory caspases. Importantly, mutations in several members of the NLR family have been linked to a variety of inflammatory diseases consistent with these molecules playing an important role in host-pathogen interactions and the inflammatory response. In this review, we focus on the role of Nod1 and Nod2 in host defense and in particular discuss recent finding regarding the role of Nlrc4, Nlpr1, and Nlrp3 inflammasomes in caspase-1 activation and subsequent release of proinflammatory cytokines such as interleukin-1β. PMID:19120480

  14. Subterfuge and sabotage: evasion of host innate defenses by invasive gram-positive bacterial pathogens.

    PubMed

    Okumura, Cheryl Y M; Nizet, Victor

    2014-01-01

    The development of a severe invasive bacterial infection in an otherwise healthy individual is one of the most striking and fascinating aspects of human medicine. A small cadre of gram-positive pathogens of the genera Streptococcus and Staphylococcus stand out for their unique invasive disease potential and sophisticated ability to counteract the multifaceted components of human innate defense. This review illustrates how these leading human disease agents evade host complement deposition and activation, impede phagocyte recruitment and activation, resist the microbicidal activities of host antimicrobial peptides and reactive oxygen species, escape neutrophil extracellular traps, and promote and accelerate phagocyte cell death through the action of pore-forming cytolysins. Understanding the molecular basis of bacterial innate immune resistance can open new avenues for therapeutic intervention geared to disabling specific virulence factors and resensitizing the pathogen to host innate immune clearance. PMID:25002085

  15. Cuckoos combat socially transmitted defenses of reed warbler hosts with a plumage polymorphism.

    PubMed

    Thorogood, Rose; Davies, Nicholas B

    2012-08-01

    In predator-prey and host-parasite interactions, an individual's ability to combat an opponent often improves with experience--for example, by learning to identify enemy signals. Although learning occurs through individual experience, individuals can also assess threats from social information. Such recognition could promote the evolution of polymorphisms if socially transmitted defenses depend on enemy morph frequency. This would allow rare variants to evade detection. Female brood parasitic common cuckoos, Cuculus canorus, are either gray or rufous. The gray morph is a Batesian mimic whose hawk-like appearance deters host attack. Hosts reject this disguise through social learning, increasing their own defenses when they witness neighbors mobbing a cuckoo. Our experiments reveal that social learning is specific to the cuckoo morph that neighbors mob. Therefore, while neighbors alert hosts to local cuckoo activity, frequency-dependent social information selects for a cuckoo plumage polymorphism to thwart host detection. Our results suggest that selection for mimicry and polymorphisms comes not only from personal experience but also from social learning. PMID:22859487

  16. Non-Host Defense Response in a Novel Arabidopsis-Xanthomonas citri subsp. citri Pathosystem

    PubMed Central

    An, Chuanfu; Mou, Zhonglin

    2012-01-01

    Citrus canker, caused by Xanthomonas citri subsp. citri (Xcc), is one of the most destructive diseases of citrus. Progress of breeding citrus canker-resistant varieties is modest due to limited resistant germplasm resources and lack of candidate genes for genetic manipulation. The objective of this study is to establish a novel heterologous pathosystem between Xcc and the well-established model plant Arabidopsis thaliana for defense mechanism dissection and resistance gene identification. Our results indicate that Xcc bacteria neither grow nor decline in Arabidopsis, but induce multiple defense responses including callose deposition, reactive oxygen species and salicylic aicd (SA) production, and defense gene expression, indicating that Xcc activates non-host resistance in Arabidopsis. Moreover, Xcc-induced defense gene expression is suppressed or attenuated in several well-characterized SA signaling mutants including eds1, pad4, eds5, sid2, and npr1. Interestingly, resistance to Xcc is compromised only in eds1, pad4, and eds5, but not in sid2 and npr1. However, combining sid2 and npr1 in the sid2npr1 double mutant compromises resistance to Xcc, suggesting genetic interactions likely exist between SID2 and NPR1 in the non-host resistance against Xcc in Arabidopsis. These results demonstrate that the SA signaling pathway plays a critical role in regulating non-host defense against Xcc in Arabidopsis and suggest that the SA signaling pathway genes may hold great potential for breeding citrus canker-resistant varieties through modern gene transfer technology. PMID:22299054

  17. NETosis and NADPH oxidase: at the intersection of host defense, inflammation, and injury

    PubMed Central

    Almyroudis, Nikolaos G.; Grimm, Melissa J.; Davidson, Bruce A.; Röhm, Marc; Urban, Constantin F.; Segal, Brahm H.

    2013-01-01

    Neutrophils are armed with both oxidant-dependent and -independent pathways for killing pathogens. Activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase constitutes an emergency response to infectious threat and results in the generation of antimicrobial reactive oxidants. In addition, NADPH oxidase activation in neutrophils is linked to activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the release of nuclear and granular components that can target extracellular pathogens. NETosis is activated during microbial threat and in certain conditions mimicking sepsis, and can result in both augmented host defense and inflammatory injury. In contrast, apoptosis, the physiological form of neutrophil death, not only leads to non-inflammatory cell death but also contributes to alleviate inflammation. Although there are significant gaps in knowledge regarding the specific contribution of NETs to host defense, we speculate that the coordinated activation of NADPH oxidase and NETosis maximizes microbial killing. Work in engineered mice and limited patient experience point to varying susceptibility of bacterial and fungal pathogens to NADPH oxidase versus NET constituents. Since reactive oxidants and NET constituents can injure host tissue, it is important that these pathways be tightly regulated. Recent work supports a role for NETosis in both acute lung injury and in autoimmunity. Knowledge gained about mechanisms that modulate NETosis may lead to novel therapeutic approaches to limit inflammation-associated injury. PMID:23459634

  18. Guardian of the Human Genome: Host Defense Mechanisms against LINE-1 Retrotransposition.

    PubMed

    Ariumi, Yasuo

    2016-01-01

    Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element comprising about 17% of the human genome, encoding a newly identified ORF0 with unknown function, ORF1p with RNA-binding activity and ORF2p with endonuclease and reverse transcriptase activities required for L1 retrotransposition. L1 utilizes an endonuclease (EN) to insert L1 cDNA into target DNA, which induces DNA double-strand breaks (DSBs). The ataxia-telangiectasia mutated (ATM) is activated by DSBs and subsequently the ATM-signaling pathway plays a role in regulating L1 retrotransposition. In addition, the host DNA repair machinery such as non-homologous end-joining (NHEJ) repair pathway is also involved in L1 retrotransposition. On the other hand, L1 is an insertional mutagenic agent, which contributes to genetic change, genomic instability, and tumorigenesis. Indeed, high-throughput sequencing-based approaches identified numerous tumor-specific somatic L1 insertions in variety of cancers, such as colon cancer, breast cancer, and hepatocellular carcinoma (HCC). In fact, L1 retrotransposition seems to be a potential factor to reduce the tumor suppressive property in HCC. Furthermore, recent study demonstrated that a specific viral-human chimeric transcript, HBx-L1, contributes to hepatitis B virus (HBV)-associated HCC. In contrast, host cells have evolved several defense mechanisms protecting cells against retrotransposition including epigenetic regulation through DNA methylation and host defense factors, such as APOBEC3, MOV10, and SAMHD1, which restrict L1 mobility as a guardian of the human genome. In this review, I focus on somatic L1 insertions into the human genome in cancers and host defense mechanisms against deleterious L1 insertions. PMID:27446907

  19. Guardian of the Human Genome: Host Defense Mechanisms against LINE-1 Retrotransposition

    PubMed Central

    Ariumi, Yasuo

    2016-01-01

    Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element comprising about 17% of the human genome, encoding a newly identified ORF0 with unknown function, ORF1p with RNA-binding activity and ORF2p with endonuclease and reverse transcriptase activities required for L1 retrotransposition. L1 utilizes an endonuclease (EN) to insert L1 cDNA into target DNA, which induces DNA double-strand breaks (DSBs). The ataxia-telangiectasia mutated (ATM) is activated by DSBs and subsequently the ATM-signaling pathway plays a role in regulating L1 retrotransposition. In addition, the host DNA repair machinery such as non-homologous end-joining (NHEJ) repair pathway is also involved in L1 retrotransposition. On the other hand, L1 is an insertional mutagenic agent, which contributes to genetic change, genomic instability, and tumorigenesis. Indeed, high-throughput sequencing-based approaches identified numerous tumor-specific somatic L1 insertions in variety of cancers, such as colon cancer, breast cancer, and hepatocellular carcinoma (HCC). In fact, L1 retrotransposition seems to be a potential factor to reduce the tumor suppressive property in HCC. Furthermore, recent study demonstrated that a specific viral-human chimeric transcript, HBx-L1, contributes to hepatitis B virus (HBV)-associated HCC. In contrast, host cells have evolved several defense mechanisms protecting cells against retrotransposition including epigenetic regulation through DNA methylation and host defense factors, such as APOBEC3, MOV10, and SAMHD1, which restrict L1 mobility as a guardian of the human genome. In this review, I focus on somatic L1 insertions into the human genome in cancers and host defense mechanisms against deleterious L1 insertions. PMID:27446907

  20. Status of pulmonary host defense in the neonatal sheep: cellular and humoral aspects

    SciTech Connect

    Weiss, R.A.; Chanana, A.D.; Joel, D.D.

    1983-01-01

    In consideration of the sheep neonate as a compromised host, we have examined the status of cellular and humoral pulmonary host defense components at selected developmental time points. The dynamic character of the early neonatal lung free cell (LFC) population, reflected in changes in subpopulations and proliferative capacity, most probably contributed to the observed changes in certain cell responses. For example blood and LFC neutrophil chemotaxis appeared intact by day 1. The ability of alveolar macrophages to elaborate a chemotactic factor(s) was first noted at day 21. Bacteria binding and killing presented a biphasic maturation pattern with full competence not present until day 180. Although the in vitro binding and killing activity of day 8 LFCs was comparable to that of the adult, it may be a poor indicator of in vivo host defense capacity, given the relative paucity of endogenous opsonins at that age. In fact, the interdependence of mediators suggests that the sheep neonate may remain a compromised host during the first three months of life. Cellular and humoral parameters begin to approximate those of adult sheep by 180 days.

  1. The complementary facets of epithelial host defenses in the genetic model organism Drosophila melanogaster: from resistance to resilience.

    PubMed

    Ferrandon, Dominique

    2013-02-01

    Significant advances have been made in our understanding of the host defense against microbial infections taking place at frontier epithelia of Drosophila flies. Immune deficiency (IMD), the major NF-κB immune response pathway induced in these epithelia, displays remarkable adaptations in its activation and regulation in the respiratory and digestive tract. The host defense against ingested pathogens is not limited to resistance, that is, the immune response. It also involves resilience, the capacity of the host to endure and repair damages inflicted by pathogens or the host's own immune response. For instance, enterocytes damaged by pathogens, the microbiota of aging flies, or host-derived reactive oxygen species (ROS), are replaced under the control of multiple pathways by the compensatory proliferation of intestinal stem cells (ISCs). PMID:23228366

  2. Conformational Analysis of the Host-Defense Peptides Pseudhymenochirin-1Pb and -2Pa and Design of Analogues with Insulin-Releasing Activities and Reduced Toxicities.

    PubMed

    Manzo, Giorgia; Scorciapino, Mariano Andrea; Srinivasan, Dinesh; Attoub, Samir; Mangoni, Maria Luisa; Rinaldi, Andrea C; Casu, Mariano; Flatt, Peter R; Conlon, J Michael

    2015-12-24

    Pseudhymenochirin-1Pb (Ps-1Pb; IKIPSFFRNILKKVGKEAVSLIAGALKQS) and pseudhymenochirin-2Pa (Ps-2Pa; GIFPIFAKLLGKVIKVASSLISKGRTE) are amphibian peptides with broad spectrum antimicrobial activities and cytotoxicity against mammalian cells. In the membrane-mimetic solvent 50% (v/v) trifluoroethanol-H2O, both peptides adopt a well-defined α-helical conformation that extends over almost all the sequence and incorporates a flexible bend. Both peptides significantly (p < 0.05) stimulate the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥ 0.1 nM but produce loss of integrity of the plasma membrane at concentrations ≥ 1 μM. Increasing cationicity by the substitution Glu(17) → l-Lys in Ps-1Pb and Glu(27) → l-Lys in Ps-2Pa generates analogues with increased cytotoxicity and reduced insulin-releasing potency. In contrast, the analogues [R8r]Ps-1Pb and [K8k,K19k]Ps-2Pa, incorporating d-amino acid residues to destabilize the α-helical domains, retain potent insulin-releasing activity but are nontoxic to BRIN-BD11 cells at concentrations of 3 μM. [R8r]Ps-1Pb produces a significant increase in insulin release rate at 0.3 nM and [K8k,K19k]Ps-2Pa at 0.01 nM. Both analogues show low hemolytic activity (IC50 > 100 μM) but retain broad-spectrum antimicrobial activity and remain cytotoxic to a range of human tumor cell lines, albeit with lower potency than the naturally occurring peptides. These analogues show potential for development into agents for type 2 diabetes therapy. PMID:26606380

  3. Identification and characterization of transforming growth factor β-activated kinase 1 from Litopenaeus vannamei involved in anti-bacterial host defense.

    PubMed

    Wang, Sheng; Li, Haoyang; L, Kai; Qian, Zhe; Weng, Shaoping; He, Jianguo; Li, Chaozheng

    2016-05-01

    LvTAK1, a member of transforming growth factor β-activated kinase 1 (TAK1) families, has been identified from Litopenaeus vannamei in this study. The full length of LvTAK1 is 2670 bp, including a 2277 bp open reading frame (ORF) that encoded a putative protein of 758 amino acids with a calculated molecular weight of ∼83.4 kDa LvTAK1 expression was most abundant in muscles and was up-regulated in gills after LPS, Vibrio parahaemolyticus, Staphhylococcu saureus, Poly (I:C) and WSSV challenge. Both in vivo and in vitro experiments indicated that LvTAK1 could activate the expression of several antimicrobial peptide genes (AMPs). In addition, the dsRNA-mediated knockdown of LvTAK1 enhanced the susceptibility of shrimps to Vibrio parahaemolyticus, a kind of Gram-negative bacteria. These results suggested LvTAK1 played important roles in anti-bacterial infection. CoIP and subcellular localization assay demonstrated that LvTAK1 could interact with its binding protein LvTAB2, a key component of IMD pathway. Moreover, over-expression of LvTAK1 in Drosophila S2 cell could strongly induce the promoter activity of Diptericin (Dpt), a typical AMP which is used to read out of the activation of IMD pathway. These findings suggested that LvTAK1 could function as a component of IMD pathway. Interestingly, with the over-expression of LvTAK1 in S2 cell, the promoter activity of Metchnikowin (Mtk), a main target gene of Toll/Dif pathway, was up-regulated over 30 times, suggesting that LvTAK1 may also take part in signal transduction of the Toll pathway. In conclusion, we provided some evidences that the involvement of LvTAK1 in the regulation of both Toll and IMD pathways, as well as innate immune against bacterial infection in shrimp. PMID:27033469

  4. Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery.

    PubMed

    Wang, Li-Fong; Lin, You-Sheng; Huang, Nan-Chieh; Yu, Chia-Yi; Tsai, Wei-Lun; Chen, Jih-Jung; Kubota, Toru; Matsuoka, Mayumi; Chen, Siang-Ru; Yang, Chih-Shiang; Lu, Ruo-Wei; Lin, Yi-Ling; Chang, Tsung-Hsien

    2015-03-01

    Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-β, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection. PMID:25321315

  5. CXCL1 Contributes to Host Defense in Polymicrobial Sepsis via Modulating T cell and Neutrophil Functions

    PubMed Central

    Liliang, Jin; Batra, Sanjay; Douda, David Nobuhiro; Palaniyar, Nades; Jeyaseelan, Samithamby

    2014-01-01

    Severe bacterial sepsis leads to a pro-inflammatory condition that can manifest as septic shock, multiple organ failure, and death. Neutrophils are critical for the rapid elimination of bacteria, however, the role of neutrophil chemoattractant CXCL1 in bacterial clearance during sepsis remains elusive. To test the hypothesis that CXCL1 is critical to host defense during sepsis. We used CXCL1-deficient mice and bone marrow chimeras to demonstrate the importance of this molecule in sepsis. We demonstrate that CXCL1 plays a pivotal role in mediating host defense to polymicrobial sepsis following cecal ligation and puncture (CLP) in gene-deficient mice. CXCL1 appears to be essential for restricting bacterial outgrowth and death in mice. CXCL1 derived from both hematopoietic and resident cells contributed to bacterial clearance. Moreover, CXCL1 is essential for neutrophil migration, expression of pro-inflammatory mediators, activation of Nuclear-Factor-κ-B (NF-κB) and Mitogen-Activated Protein (MAP) kinases and upregulation of adhesion molecule Intercellular Adhesion Molecule-1 (ICAM-1). Recombinant interleukin 17 (IL-17) rescued impaired host defenses in cxcl1−/− mice. CXCL1 is important for IL-17A production via Th17 differentiation. CXCL1 is essential for Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase-mediated reactive oxygen species production and neutrophil extracellular trap (NET) formation. This study reveals a novel role for CXCL1 in neutrophil recruitment via modulating T cell function and neutrophil-related bactericidal functions. These studies suggest that modulation of CXCL1 levels in tissues and blood could reduce bacterial burden in sepsis. PMID:25172493

  6. IL-32 is a molecular marker of a host defense network in human tuberculosis

    PubMed Central

    Montoya, Dennis; Inkeles, Megan S.; Liu, Phillip T.; Realegeno, Susan; Teles, Rosane M. B.; Vaidya, Poorva; Munoz, Marcos A.; Schenk, Mirjam; Swindell, William R.; Chun, Rene; Zavala, Kathryn; Hewison, Martin; Adams, John S.; Horvath, Steve; Pellegrini, Matteo; Bloom, Barry R.; Modlin, Robert L.

    2014-01-01

    Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32 induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis. PMID:25143364

  7. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor.

    PubMed

    Mata, Miguel A; Satterly, Neal; Versteeg, Gijs A; Frantz, Doug; Wei, Shuguang; Williams, Noelle; Schmolke, Mirco; Peña-Llopis, Samuel; Brugarolas, James; Forst, Christian V; White, Michael A; García-Sastre, Adolfo; Roth, Michael G; Fontoura, Beatriz M A

    2011-10-01

    A chemical genetics approach was taken to identify inhibitors of NS1, a major influenza A virus virulence factor that inhibits host gene expression. A high-throughput screen of 200,000 synthetic compounds identified small molecules that reversed NS1-mediated inhibition of host gene expression. A counterscreen for suppression of influenza virus cytotoxicity identified naphthalimides that inhibited replication of influenza virus and vesicular stomatitis virus (VSV). The mechanism of action occurs through activation of REDD1 expression and concomitant inhibition of mammalian target of rapamycin complex 1 (mTORC1) via TSC1-TSC2 complex. The antiviral activity of naphthalimides was abolished in REDD1(-/-) cells. Inhibition of REDD1 expression by viruses resulted in activation of the mTORC1 pathway. REDD1(-/-) cells prematurely upregulated viral proteins via mTORC1 activation and were permissive to virus replication. In contrast, cells conditionally expressing high concentrations of REDD1 downregulated the amount of viral protein. Thus, REDD1 is a new host defense factor, and chemical activation of REDD1 expression represents a potent antiviral intervention strategy. PMID:21909097

  8. The Hypervariable Amino-Terminus of P1 Protease Modulates Potyviral Replication and Host Defense Responses

    PubMed Central

    Pasin, Fabio; Simón-Mateo, Carmen; García, Juan Antonio

    2014-01-01

    The replication of many RNA viruses involves the translation of polyproteins, whose processing by endopeptidases is a critical step for the release of functional subunits. P1 is the first protease encoded in plant potyvirus genomes; once activated by an as-yet-unknown host factor, it acts in cis on its own C-terminal end, hydrolyzing the P1-HCPro junction. Earlier research suggests that P1 cooperates with HCPro to inhibit host RNA silencing defenses. Using Plum pox virus as a model, we show that although P1 does not have a major direct role in RNA silencing suppression, it can indeed modulate HCPro function by its self-cleavage activity. To study P1 protease regulation, we used bioinformatic analysis and in vitro activity experiments to map the core C-terminal catalytic domain. We present evidence that the hypervariable region that precedes the protease domain is predicted as intrinsically disordered, and that it behaves as a negative regulator of P1 proteolytic activity in in vitro cleavage assays. In viral infections, removal of the P1 protease antagonistic regulator is associated with greater symptom severity, induction of salicylate-dependent pathogenesis-related proteins, and reduced viral loads. We suggest that fine modulation of a viral protease activity has evolved to keep viral amplification below host-detrimental levels, and thus to maintain higher long-term replicative capacity. PMID:24603811

  9. In Defense of Active Learning

    ERIC Educational Resources Information Center

    Pica, Rae

    2008-01-01

    Effective early childhood teachers use what they know about and have observed in young children to design programs to meet children's developmental needs. Play and active learning are key tools to address those needs and facilitate children's early education. In this article, the author discusses the benefits of active learning in the education of…

  10. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation

    PubMed Central

    Muralidharan, Sujatha; Mandrekar, Pranoti

    2013-01-01

    Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders. PMID:23990626

  11. Crosstalk at the initial encounter: Interplay between host defense and ameba survival strategies

    PubMed Central

    Guo, Xiaoti; Houpt, Eric; Petri, William A.

    2009-01-01

    The host-parasite relationship is based on a series of interplays between host defense mechanisms and parasite survival strategies. Progress has been made in understanding the role of host immune response in amebiasis. While host cells elaborate diverse mechanisms for pathogen expulsion, amebae have also developed complex strategies to modulate host immune response and facilitate their own survival. This paper will give an overview of current research on the mutual interactions between host and Entamoeba histolytica in human and experimental amebiasis. Understanding this crosstalk is crucial for the effective design and implementation of new vaccines and drugs for this leading parasitic disease. PMID:17702556

  12. Ubiquitination of pathogen-containing vacuoles promotes host defense to Chlamydia trachomatis and Toxoplasma gondii.

    PubMed

    Coers, Jörn; Haldar, Arun K

    2015-01-01

    Many intracellular bacterial and protozoan pathogens reside within host cell vacuoles customized by the microbial invaders to fit their needs. Within such pathogen-containing vacuoles (PVs) microbes procure nutrients and simultaneously hide from cytosolic host defense systems. Among the many PV-resident human pathogens are the bacterium Chlamydia trachomatis and the protozoan Toxoplasma gondii. Immune responses directed against their PVs are poorly characterized. We reported that activation of host cells with IFNγ triggers the attachment of polyubiquitin chains to Toxoplasma- and Chlamydia-containing vacuoles and thereby marks PVs for destruction. In murine cells PV ubiquitination is dependent on IFNγ-inducible Immunity Related GTPases (IRGs). Human cells also decorate PVs with ubiquitin upon IFNγ priming; however, the molecular machinery promoting PV ubiquitination in human cells remains unknown and is likely to be distinct from the IRG-dependent pathway we described in murine cells. Thus, IFNγ-inducible PV ubiquitination constitutes a critical event in cell-autonomous immunity to C. trachomatis and T. gondii in mice and humans, but the molecular machinery underlying PV ubiquitination is expected to be multifaceted and possibly host species-specific. PMID:27066178

  13. Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis.

    PubMed

    Herbert, B A; Novince, C M; Kirkwood, K L

    2016-06-01

    Aggregatibacter actinomycetemcomitans is a perio-pathogenic bacteria that has long been associated with localized aggressive periodontitis. The mechanisms of its pathogenicity have been studied in humans and preclinical experimental models. Although different serotypes of A. actinomycetemcomitans have differential virulence factor expression, A. actinomycetemcomitans cytolethal distending toxin (CDT), leukotoxin, and lipopolysaccharide (LPS) have been most extensively studied in the context of modulating the host immune response. Following colonization and attachment in the oral cavity, A. actinomycetemcomitans employs CDT, leukotoxin, and LPS to evade host innate defense mechanisms and drive a pathophysiologic inflammatory response. This supra-physiologic immune response state perturbs normal periodontal tissue remodeling/turnover and ultimately has catabolic effects on periodontal tissue homeostasis. In this review, we have divided the host response into two systems: non-hematopoietic and hematopoietic. Non-hematopoietic barriers include epithelium and fibroblasts that initiate the innate immune host response. The hematopoietic system contains lymphoid and myeloid-derived cell lineages that are responsible for expanding the immune response and driving the pathophysiologic inflammatory state in the local periodontal microenvironment. Effector systems and signaling transduction pathways activated and utilized in response to A. actinomycetemcomitans will be discussed to further delineate immune cell mechanisms during A. actinomycetemcomitans infection. Finally, we will discuss the osteo-immunomodulatory effects induced by A. actinomycetemcomitans and dissect the catabolic disruption of balanced osteoclast-osteoblast-mediated bone remodeling, which subsequently leads to net alveolar bone loss. PMID:26197893

  14. IL-36γ Augments Host Defense and Immune Responses in Human Female Reproductive Tract Epithelial Cells

    PubMed Central

    Winkle, Sean M.; Throop, Andrea L.; Herbst-Kralovetz, Melissa M.

    2016-01-01

    IL-36γ is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36γ in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36γ and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36γ in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36γ treatment resulted in self-amplification of IL-36γ and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36γ are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36γ is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT. PMID:27379082

  15. Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

    PubMed Central

    Yang, Zhiping; Chiou, Terry Ting-Yu; Stossel, Thomas P.

    2015-01-01

    Plasma gelsolin (pGSN) functions as part of the “extracellular actin-scavenging system,” but its potential to improve host defense against infection has not been studied. In a mouse model of primary pneumococcal pneumonia, recombinant human pGSN (rhu-pGSN) caused enhanced bacterial clearance, reduced acute inflammation, and improved survival. In vitro, rhu-pGSN rapidly improved lung macrophage uptake and killing of bacteria (Streptococcus pneumoniae, Escherichia coli, and Francisella tularensis). pGSN triggers activating phosphorylation (Ser1177) of macrophage nitric oxide synthase type III (NOS3), an enzyme with important bactericidal functions in lung macrophages. rhu-pGSN failed to enhance bacterial killing by NOS3−/− macrophages in vitro or bacterial clearance in NOS3−/− mice in vivo. Prophylaxis with immunomodulators may be especially relevant for patients at risk for secondary bacterial pneumonia, e.g., after influenza. Treatment of mice with pGSN challenged with pneumococci on postinfluenza day 7 (the peak of enhanced susceptibility to secondary infection) caused a ∼15-fold improvement in bacterial clearance, reduced acute neutrophilic inflammation, and markedly improved survival, even without antibiotic therapy. pGSN is a potential immunomodulator for improving lung host defense against primary and secondary bacterial pneumonia. PMID:25957291

  16. Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function.

    PubMed

    Yang, Zhiping; Chiou, Terry Ting-Yu; Stossel, Thomas P; Kobzik, Lester

    2015-07-01

    Plasma gelsolin (pGSN) functions as part of the "extracellular actin-scavenging system," but its potential to improve host defense against infection has not been studied. In a mouse model of primary pneumococcal pneumonia, recombinant human pGSN (rhu-pGSN) caused enhanced bacterial clearance, reduced acute inflammation, and improved survival. In vitro, rhu-pGSN rapidly improved lung macrophage uptake and killing of bacteria (Streptococcus pneumoniae, Escherichia coli, and Francisella tularensis). pGSN triggers activating phosphorylation (Ser(1177)) of macrophage nitric oxide synthase type III (NOS3), an enzyme with important bactericidal functions in lung macrophages. rhu-pGSN failed to enhance bacterial killing by NOS3(-/-) macrophages in vitro or bacterial clearance in NOS3(-/-) mice in vivo. Prophylaxis with immunomodulators may be especially relevant for patients at risk for secondary bacterial pneumonia, e.g., after influenza. Treatment of mice with pGSN challenged with pneumococci on postinfluenza day 7 (the peak of enhanced susceptibility to secondary infection) caused a ∼15-fold improvement in bacterial clearance, reduced acute neutrophilic inflammation, and markedly improved survival, even without antibiotic therapy. pGSN is a potential immunomodulator for improving lung host defense against primary and secondary bacterial pneumonia. PMID:25957291

  17. A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

    Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications. PMID:26881892

  18. CXCL1 Regulates Pulmonary Host Defense to Klebsiella Infection via CXCL2 , CXCL5, NF-κB and MAPKs

    PubMed Central

    Cai, Shanshan; Batra, Sanjay; Lira, Sergio A.; Kolls, Jay K.; Jeyaseelan, Samithamby

    2010-01-01

    Pulmonary bacterial infections are a leading cause of death. Since the introduction of antibiotics, multidrug-resistant Klebsiella pneumoniae (Kp) became an escalating threat. Therefore, development of methods to augment antibacterial defense is warranted. Neutrophil recruitment is critical to clear bacteria and neutrophil migration in the lung requires the production of ELR+ CXC chemokines. Although lung specific CXCL1/KC transgene expression causes neutrophil-mediated clearance of Kp, the mechanisms underlying KC-mediated host defense against Kp have not been explored. Here we delineated the host defense functions of KC during pulmonary Kp infection using KC-/- mice. Our findings demonstrate that KC is important for expression of CXCL2/MIP-2 and CXCL5/LIX and activation of NF-κB, and MAPKs in the lung. Furthermore, KC-derived from both hematopoietic and resident cells contributes to host defense against Kp. Neutrophil depletion in mice prior to Kp infection reveals no differences in the production of MIP-2 and LIX or activation of NF-κB and MAPKs in the lung. Using murine bone marrow-derived (BMMs) and alveolar macrophages, we confirmed KC-mediated upregulation of MIP-2 and activation of NF-κB and MAPKs upon Kp infection. Moreover, neutralizing KC in BMMs prior to Kp challenge decreases bacteria-induced production of KC, MIP-2 and activation of NF-κB and MAPKs. These findings reveal the importance of KC produced by hematopoietic and resident cells in regulating pulmonary host defense against a bacterial pathogen via the activation of transcription factors and MAPKs as well as the expression of cell adhesion molecules and other neutrophil chemoattractants. PMID:20937845

  19. Two Human Host Defense Ribonucleases against Mycobacteria, the Eosinophil Cationic Protein (RNase 3) and RNase 7

    PubMed Central

    Pulido, David; Torrent, Marc; Andreu, David; Nogués, M. Victoria

    2013-01-01

    There is an urgent need to develop new agents against mycobacterial infections, such as tuberculosis and other respiratory tract or skin affections. In this study, we have tested two human antimicrobial RNases against mycobacteria. RNase 3, also called the eosinophil cationic protein, and RNase 7 are two small cationic proteins secreted by innate cells during host defense. Both proteins are induced upon infection displaying a wide range of antipathogen activities. In particular, they are released by leukocytes and epithelial cells, contributing to tissue protection. Here, the two RNases have been proven effective against Mycobacterium vaccae at a low micromolar level. High bactericidal activity correlated with their bacterial membrane depolarization and permeabilization activities. Further analysis on both protein-derived peptides identified for RNase 3 an N-terminus fragment that is even more active than the parental protein. Also, a potent bacterial agglutinating activity was unique to RNase 3 and its derived peptide. The particular biophysical properties of the RNase 3 active peptide are envisaged as a suitable reference for the development of novel antimycobacterial drugs. The results support the contribution of secreted RNases to the host immune response against mycobacteria. PMID:23716047

  20. Host differentially expressed genes during association with its defensive endosymbiont.

    PubMed

    Mathew, Meril; Lopanik, Nicole B

    2014-04-01

    Mutualism, a beneficial relationship between two species, often requires intimate interaction between the host and symbiont to establish and maintain the partnership. The colonial marine bryozoan Bugula neritina harbors an as yet uncultured endosymbiont, "Candidatus Endobugula sertula," throughout its life stages. The bacterial symbiont is the putative source of bioactive complex polyketide metabolites, the bryostatins, which chemically defend B. neritina larvae from predation. Despite the presence of "Ca. Endobugula sertula" in all life stages of the host, deterrent bryostatins appear to be concentrated in reproductive portions of the host colony, suggesting an interaction between the two partners to coordinate production and distribution of the metabolites within the colony. In this study, we identified host genes that were differentially expressed in control colonies and in colonies cured of the symbiont. Genes that code for products similar to glycosyl hydrolase family 9 and family 20 proteins, actin, and a Rho-GDP dissociation inhibitor were significantly downregulated (more than twice) in antibiotic-cured non-reproductive zooids compared to control symbiotic ones. Differential expression of these genes leads us to hypothesize that the host B. neritina may regulate the distribution of the symbiont within the colony via mechanisms of biofilm degradation and actin rearrangement, and consequently, influences bryostatin localization to bestow symbiont-associated protection to larvae developing in the reproductive zooids. PMID:24797097

  1. The role of Toll-like receptors in host defense against microbial infection.

    PubMed

    Krutzik, S R; Sieling, P A; Modlin, R L

    2001-02-01

    The Toll family of proteins is central to Drosophila host defense against microbial infection. Maintained throughout evolution, mammalian Toll-like receptors (TLRs) are proteins that participate in innate immunity to bacteria in at least four ways. First, TLRs participate in the recognition of molecular patterns present on microorganisms. Second, TLRs are expressed at the interface with the environment, the site of microbial invasion. Third, activation of TLRs induces expression of co-stimulatory molecules and the release of cytokines that instruct the adaptive immune response. Fourth, activation of TLRs leads to direct antimicrobial effector pathways that can result in elimination of the foreign invader. The recent investigation of TLRs in these areas has provided new insights into mechanisms of innate immunity. PMID:11154925

  2. The Cnes2 Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

    PubMed Central

    Shourian, Mitra; Flaczyk, Adam; Angers, Isabelle; Mindt, Barbara C.; Fritz, Jörg H.

    2015-01-01

    The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+ dendritic cells, and CD4+ cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection. PMID:26371125

  3. Microbial Pathogens Trigger Host DNA Double-Strand Breaks Whose Abundance Is Reduced by Plant Defense Responses

    PubMed Central

    Song, Junqi; Bent, Andrew F.

    2014-01-01

    Immune responses and DNA damage repair are two fundamental processes that have been characterized extensively, but the links between them remain largely unknown. We report that multiple bacterial, fungal and oomycete plant pathogen species induce double-strand breaks (DSBs) in host plant DNA. DNA damage detected by histone γ-H2AX abundance or DNA comet assays arose hours before the disease-associated necrosis caused by virulent Pseudomonas syringae pv. tomato. Necrosis-inducing paraquat did not cause detectable DSBs at similar stages after application. Non-pathogenic E. coli and Pseudomonas fluorescens bacteria also did not induce DSBs. Elevation of reactive oxygen species (ROS) is common during plant immune responses, ROS are known DNA damaging agents, and the infection-induced host ROS burst has been implicated as a cause of host DNA damage in animal studies. However, we found that DSB formation in Arabidopsis in response to P. syringae infection still occurs in the absence of the infection-associated oxidative burst mediated by AtrbohD and AtrbohF. Plant MAMP receptor stimulation or application of defense-activating salicylic acid or jasmonic acid failed to induce a detectable level of DSBs in the absence of introduced pathogens, further suggesting that pathogen activities beyond host defense activation cause infection-induced DNA damage. The abundance of infection-induced DSBs was reduced by salicylic acid and NPR1-mediated defenses, and by certain R gene-mediated defenses. Infection-induced formation of γ-H2AX still occurred in Arabidopsis atr/atm double mutants, suggesting the presence of an alternative mediator of pathogen-induced H2AX phosphorylation. In summary, pathogenic microorganisms can induce plant DNA damage. Plant defense mechanisms help to suppress rather than promote this damage, thereby contributing to the maintenance of genome integrity in somatic tissues. PMID:24699527

  4. Elicitation of jasmonate-mediated host defense in Brassica juncea (L.) attenuates population growth of mustard aphid Lipaphis erysimi (Kalt.).

    PubMed

    Koramutla, Murali Krishna; Kaur, Amandeep; Negi, Manisha; Venkatachalam, Perumal; Bhattacharya, Ramcharan

    2014-07-01

    The productivity of Brassica oilseeds is severely affected by its major pest: aphids. Unavailability of resistance source within the crossable germplasms has stalled the breeding efforts to derive aphid resistant cultivars. In this study, jasmonate-mediated host defense in Indian mustard Brassica juncea (L.) Czern. was evaluated and compared with regard to its elicitation in response to mustard aphid Lipaphis erysimi (Kalt.) and the defense elicitor methyl jasmonate (MeJ). Identification of jasmonate-induced unigenes in B. juncea revealed that most are orthologous to aphid-responsive genes, identified in taxonomically diverse plant-aphid interactions. The unigenes largely represented genes related to signal transduction, response to biotic and abiotic stimuli and homeostasis of reactive oxygen species (ROS), in addition to genes related to cellular and metabolic processes involved in cell organization, biogenesis, and development. Gene expression studies revealed induction of the key jasmonate biosynthetic genes (LOX, AOC, 12-OPDR), redox genes (CAT3 and GST6), and other downstream defense genes (PAL, ELI3, MYR, and TPI) by several folds, both in response to MeJ and plant-wounding. However, interestingly aphid infestation even after 24 h did not elicit any activation of these genes. In contrast, when the jasmonate-mediated host defense was elicited by exogenous application of MeJ the treated B. juncea plants showed a strong antibiosis effect on the infesting aphids and reduced the growth of aphid populations. The level of redox enzymes CAT, APX, and SOD, involved in ROS homeostasis in defense signaling, and several defense enzymes viz. POD, PPO, and PAL, remained high in treated plants. We conclude that in B. juncea, the jasmonate activated endogenous-defense, which is not effectively activated in response to mustard aphids, has the potential to reduce population growth of mustard aphids. PMID:24771023

  5. Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

    PubMed Central

    Hilliard, Kristie L.; Allen, Eri; Traber, Katrina E.; Kim, Yuri; Wasserman, Gregory A.; Jones, Matthew R.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (106 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3−/−). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3−/− mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3−/− mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3−/− mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. PMID:26216424

  6. Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia.

    PubMed

    Hilliard, Kristie L; Allen, Eri; Traber, Katrina E; Kim, Yuri; Wasserman, Gregory A; Jones, Matthew R; Mizgerd, Joseph P; Quinton, Lee J

    2015-10-01

    Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10(6) CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3(-/-)). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3(-/-) mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3(-/-) mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3(-/-) mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. PMID:26216424

  7. Synergy of local, regional, and systemic non-specific stressors for host defense against pathogens.

    PubMed

    Day, J D; LeGrand, E K

    2015-02-21

    The immune brinksmanship conceptual model postulates that many of the non-specific stressful components of the acute-phase response (e.g. fever, loss of appetite, iron and zinc sequestration) are host-derived systemic stressors used with the "hope" that pathogens will be harmed relatively more than the host. The concept proposes that pathogens, needing to grow and replicate in order to invade their host, should be relatively more vulnerable to non-specific systemic stress than the host and its cells. However, the conceptual model acknowledges the risk to the host in that the gamble to induce systemic self-harming stress to harm pathogens may not pay off in the end. We developed an agent-based model of a simplified host having a local infection to evaluate the utility of non-specific stress, harming host and pathogen alike, for host defense. With our model, we explore the benefits and risks of self-harming strategies and confirm the immune brinksmanship concept of the potential of systemic stressors to be an effective but costly host defense. Further, we extend the concept by including in our model the effects of local and regional non-specific stressors at sites of infection as additional defenses. These include the locally hostile inflammatory environment and the stress of reduced perfusion in the infected region due to coagulation and vascular leakage. In our model, we found that completely non-specific stressors at the local, regional, and systemic levels can act synergistically in host defense. PMID:25457230

  8. Extreme resistance as a host counter-counter defense against viral suppression of RNA silencing.

    PubMed

    Sansregret, Raphaël; Dufour, Vanessa; Langlois, Mathieu; Daayf, Fouad; Dunoyer, Patrice; Voinnet, Olivier; Bouarab, Kamal

    2013-01-01

    RNA silencing mediated by small RNAs (sRNAs) is a conserved regulatory process with key antiviral and antimicrobial roles in eukaryotes. A widespread counter-defensive strategy of viruses against RNA silencing is to deploy viral suppressors of RNA silencing (VSRs), epitomized by the P19 protein of tombusviruses, which sequesters sRNAs and compromises their downstream action. Here, we provide evidence that specific Nicotiana species are able to sense and, in turn, antagonize the effects of P19 by activating a highly potent immune response that protects tissues against Tomato bushy stunt virus infection. This immunity is salicylate- and ethylene-dependent, and occurs without microscopic cell death, providing an example of "extreme resistance" (ER). We show that the capacity of P19 to bind sRNA, which is mandatory for its VSR function, is also necessary to induce ER, and that effects downstream of P19-sRNA complex formation are the likely determinants of the induced resistance. Accordingly, VSRs unrelated to P19 that also bind sRNA compromise the onset of P19-elicited defense, but do not alter a resistance phenotype conferred by a viral protein without VSR activity. These results show that plants have evolved specific responses against the damages incurred by VSRs to the cellular silencing machinery, a likely necessary step in the never-ending molecular arms race opposing pathogens to their hosts. PMID:23785291

  9. Parasitic aphrodisiacs: manipulation of the hosts' behavioral defenses by sexually transmitted parasites.

    PubMed

    Adamo, Shelley A

    2014-07-01

    Animals have a number of behavioral defenses against infection. For example, they typically avoid sick conspecifics, especially during mating. Most animals also alter their behavior after infection and thereby promote recovery (i.e., sickness behavior). For example, sick animals typically reduce the performance of energetically demanding behaviors, such as sexual behavior. Finally, some animals can increase their reproductive output when they face a life-threatening immune challenge (i.e., terminal reproductive investment). All of these behavioral responses probably rely on immune/neural communication signals for their initiation. Unfortunately, this communication channel is prone to manipulation by parasites. In the case of sexually transmitted infections (STIs), these parasites/pathogens must subvert some of these behavioral defenses for successful transmission. There is evidence that STIs suppress systemic signals of immune activation (e.g., pro-inflammatory cytokines). This manipulation is probably important for the suppression of sickness behavior and other behavioral defenses, as well as for the prevention of attack by the host's immune system. For example, the cricket, Gryllus texensis, is infected with an STI, the iridovirus IIV-6/CrIV. The virus attacks the immune system, which suffers a dramatic decline in its ability to make proteins important for immune function. This attack also hampers the ability of the immune system to activate sickness behavior. Infected crickets cannot express sickness behavior, even when challenged with heat-killed bacteria. Understanding how STIs suppress sickness behavior in humans and other animals will significantly advance the field of psychoneuroimmunology and could also provide practical benefits. PMID:24813461

  10. Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

    PubMed Central

    2011-01-01

    Background Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse). Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection. PMID:21943386

  11. Anti-endotoxic and antibacterial effects of a dermal substitute coated with host defense peptides.

    PubMed

    Kasetty, Gopinath; Kalle, Martina; Mörgelin, Matthias; Brune, Jan C; Schmidtchen, Artur

    2015-01-01

    Biomaterials used during surgery and wound treatment are of increasing importance in modern medical care. In the present study we set out to evaluate the addition of thrombin-derived host defense peptides to human acellular dermis (hAD, i.e. epiflex(®)). Antimicrobial activity of the functionalized hAD was demonstrated using radial diffusion and viable count assays against Gram-negative Escherichia coli, Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus bacteria. Electron microscopy analyses showed that peptide-mediated bacterial killing led to reduced hAD degradation. Furthermore, peptide-functionalized hAD displayed endotoxin-binding activity in vitro, as evidenced by inhibition of NF-κB activation in human monocytic cells (THP-1 cells) and a reduction of pro-inflammatory cytokine production in whole blood in response to lipopolysaccharide stimulation. The dermal substitute retained its anti-endotoxic activity after washing, compatible with results showing that the hAD bound a significant amount of peptide. Furthermore, bacteria-induced contact activation was inhibited by peptide addition to the hAD. E. coli infected hAD, alone, or after treatment with the antiseptic substance polyhexamethylenebiguanide (PHMB), yielded NF-κB activation in THP-1 cells. The activation was abrogated by peptide addition. Thus, thrombin-derived HDPs should be of interest in the further development of new biomaterials with combined antimicrobial and anti-endotoxic functions for use in surgery and wound treatment. PMID:25890739

  12. IL-17 Signaling in Host Defense Against Candida albicans

    PubMed Central

    Gaffen, Sarah L.; Hernandez-Santos, Nydiaris; Peterson, Alanna C.

    2012-01-01

    The discovery of the Th17 lineage in 2005 triggered a major change in how immunity to infectious diseases is viewed. Fungal infections, in particular, have long been a relatively understudied area of investigation in terms of the host immune response. Candida albicans is a commensal yeast that colonizes mucosal sites and skin. In healthy individuals it is non-pathogenic, but in conditions of immune deficiency, this organism can cause a variety of infections associated with considerable morbidity. Candida can also cause disseminated infections that have a high mortality rate and are a major clinical problem in hospital settings. Although immunity to Candida albicans was long considered to be mediated by Th1 cells, new data in both rodent models and in humans have revealed an essential role for the Th17 lineage, and in particular its signature cytokine IL-17. PMID:21717069

  13. Cost-effective expression and purification of antimicrobial and host defense peptides in Escherichia coli.

    PubMed

    Bommarius, B; Jenssen, H; Elliott, M; Kindrachuk, J; Pasupuleti, Mukesh; Gieren, H; Jaeger, K-E; Hancock, R E W; Kalman, D

    2010-11-01

    Cationic antimicrobial host defense peptides (HDPs) combat infection by directly killing a wide variety of microbes, and/or modulating host immunity. HDPs have great therapeutic potential against antibiotic-resistant bacteria, viruses and even parasites, but there are substantial roadblocks to their therapeutic application. High manufacturing costs associated with amino acid precursors have limited the delivery of inexpensive therapeutics through industrial-scale chemical synthesis. Conversely, the production of peptides in bacteria by recombinant DNA technology has been impeded by the antimicrobial activity of these peptides and their susceptibility to proteolytic degradation, while subsequent purification of recombinant peptides often requires multiple steps and has not been cost-effective. Here we have developed methodologies appropriate for large-scale industrial production of HDPs; in particular, we describe (i) a method, using fusions to SUMO, for producing high yields of intact recombinant HDPs in bacteria without significant toxicity and (ii) a simplified 2-step purification method appropriate for industrial use. We have used this method to produce seven HDPs to date (IDR1, MX226, LL37, CRAMP, HHC-10, E5 and E6). Using this technology, pilot-scale fermentation (10L) was performed to produce large quantities of biologically active cationic peptides. Together, these data indicate that this new method represents a cost-effective means to enable commercial enterprises to produce HDPs in large-scale under Good Laboratory Manufacturing Practice (GMP) conditions for therapeutic application in humans. PMID:20713107

  14. NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

    PubMed Central

    Caruso, Roberta; Warner, Neil; Inohara, Naohiro; Núñez, Gabriel

    2014-01-01

    Summary The nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce pro-inflammatory and anti-microbial responses. Here we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies suggest several mechanisms to account for the link between NOD2 mutations and susceptibility to Crohn’s disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders. PMID:25526305

  15. Bemisia tabaci Q carrying tomato yellow leaf curl virus strongly suppresses host plant defenses

    PubMed Central

    Shi, Xiaobin; Pan, Huipeng; Zhang, Hongyi; Jiao, Xiaoguo; Xie, Wen; Wu, Qingjun; Wang, Shaoli; Fang, Yong; Chen, Gong; Zhou, Xuguo; Zhang, Youjun

    2014-01-01

    The concurrence of tomato yellow leaf curl virus (TYLCV) with the spread of its vector Bemisia tabaci Q rather than B in China suggests a more mutualistic relationship between TYLCV and Q. Here, we investigated the hypothesis that viruliferous B and Q have different effects on plant defenses. We found the fecundity of nonviruliferous B, nonviruliferous Q, viruliferous Q and viruliferous B was 11.080, 12.060, 10.760, and 11.220 respectively on plants previously attacked by the other biotype, however, on their respective noninfested control leaves fecundity was 12.000, 10.880, 9.760, and 8.020 respectively. Only viruliferous B had higher fecundity on viruliferous Q-infested plants than on control plants. The longevity of viruliferous B showed the same phenomenon. At 1 d infestion, the jasmonic acid content in leaves noninfested and in leaves infested with nonviruliferous B, nonviruliferous Q, viruliferous B and viruliferous Q was 407.000, 281.333, 301.333, 266.667 and 134.000 ng/g FW, respectively. The JA content was lowest in viruliferous Q-infested leaves. The proteinase inhibitor activity and expression of JA-related upstream gene LOX and downstream gene PI II showed the same trend. The substantial suppression of host defenses by Q carrying TYLCV probably enhances the spread of Q and TYLCV in China. PMID:24912756

  16. Hyperleptinemia is associated with impaired pulmonary host defense

    PubMed Central

    Ubags, Niki D.J.; Stapleton, Renee D.; Vernooy, Juanita H.J.; Burg, Elianne; Bement, Jenna; Hayes, Catherine M.; Ventrone, Sebastian; Zabeau, Lennart; Tavernier, Jan; Poynter, Matthew E.; Parsons, Polly E.; Dixon, Anne E.; Wargo, Matthew J.; Littenberg, Benjamin; Wouters, Emiel F.M.; Suratt, Benjamin T.

    2016-01-01

    We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia. PMID:27347561

  17. Fear of pain and defensive activation.

    PubMed

    Bradley, Margaret M; Silakowski, Tammy; Lang, Peter J

    2008-07-01

    Fear of pain and its relationship to dental fear was investigated by measuring autonomic reactions (skin conductance and heart rate) in individuals reporting high and low dental fear when in the presence of a cue that threatened the presentation of electric shock ("threat") or not ("safe"). Acoustic startle probes were also presented during both threat and safe periods, and the reflexive eye blink, the skin conductance response, and cardiac changes to the startle probe measured. All participants reacted with greater defensive reactivity, including potentiated startle blinks, heightened skin conductance, and cardiac deceleration in the context of threat, compared to safe, cues. Individuals reporting high dental fear were significantly more reactive during threat periods, compared to low fear individuals, showing larger blink reflexes and heightened electrodermal activity, as well as heightened autonomic responses to the startle probe itself. Individual differences in defensive reactivity persisted even after participants received a single mild shock halfway through the experiment. The data indicate that threat of shock elicits heightened defensive reactivity in those reporting high dental fear, consistent with the hypothesis that fear of potentially painful events may be a potent mediator of the anxiety involved in anticipated medical and dental treatment. PMID:17904289

  18. Effects of elicitors of host plant defenses on pear psylla (Cacopsylla pyricola: Psyllidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pear psylla, Cacopsylla pyricola (Foerster) (Hemiptera: Psyllidae), is a key pest of cultivated pear (Pyrus communis L.) in North America and Europe. We examined the effects of foliar applications of three commercially available chemical elicitors of host-plant defenses, Actigard, Employ, and ODC, ...

  19. Reed warbler hosts fine-tune their defenses to track three decades of cuckoo decline.

    PubMed

    Thorogood, Rose; Davies, Nicholas B

    2013-12-01

    Interactions between avian hosts and brood parasites can provide a model for how animals adapt to a changing world. Reed warbler (Acrocephalus scirpaceus) hosts employ costly defenses to combat parasitism by common cuckoos (Cuculus canorus). During the past three decades cuckoos have declined markedly across England, reducing parasitism at our study site (Wicken Fen) from 24% of reed warbler nests in 1985 to 1% in 2012. Here we show with experiments that host mobbing and egg rejection defenses have tracked this decline in local parasitism risk: the proportion of reed warbler pairs mobbing adult cuckoos (assessed by responses to cuckoo mounts and models) has declined from 90% to 38%, and the proportion rejecting nonmimetic cuckoo eggs (assessed by responses to model eggs) has declined from 61% to 11%. This is despite no change in response to other nest enemies or mimetic model eggs. Individual variation in both defenses is predicted by parasitism risk during the host's egg-laying period. Furthermore, the response of our study population to temporal variation in parasitism risk can also explain spatial variation in egg rejection behavior in other populations across Europe. We suggest that spatial and temporal variation in parasitism risk has led to the evolution of plasticity in reed warbler defenses. PMID:24299407

  20. Chapter 13. Physiology and ecology of host defense against microbial invaders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insects mount a complex hierarchy of defenses that pathogens must overcome before successful infection is achieved. Behavioral avoidance and antiseptic behaviors by host insects reduce the degree of encounters between the insect and pathogens. Any pathogen that contacts or establishes on a potentia...

  1. A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses

    PubMed Central

    Hyun, Jinhee; Kanagavelu, Saravana; Fukata, Masayuki

    2012-01-01

    Both anti-viral and anti-bacterial host defense mechanisms involve TRIF signaling. TRIF provides early clearance of pathogens and coordination of a local inflammatory ensemble through an interferon cascade, while it may trigger organ damage. The multipotentiality of TRIF-mediated immune machinery may direct the fate of our continuous battle with microbes. PMID:23116944

  2. Butyrate enhances disease resistance of chickens by inducing antimicrobial host defense peptide gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Host defense peptides (HDPs) constitute a large group of natural broad-spectrum antimicrobials and an important first line of immunity in virtually all forms of life. Specific augmentation of synthesis of endogenous HDPs may represent a promising antibiotic-alternative approach to disease control. I...

  3. Expression of proteins involved in host plant defense against greenbug infestation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The greenbug, Schizaphis graminum (Rondani), has been recognized as a major pest of small grains, including sorghum and wheat. To understand the molecular mechanisms involved in host plant defense against greenbug aphids, a proteomic analysis of greenbug-induced proteins in the seedlings of sorghum...

  4. A Proteomics Perspective on Viral DNA Sensors in Host Defense and Viral Immune Evasion Mechanisms

    PubMed Central

    Crow, Marni S.; Javitt, Aaron; Cristea, Ileana M.

    2015-01-01

    The sensing of viral DNA is an essential step of cellular immune response to infections with DNA viruses. These human pathogens are spread worldwide, triggering a wide range of virus-induced diseases, and are associated with high levels of morbidity and mortality. Despite similarities between DNA molecules, mammalian cells have the remarkable ability to distinguish viral DNA from their own DNA. This detection is carried out by specialized antiviral proteins, called DNA sensors. These sensors bind to foreign DNA to activate downstream immune signaling pathways and alert neighboring cells by eliciting the expression of antiviral cytokines. The sensing of viral DNA was shown to occur both in the cytoplasm and nucleus of infected cells, disproving the notion that sensing occurred by simple spatial separation of viral and host DNA. A number of omic approaches, in particular mass spectrometry-based proteomic methods, have significantly contributed to the constantly evolving field of viral DNA sensing. Here, we review the impact of omic methods on the identification of viral DNA sensors, as well as on the characterization of mechanisms involved in host defense or viral immune evasion. PMID:25728651

  5. Developmental strategy of the endoparasite Xenos vesparum (strepsiptera, Insecta): host invasion and elusion of its defense reactions.

    PubMed

    Manfredini, Fabio; Giusti, Fabiola; Beani, Laura; Dallai, Romano

    2007-07-01

    To successfully complete its endoparasitic development, the strepsipteran Xenos vesparum needs to elude the defense mechanisms of its host, the wasp Polistes dominulus. SEM and TEM observations after artificial infections allow us to outline the steps of this intimate host-parasite association. Triungulins, the mobile 1st instar larvae of this parasite, are able to "softly" overcome structural barriers of the larval wasp (cuticle and epidermis) without any traumatic reaction at the entry site, to reach the hemocoel where they settle. The parasite molts 48 h later to a 2nd instar larva, which moves away from the 1st instar exuvium, molts twice more without ecdysis (a feature unique to Strepsiptera) and pupates, if male, or develops into a neotenic female. Host encapsulation involves the abandoned 1st larval exuvium, but not the living parasite. In contrast to the usual process of encapsulation, it occurs only 48 h after host invasion or later, and without any melanization. In further experiments, first, we verified Xenos vesparum's ability to reinfect an already parasitized wasp larva. Second, 2nd instar larvae implanted in a new host did not evoke any response by hemocytes. Third, we tested the efficiency of host defense mechanisms by implanting nylon filaments in control larval wasps, excluding any effect due the dynamic behavior of a living parasite; within a few minutes, we observed the beginning of a typical melanotic encapsulation plus an initial melanization in the wound site. We conclude that the immune response of the wasp is manipulated by the parasite, which is able to delay and redirect encapsulation towards a pseudo-target, the exuvia of triungulins, and to elude hemocyte attack through an active suppression of the immune defense and/or a passive avoidance of encapsulation by peculiar surface chemical properties. PMID:17437299

  6. Defense-Inducing Volatiles: In Search of the Active Motif

    PubMed Central

    Lion, Ulrich; Boland, Wilhelm

    2008-01-01

    Herbivore-induced volatile organic compounds (VOCs) are widely appreciated as an indirect defense mechanism since carnivorous arthropods use VOCs as cues for host localization and then attack herbivores. Another function of VOCs is plant–plant signaling. That VOCs elicit defensive responses in neighboring plants has been reported from various species, and different compounds have been found to be active. In order to search for a structural motif that characterizes active VOCs, we used lima bean (Phaseolus lunatus), which responds to VOCs released from damaged plants with an increased secretion of extrafloral nectar (EFN). We exposed lima bean to (Z)-3-hexenyl acetate, a substance naturally released from damaged lima bean and known to induce EFN secretion, and to several structurally related compounds. (E)-3-hexenyl acetate, (E)-2-hexenyl acetate, 5-hexenyl acetate, (Z)-3-hexenylisovalerate, and (Z)-3-hexenylbutyrate all elicited significant increases in EFN secretion, demonstrating that neither the (Z)-configuration nor the position of the double-bond nor the size of the acid moiety are critical for the EFN-inducing effect. Our result is not consistent with previous concepts that postulate reactive electrophile species (Michael-acceptor-systems) for defense-induction in Arabidopsis. Instead, we postulate that physicochemical processes, including interactions with odorant binding proteins and resulting in changes in transmembrane potentials, can underlie VOCs-mediated signaling processes. PMID:18408973

  7. Role of enteric neurotransmission in host defense and protection of the gastrointestinal tract

    PubMed Central

    Sharkey, Keith A.; Savidge, Tor C.

    2014-01-01

    Host defense is a vital role played by the gastrointestinal tract. As host to an enormous and diverse microbiome, the gut has evolved an elaborate array of chemical and physicals barriers that allow the digestion and absorption of nutrients without compromising the mammalian host. The control of such barrier functions requires the integration of neural, humoral, paracrine and immune signaling, involving redundant and overlapping mechanisms to ensure, under most circumstances, the integrity of the gastrointestinal epithelial barrier. Here we focus on selected recent developments in the autonomic neural control of host defense functions used in the protection of the gut from luminal agents, and discuss how the microbiota may potentially play a role in enteric neurotransmission. Key recent findings include: the important role played by subepithelial enteric glia in modulating intestinal barrier function, identification of stress-induced mechanisms evoking barrier breakdown, neural regulation of epithelial cell proliferation, the role of afferent and efferent vagal pathways in regulating barrier function, direct evidence for bacterial communication to the enteric nervous system, and microbial sources of enteric neurotransmitters. We discuss these new and interesting developments in our understanding of the role of the autonomic nervous system in gastrointestinal host defense. PMID:24412639

  8. SIM2 maintains innate host defense of the small intestine.

    PubMed

    Chen, Kuan-Jung; Lizaso, Analyn; Lee, Ying-Hue

    2014-12-01

    The single-minded 2 (SIM2) protein is a basic helix-loop-helix transcription factor regulating central nervous system (CNS) development in Drosophila. In humans, SIM2 is located within the Down syndrome critical region on chromosome 21 and may be involved in the development of mental retardation phenotype in Down syndrome. In this study, knockout of SIM2 expression in mice resulted in a gas distention phenotype in the gastrointestinal tract. We found that SIM2 is required for the expression of all cryptdins and numerous other antimicrobial peptides (AMPs) expressed in the small intestine. The mechanism underlying how SIM2 controls AMP expression involves both direct and indirect regulations. For the cryptdin genes, SIM2 regulates their expression by modulating transcription factor 7-like 2, a crucial regulator in the Wnt/β-catenin signaling pathway, while for other AMP genes, such as RegIIIγ, SIM2 directly activates their promoter activity. Our results establish that SIM2 is a crucial regulator in controlling expression of intestinal AMPs to maintain intestinal innate immunity against microbes. PMID:25277798

  9. Neoplastic "Black Ops": Cancer's Subversive Tactics in Overcoming Host Defenses

    PubMed Central

    Biragyn, Arya; Longo, Dan L.

    2012-01-01

    Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack. PMID:22257681

  10. Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses

    SciTech Connect

    Dong, Na; Zhu, Yongqun; Lu, Qiuhe; Hu, Liyan; Zheng, Yuqing; Shao, Feng

    2012-10-10

    Rab GTPases are frequent targets of vacuole-living bacterial pathogens for appropriate trafficking of the vacuole. Here we discover that bacterial effectors including VirA from nonvacuole Shigella flexneri and EspG from extracellular Enteropathogenic Escherichia coli (EPEC) harbor TBC-like dual-finger motifs and exhibits potent RabGAP activities. Specific inactivation of Rab1 by VirA/EspG disrupts ER-to-Golgi trafficking. S. flexneri intracellular persistence requires VirA TBC-like GAP activity that mediates bacterial escape from autophagy-mediated host defense. Rab1 inactivation by EspG severely blocks host secretory pathway, resulting in inhibited interleukin-8 secretion from infected cells. Crystal structures of VirA/EspG-Rab1-GDP-aluminum fluoride complexes highlight TBC-like catalytic role for the arginine and glutamine finger residues and reveal a 3D architecture distinct from that of the TBC domain. Structure of Arf6-EspG-Rab1 ternary complex illustrates a pathogenic signaling complex that rewires host Arf signaling to Rab1 inactivation. Structural distinctions of VirA/EspG further predict a possible extensive presence of TBC-like RabGAP effectors in counteracting various host defenses.

  11. NKG2D receptor and its ligands in host defense

    PubMed Central

    Lanier, Lewis L.

    2015-01-01

    NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, and subsets of CD4+ T cells, iNKT cells, and γδ T cells. In humans NKG2D transmits signals by its association with the DAP10 adapter subunit and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least 8 genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and post-translation. In general healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyper-proliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves a mechanism for the immune system to detect and eliminate cells that have undergone “stress”. Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases. PMID:26041808

  12. Reed Warbler Hosts Fine-Tune their Defenses to Track Three Decades of Cuckoo Decline

    PubMed Central

    Thorogood, Rose; Davies, Nicholas B

    2013-01-01

    Interactions between avian hosts and brood parasites can provide a model for how animals adapt to a changing world. Reed warbler (Acrocephalus scirpaceus) hosts employ costly defenses to combat parasitism by common cuckoos (Cuculus canorus). During the past three decades cuckoos have declined markedly across England, reducing parasitism at our study site (Wicken Fen) from 24% of reed warbler nests in 1985 to 1% in 2012. Here we show with experiments that host mobbing and egg rejection defenses have tracked this decline in local parasitism risk: the proportion of reed warbler pairs mobbing adult cuckoos (assessed by responses to cuckoo mounts and models) has declined from 90% to 38%, and the proportion rejecting nonmimetic cuckoo eggs (assessed by responses to model eggs) has declined from 61% to 11%. This is despite no change in response to other nest enemies or mimetic model eggs. Individual variation in both defenses is predicted by parasitism risk during the host’s egg-laying period. Furthermore, the response of our study population to temporal variation in parasitism risk can also explain spatial variation in egg rejection behavior in other populations across Europe. We suggest that spatial and temporal variation in parasitism risk has led to the evolution of plasticity in reed warbler defenses. PMID:24299407

  13. Multitasking antimicrobial peptides in plant development and host defense against biotic/abiotic stress.

    PubMed

    Goyal, Ravinder K; Mattoo, Autar K

    2014-11-01

    Crop losses due to pathogens are a major threat to global food security. Plants employ a multilayer defense against a pathogen including the use of physical barriers (cell wall), induction of hypersensitive defense response (HR), resistance (R) proteins, and synthesis of antimicrobial peptides (AMPs). Unlike a complex R gene-mediated immunity, AMPs directly target diverse microbial pathogens. Many a times, R-mediated immunity breaks down and plant defense is compromised. Although R-gene dependent pathogen resistance has been well studied, comparatively little is known about the interactions of AMPs with host defense and physiology. AMPs are ubiquitous, low molecular weight peptides that display broad spectrum resistance against bacteria, fungi and viruses. In plants, AMPs are mainly classified into cyclotides, defensins, thionins, lipid transfer proteins, snakins, and hevein-like vicilin-like and knottins. Genetic distance lineages suggest their conservation with minimal effect of speciation events during evolution. AMPs provide durable resistance in plants through a combination of membrane lysis and cellular toxicity of the pathogen. Plant hormones - gibberellins, ethylene, jasmonates, and salicylic acid, are among the physiological regulators that regulate the expression of AMPs. Transgenically produced AMP-plants have become a means showing that AMPs are able to mitigate host defense responses while providing durable resistance against pathogens. PMID:25438794

  14. Thiamine induced resistance to Plasmopara viticola in grapevine and elicited host-defense responses, including HR like-cell death.

    PubMed

    Boubakri, Hatem; Wahab, Mohamed Ali; Chong, Julie; Bertsch, Christophe; Mliki, Ahmed; Soustre-Gacougnolle, Isabelle

    2012-08-01

    Recently, thiamine (VitaminB1) has been shown to induce resistance against Pseudomonas syringae in Arabidopsis plants through priming of defense responses. In this paper, we have demonstrated the efficiency of thiamine to induce resistance against downy mildew caused by the oomycete Plasmopara viticola in a susceptible Vitis vinifera cultivar "Chardonnay" under glasshouse controlled conditions by providing a dual mode of action involving direct antifungal activity and elicitation of host-defense responses. Thiamine-induced defense responses included the generation of hydrogen peroxide (H(2)O(2)) in both grapevine suspension cultured cells (SCC) and plant leaves, upregulation of an array of defense-related genes and the induction of other defense responses at subcellular level such as callose deposition in stomata cells, phenolic compounds accumulation and hypersensitive response (HR) like-cell death. Epifluorescence microscopy studies revealed dramatic changes in P. viticola individual developmental stages during its colonization of the intercellular space of the leaf mesophyll in thiamine-treated plants. Collectively, our report evidenced the efficiency of thiamine in the control of downy mildew in grapevine by direct and indirect effects, suggesting that thiamine could be an attractive alternative to chemical fungicides in disease management in vineyards. PMID:22698755

  15. A Novel Pathogenicity Gene Is Required in the Rice Blast Fungus to Suppress the Basal Defenses of the Host

    PubMed Central

    Chi, Myoung-Hwan; Park, Sook-Young; Kim, Soonok; Lee, Yong-Hwan

    2009-01-01

    For successful colonization and further reproduction in host plants, pathogens need to overcome the innate defenses of the plant. We demonstrate that a novel pathogenicity gene, DES1, in Magnaporthe oryzae regulates counter-defenses against host basal resistance. The DES1 gene was identified by screening for pathogenicity-defective mutants in a T-DNA insertional mutant library. Bioinformatic analysis revealed that this gene encodes a serine-rich protein that has unknown biochemical properties, and its homologs are strictly conserved in filamentous Ascomycetes. Targeted gene deletion of DES1 had no apparent effect on developmental morphogenesis, including vegetative growth, conidial germination, appressorium formation, and appressorium-mediated penetration. Conidial size of the mutant became smaller than that of the wild type, but the mutant displayed no defects on cell wall integrity. The Δdes1 mutant was hypersensitive to exogenous oxidative stress and the activity and transcription level of extracellular enzymes including peroxidases and laccases were severely decreased in the mutant. In addition, ferrous ion leakage was observed in the Δdes1 mutant. In the interaction with a susceptible rice cultivar, rice cells inoculated with the Δdes1 mutant exhibited strong defense responses accompanied by brown granules in primary infected cells, the accumulation of reactive oxygen species (ROS), the generation of autofluorescent materials, and PR gene induction in neighboring tissues. The Δdes1 mutant displayed a significant reduction in infectious hyphal extension, which caused a decrease in pathogenicity. Notably, the suppression of ROS generation by treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, resulted in a significant reduction in the defense responses in plant tissues challenged with the Δdes1 mutant. Furthermore, the Δdes1 mutant recovered its normal infectious growth in DPI-treated plant tissues. These results suggest that DES1

  16. Aberrant host defense against Leishmania major in the absence of SLPI

    PubMed Central

    McCartney-Francis, Nancy; Jin, Wenwen; Belkaid, Yasmine; McGrady, George; Wahl, Sharon M.

    2014-01-01

    SLPI, a potent epithelial and myeloid-derived serine protease inhibitor with antimicrobial and anti-inflammatory functions, is induced by the intracellular parasite Leishmania major, and increased SLPI expression is evident within lesions that follow L. major infection. In contrast to self-resolving infection in C57Bl/6 WT mice, Slpi−/− mice launch a strong Th1 response to L. major, yet fail to control infection and develop destructive, nonhealing lesions with systemic spread of parasites. Because SLPI is both produced by murine macrophages and antagonizes their function, we examined the contribution of macrophage polarization to the defective host response in the absence of SLPI. Slpi−/− and Slpi+/+ macrophages were first primed with either IFNγ or IL-4 to generate classically activated M1 or alternatively activated M2 macrophages. After infection with L. major, Slpi−/− M1 macrophages expressed elevated iNOS RNA, whereas arginase was more highly expressed in WT than Slpi−/− M2 macrophages. After in vivo infection, we found that both IFNγ and iNOS were persistently overexpressed in chronic lesions in Slpi−/− mice, but surprisingly, IL-4 and arginase concomitantly remained elevated. Moreover, overexpression of the negative regulators SOCS1 and IL-27 provided insight into the failure of IFNγ to clear L. major from the dermal lesions. Notably, adenoviral delivery of SLPI to L. major-infected Slpi−/− mice significantly limited the progression of infection. These studies suggest that convergence of M1 and M2 macrophage responses may influence the outcome of innate host defense against intracellular parasites and that SLPI is critical for coordinating resistance to chronic leishmaniasis. PMID:25030421

  17. Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition.

    PubMed

    Xiong, Haitao; Guo, Bingxiu; Gan, Zhenshun; Song, Deguang; Lu, Zeqing; Yi, Hongbo; Wu, Yueming; Wang, Yizhen; Du, Huahua

    2016-01-01

    Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition. PMID:27230284

  18. Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition

    PubMed Central

    Xiong, Haitao; Guo, Bingxiu; Gan, Zhenshun; Song, Deguang; Lu, Zeqing; Yi, Hongbo; Wu, Yueming; Wang, Yizhen; Du, Huahua

    2016-01-01

    Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition. PMID:27230284

  19. Potential effects of erythromycin on host defense systems and virulence of Pseudomonas aeruginosa.

    PubMed Central

    Hirakata, Y; Kaku, M; Mizukane, R; Ishida, K; Furuya, N; Matsumoto, T; Tateda, K; Yamaguchi, K

    1992-01-01

    We evaluated several potential effects of erythromycin (EM) on host defense systems and the virulence of Pseudomonas aeruginosa. Peritoneal macrophages obtained from mice given 250 mg of EM per kg of body weight for 7 days by the intraperitoneal, intravenous, subcutaneous, or oral route produced significantly greater amounts of thymocyte-activating factors. These data suggest that EM enhances the in vivo production of cytokines, such as interleukins 1 and 6. Treatment of P. aeruginosa D4 with subinhibitory concentrations of EM enhanced the association of bacteria with murine Kupffer cells in vitro and increased bacterial clearance from the blood in mice. EM suppressed the in vitro production of exotoxin A, total protease, elastase, and phospholipase C by P. aeruginosa D4; exotoxin A production by P. aeruginosa PA-103; and total protease production by P. aeruginosa B16 and PAO1 in a generally dose-dependent manner. These data demonstrate that EM produces various effects in addition to its direct antimicrobial activity, suggesting that it has potential as an immunomodulator or bacterial virulence-suppressing agent against P. aeruginosa and other infections. PMID:1416882

  20. Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense.

    PubMed

    Li, Xiaopeng; Tang, Xiao Xiao; Vargas Buonfiglio, Luis G; Comellas, Alejandro P; Thornell, Ian M; Ramachandran, Shyam; Karp, Philip H; Taft, Peter J; Sheets, Kelsey; Abou Alaiwa, Mahmoud H; Welsh, Michael J; Meyerholz, David K; Stoltz, David A; Zabner, Joseph

    2016-04-01

    While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl(-) and bicarbonate (HCO3 (-)) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl(-) and HCO3 (-) transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization. PMID:26801568

  1. Role of B Cells in Host Defense against Primary Coxiella burnetii Infection

    PubMed Central

    Schoenlaub, Laura; Elliott, Alexandra; Freches, Danielle; Mitchell, William J.

    2015-01-01

    Despite Coxiella burnetii being an obligate intracellular bacterial pathogen, our recent study demonstrated that B cells play a critical role in vaccine-induced immunity to C. burnetii infection by producing protective antibodies. However, the role of B cells in host defense against primary C. burnetii infection remains unclear. In this study, we investigated whether B cells play an important role in host defense against primary C. burnetii infection. The results showed that peritoneal B cells were able to phagocytose virulent C. burnetii bacteria and form Coxiella-containing vacuoles (CCVs) and that C. burnetii can infect and replicate in peritoneal B1a subset B cells in vitro, demonstrating a potential role for peritoneal B cells in host defense against C. burnetii infection in vivo. In addition, the results showing that B1a cells secreted a high level of interleukin-10 (IL-10) in response to C. burnetii infection in vitro suggest that B1a cells may play an important role in inhibiting the C. burnetii infection-induced inflammatory response. The observation that adoptive transfer of peritoneal B cells did not significantly affect the severity of C. burnetii infection-induced diseases in both severe combined immunity-deficient (SCID) and μMT mice indicates that peritoneal B cells alone may not be able to control C. burnetii infection. In contrast, our finding that C. burnetii infection induced more-severe splenomegaly and a higher bacterial burden in the spleens of B1a cell-deficient Bruton's tyrosine kinase x-linked immunity-deficient (BTKxid) mice than in their wild-type counterparts further suggests that B1a cells play an important role in host defense against primary C. burnetii infection. PMID:26438792

  2. Role of B cells in host defense against primary Coxiella burnetii infection.

    PubMed

    Schoenlaub, Laura; Elliott, Alexandra; Freches, Danielle; Mitchell, William J; Zhang, Guoquan

    2015-12-01

    Despite Coxiella burnetii being an obligate intracellular bacterial pathogen, our recent study demonstrated that B cells play a critical role in vaccine-induced immunity to C. burnetii infection by producing protective antibodies. However, the role of B cells in host defense against primary C. burnetii infection remains unclear. In this study, we investigated whether B cells play an important role in host defense against primary C. burnetii infection. The results showed that peritoneal B cells were able to phagocytose virulent C. burnetii bacteria and form Coxiella-containing vacuoles (CCVs) and that C. burnetii can infect and replicate in peritoneal B1a subset B cells in vitro, demonstrating a potential role for peritoneal B cells in host defense against C. burnetii infection in vivo. In addition, the results showing that B1a cells secreted a high level of interleukin-10 (IL-10) in response to C. burnetii infection in vitro suggest that B1a cells may play an important role in inhibiting the C. burnetii infection-induced inflammatory response. The observation that adoptive transfer of peritoneal B cells did not significantly affect the severity of C. burnetii infection-induced diseases in both severe combined immunity-deficient (SCID) and μMT mice indicates that peritoneal B cells alone may not be able to control C. burnetii infection. In contrast, our finding that C. burnetii infection induced more-severe splenomegaly and a higher bacterial burden in the spleens of B1a cell-deficient Bruton's tyrosine kinase x-linked immunity-deficient (BTK(xid)) mice than in their wild-type counterparts further suggests that B1a cells play an important role in host defense against primary C. burnetii infection. PMID:26438792

  3. Host defense benefits of breastfeeding for the infant. Effect of breastfeeding duration and exclusivity.

    PubMed

    Heinig, M J

    2001-02-01

    Breastfeeding confers lifesaving protection against infectious illness among disadvantaged populations. As a result, breastfeeding promotion has an important part in child health programs throughout the world. In this article, the evidence regarding the host defense benefits of breastfeeding for term infants of normal birth weight is reviewed, with an emphasis on recent information from industrialized countries regarding how the degree and duration of breastfeeding affect infant health. PMID:11236719

  4. Allergic airway inflammation disrupts interleukin-17 mediated host defense against streptococcus pneumoniae infection.

    PubMed

    Guo, Sheng; Wu, Liang-Xia; Jones, Can-Xin; Chen, Ling; Hao, Chun-Li; He, Li; Zhang, Jian-Hua

    2016-02-01

    Despite decreasing rates of invasive pneumococcal disease caused by vaccine serotypes, the prevalence of invasive pneumococcal pneumonia in asthmatic patients remains high. However, little is known about the mechanisms underlying the susceptibility of the asthmatic airway to bacterial infections. In this study, we used a combined model of allergic airway inflammation and Streptococcus pneumoniae lung infection to investigate the association between persistent allergic inflammation in the airway and antibacterial host defenses against S. pneumoniae. When challenged with S. pneumoniae, allergic mice exhibited higher airway bacterial burdens, greater eosinophil infiltration, lower neutrophil infiltration, and more severe structural damage than non-allergic mice. In sensitized mice, S. pneumoniae infection elicited higher IL-4 but lower IFN-γ, IL-17 and defensin-β2 expression than in control mice. These results indicate that persistent allergic inflammation impaired airway host defense against S. pneumoniae is associated with the insufficient IL-17 responses. To elicit IL-17 induced-anti-bacterial immune responses, mice were intranasally immunized with rIL-17. Immunized mice exhibited fewer bacterial colonies in the respiratory tract and less severe lung pathology than unimmunized mice. rIL-17 contributed to airway host defense enhancement and innate immune response promotion, which was associated with increased IL-23, MIP-2 and defensin-β2 expression. Administration of exogenous IL-17 (2μg/mouse) suppressed eosinophil-related immune responses. The results demonstrate IL-17 plays a key role in host defenses against bacterial infection in allergic airways and suggest that exogenous IL-17 administration promotes the anti-becterial immune responses and attenuates the existed allergic inflammation. PMID:26699848

  5. Mast cells: Versatile regulators of inflammation, tissue remodeling, host defense and homeostasis

    PubMed Central

    Galli, Stephen J.; Tsai, Mindy

    2009-01-01

    Summary The possible roles of mast cells in heath and disease have been a topic of interest for over one hundred and twenty five years. Many adaptive or pathological processes affecting the skin or other anatomical sites have been associated with morphological evidence of mast cell activation, and/or with changes in mast cell numbers or phenotype. Such observations, taken together with the known functions of the diverse mediators, cytokines and growth factors which can be secreted by mast cells, have suggested many potential functions for mast cells in health and disease. Definitively identifying the importance of mast cells in biological responses in humans is difficult. However, mutant mice which are profoundly mast cell-deficient, especially those which can undergo engraftment with wild type or genetically-altered mast cells, provide an opportunity to investigate the importance of mast cells, and specific mast cell functions or products, in various adaptive or pathological responses in mice. Such work has shown that mast cells can significantly influence multiple features of inflammatory or immune responses, through diverse effects that can either promote or, surprisingly, suppress, aspects of these responses. Through such functions, mast cells can significantly influence inflammation, tissue remodeling, host defense and homeostasis. PMID:18024086

  6. Host Defense Functions of Proteolytically Processed and Parent (Unprocessed) Cathelicidins of Rabbit Granulocytes

    PubMed Central

    Zarember, Kol A.; Katz, Seth S.; Tack, Brian F.; Doukhan, Laurence; Weiss, Jerrold; Elsbach, Peter

    2002-01-01

    Members of the cathelicidin family are present in all mammals studied. Generally, these proteins contain a conserved N-terminal domain and a structurally and functionally divergent C-terminal region that expresses antibacterial or other activities when proteolytically released. Rabbit granulocytes produce CAP18, a cathelicidin that conforms to this structural and functional organization, and also 15-kDa protein isoforms (p15s) that share several key structural features with other cathelicidins but apparently do not undergo processing with release of an active peptide. To further define the importance of proteolysis in the antibacterial activities of these proteins, we have purified from granulocytes proCAP18, its C-terminal peptide (CAP18p), and two p15 isoforms to apparent homogeneity. Of these four polypeptides, only CAP18p was independently cytotoxic to encapsulated Escherichia coli (90% inhibitory concentration, ∼600 nM) but it was ∼50-fold less potent on a molar basis than the bactericidal/permeability-increasing protein (BPI). However, all four cathelicidin species, notably including proCAP18, exhibited antibacterial synergy with BPI, and the p15s also displayed synergy with CAP18p in the absence of BPI. Subnanomolar concentrations of proCAP18 blocked lipopolysaccharide-induced chemiluminescence of human leukocytes, showing a molar potency more than 100-fold greater than that of CAP18p (∼20 nM) or BPI (∼50 nM). Thus, while independent bactericidal activity of cathelicidins requires processing, other host-defense functions do not and are more potently expressed by the unprocessed protein than by the C-terminal peptide. PMID:11796584

  7. NIK1, a host factor specialized in antiviral defense or a novel general regulator of plant immunity?

    PubMed

    Machado, Joao P B; Brustolini, Otavio J B; Mendes, Giselle C; Santos, Anésia A; Fontes, Elizabeth P B

    2015-11-01

    NIK1 is a receptor-like kinase involved in plant antiviral immunity. Although NIK1 is structurally similar to the plant immune factor BAK1, which is a key regulator in plant immunity to bacterial pathogens, the NIK1-mediated defenses do not resemble BAK1 signaling cascades. The underlying mechanism for NIK1 antiviral immunity has recently been uncovered. NIK1 activation mediates the translocation of RPL10 to the nucleus, where it interacts with LIMYB to fully down-regulate translational machinery genes, resulting in translation inhibition of host and viral mRNAs and enhanced tolerance to begomovirus. Therefore, the NIK1 antiviral immunity response culminates in global translation suppression, which represents a new paradigm for plant antiviral defenses. Interestingly, transcriptomic analyses in nik1 mutant suggest that NIK1 may suppress antibacterial immune responses, indicating a possible opposite effect of NIK1 in bacterial and viral infections. PMID:26335701

  8. Relative Roles of the Cellular and Humoral Responses in the Drosophila Host Defense against Three Gram-Positive Bacterial Infections

    PubMed Central

    Cho, Ju Hyun; Lee, Janice; Lafarge, Marie-Céline; Kocks, Christine; Ferrandon, Dominique

    2011-01-01

    Background Two NF-kappaB signaling pathways, Toll and immune deficiency (imd), are required for survival to bacterial infections in Drosophila. In response to septic injury, these pathways mediate rapid transcriptional activation of distinct sets of effector molecules, including antimicrobial peptides, which are important components of a humoral defense response. However, it is less clear to what extent macrophage-like hemocytes contribute to host defense. Methodology/Principal Findings In order to dissect the relative importance of humoral and cellular defenses after septic injury with three different Gram-positive bacteria (Micrococcus luteus, Enterococcus faecalis, Staphylococcus aureus), we used latex bead pre-injection to ablate macrophage function in flies wildtype or mutant for various Toll and imd pathway components. We found that in all three infection models a compromised phagocytic system impaired fly survival – independently of concomitant Toll or imd pathway activation. Our data failed to confirm a role of the PGRP-SA and GNBP1 Pattern Recognition Receptors for phagocytosis of S. aureus. The Drosophila scavenger receptor Eater mediates the phagocytosis by hemocytes or S2 cells of E. faecalis and S. aureus, but not of M. luteus. In the case of M. luteus and E. faecalis, but not S. aureus, decreased survival due to defective phagocytosis could be compensated for by genetically enhancing the humoral immune response. Conclusions/Significance Our results underscore the fundamental importance of both cellular and humoral mechanisms in Drosophila immunity and shed light on the balance between these two arms of host defense depending on the invading pathogen. PMID:21390224

  9. Host-virus interaction: the antiviral defense function of small interfering RNAs can be enhanced by host microRNA-7 in vitro

    PubMed Central

    Zhang, Xiaoying; Liu, Dongyun; Zhang, Sheng; Wei, Xiujuan; Song, Jie; Zhang, Yupei; Jin, Min; Shen, Zhiqiang; Wang, Xinwei; Feng, Zhichun; Li, Junwen

    2015-01-01

    Small interfering RNAs (siRNAs) directed against poliovirus (PV) and other viruses effectively inhibit viral replication and have been developed as antiviral agents. Here, we demonstrate that a specific siRNA targeting the region between nucleotides 100–125 (siRNA-100) from the 5′-untranslated region (5′-UTR) of PV plays a critical role in inhibiting PV replication. Our data demonstrate that siRNA-100 treatment can greatly reduce PV titers, resulting in up-regulation of host microRNA-7 (miR-7), which in turn, leads to enhance inhibition of PV infection further. Moreover, our results suggest that siRNA-100 can also impair the spread of PV to uninfected cells by increasing host resistance to PV, resulting in decreasing necrosis and cytopathic effects (CPE) levels, as well as prolonging the survival of infected cells. Indeed, the active antiviral effect of siRNA-100 was potentially supplemented by the activity of miR-7, and both of them can serve as stabilizing factors for maintenance of cellular homeostasis. Results of this study identify a molecular mechanism of RNAi for antiviral defense, and extend our knowledge of the complex interplay between host and PV, which will provide a basis for the development of effective RNAi-based therapies designed to inhibit PV replication and protect host cells. PMID:26067353

  10. Ticks and tick-borne pathogens at the cutaneous interface: host defenses, tick countermeasures, and a suitable environment for pathogen establishment.

    PubMed

    Wikel, Stephen

    2013-01-01

    Ticks are unique among hematophagous arthropods by continuous attachment to host skin and blood feeding for days; complexity and diversity of biologically active molecules differentially expressed in saliva of tick species; their ability to modulate the host defenses of pain and itch, hemostasis, inflammation, innate and adaptive immunity, and wound healing; and, the diverse array of infectious agents they transmit. All of these interactions occur at the cutaneous interface in a complex sequence of carefully choreographed host defense responses and tick countermeasures resulting in an environment that facilitates successful blood feeding and establishment of tick-borne infectious agents within the host. Here, we examine diverse patterns of tick attachment to host skin, blood feeding mechanisms, salivary gland transcriptomes, bioactive molecules in tick saliva, timing of pathogen transmission, and host responses to tick bite. Ticks engage and modulate cutaneous and systemic immune defenses involving keratinocytes, natural killer cells, dendritic cells, T cell subpopulations (Th1, Th2, Th17, Treg), B cells, neutrophils, mast cells, basophils, endothelial cells, cytokines, chemokines, complement, and extracellular matrix. A framework is proposed that integrates tick induced changes of skin immune effectors with their ability to respond to tick-borne pathogens. Implications of these changes are addressed. What are the consequences of tick modulation of host cutaneous defenses? Does diversity of salivary gland transcriptomes determine differential modulation of host inflammation and immune defenses and therefore, in part, the clades of pathogens effectively transmitted by different tick species? Do ticks create an immunologically modified cutaneous environment that enhances specific pathogen establishment? Can tick saliva molecules be used to develop vaccines that block pathogen transmission? PMID:24312085

  11. Induced plant defenses, host-pathogen interactions, and forest insect outbreaks.

    PubMed

    Elderd, Bret D; Rehill, Brian J; Haynes, Kyle J; Dwyer, Greg

    2013-09-10

    Cyclic outbreaks of defoliating insects devastate forests, but their causes are poorly understood. Outbreak cycles are often assumed to be driven by density-dependent mortality due to natural enemies, because pathogens and predators cause high mortality and because natural-enemy models reproduce fluctuations in defoliation data. The role of induced defenses is in contrast often dismissed, because toxic effects of defenses are often weak and because induced-defense models explain defoliation data no better than natural-enemy models. Natural-enemy models, however, fail to explain gypsy moth outbreaks in North America, in which outbreaks in forests with a higher percentage of oaks have alternated between severe and mild, whereas outbreaks in forests with a lower percentage of oaks have been uniformly moderate. Here we show that this pattern can be explained by an interaction between induced defenses and a natural enemy. We experimentally induced hydrolyzable-tannin defenses in red oak, to show that induction reduces variability in a gypsy moth's risk of baculovirus infection. Because this effect can modulate outbreak severity and because oaks are the only genus of gypsy moth host tree that can be induced, we extended a natural-enemy model to allow for spatial variability in inducibility. Our model shows alternating outbreaks in forests with a high frequency of oaks, and uniform outbreaks in forests with a low frequency of oaks, matching the data. The complexity of this effect suggests that detecting effects of induced defenses on defoliator cycles requires a combination of experiments and models. PMID:23966566

  12. The adaptor molecule Trif contributes to murine host defense during Leptospiral infection.

    PubMed

    Jayaraman, Priya A; Devlin, Amy A; Miller, Jennifer C; Scholle, Frank

    2016-09-01

    Leptospirosis is a zoonotic disease and is caused by pathogenic species of the Leptospira genus, including Leptospira interrogans (L. interrogans). Humans, domestic and wild animals are susceptible to acute or chronic infection. The innate immune response is a critical defense mechanism against Leptospira interrogans, and has been investigated in mouse models. Murine Toll-like receptors (TLRs) have been shown to be key factors in sensing and responding to L. interrogans infection. Specifically, TLR2, TLR4 and the TLR adaptor molecule MyD88 are essential for host defense against L. interrogans; however, the role of the TLR adaptor molecule TIR-domain-containing adaptor-inducing interferon β (TRIF) in the response to L. interrogans has not been previously determined. In the present study, TRIF was found to play an important role during leptospiral infection. Following challenge with L. interrogans, Trif(-/-) mice exhibited delayed weight gain compared to wild-type mice. Moreover, Trif(-/-) mice exhibited an increase in L. interrogans burden in the kidneys, lungs, and blood at early time points (less than 7days post infection). Multiple components of the innate immune responses were dampened in response to leptospiral infection including transcription and production of cytokines, and the humoral response, which suggested that TRIF contributes to expression and production of cytokines important for the host defense against L. interrogans. PMID:27259371

  13. INHALABLE PARTICLES AND PULMONARY HOST DEFENSE: 'IN VIVO' AND 'IN VITRO' EFFECTS OF AMBIENT AIR AND COMBUSTION PARTICLES

    EPA Science Inventory

    The ability of particulate air pollutants (and possible constituents) to alter pulmonary host defenses was examined using an in vitro alveolar macrophage cytotoxicity assay and an in vivo bacterial infectivity screening test which employed intratracheal injection of the particles...

  14. Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.

    PubMed

    Gay, Gabrielle; Braun, Laurence; Brenier-Pinchart, Marie-Pierre; Vollaire, Julien; Josserand, Véronique; Bertini, Rose-Laurence; Varesano, Aurélie; Touquet, Bastien; De Bock, Pieter-Jan; Coute, Yohann; Tardieux, Isabelle; Bougdour, Alexandre; Hakimi, Mohamed-Ali

    2016-08-22

    An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii-targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ-stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism. PMID:27503074

  15. Triticum mosaic poacevirus enlists P1 rather than HC-Pro to suppress RNA silencing-mediated host defense

    Technology Transfer Automated Retrieval System (TEKTRAN)

    RNA silencing, or posttranscriptional gene silencing (PTGS) is one of the most important defense mechanisms employed by higher plants and animals to defend against viral infections. Plant viruses evolved by adopting divergent proteins, even within single virus families, to counter this host defense ...

  16. Relationships among CFTR expression, HCO3- secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies.

    PubMed

    Shah, Viral S; Ernst, Sarah; Tang, Xiao Xiao; Karp, Philip H; Parker, Connor P; Ostedgaard, Lynda S; Welsh, Michael J

    2016-05-10

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10-50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl(-) secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3 (-) secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3 (-) at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR(+/-) or CFTR(+/∆F508)) expressed CFTR and secreted HCO3 (-) at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3 (-) secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl(-) secretion, the amount of CFTR is rate-limiting for HCO3 (-) secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers. PMID:27114540

  17. NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis.

    PubMed

    West, T Eoin; Myers, Nicolle D; Chantratita, Narisara; Chierakul, Wirongrong; Limmathurotsakul, Direk; Wuthiekanun, Vanaporn; Miao, Edward A; Hajjar, Adeline M; Peacock, Sharon J; Liggitt, H Denny; Skerrett, Shawn J

    2014-09-01

    Burkholderia pseudomallei causes the tropical infection melioidosis. Pneumonia is a common manifestation of melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4(-/-) mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory melioidosis. PMID:25232720

  18. The role of NOD1 and NOD2 in host defense against chlamydial infection.

    PubMed

    Zou, Yan; Lei, Wenbo; He, Zhansheng; Li, Zhongyu

    2016-09-01

    Chlamydial species are common intracellular parasites that cause various diseases, mainly characterized by persistent infection, which lead to inflammatory responses modulated by pattern recognition receptors (PRRs). The best understood PRRs are the extracellular Toll-like receptors, but recent significant advances have focused on two important proteins, NOD1 and NOD2, which are members of the intracellular nucleotide-binding oligomerization domain receptor family and are capable of triggering the host innate immune signaling pathways. This results in the production of pro-inflammatory cytokines, which is vital for an adequate host defense against intracellular chlamydial infection. NOD1/2 ligands are known to derive from peptidoglycan, and the latest research has resolved the paradox of whether chlamydial species possess this bacterial cell wall component; this finding is likely to promote in-depth investigations into the interaction between the NOD proteins and chlamydial pathogens. In this review, we summarize the basic characteristics and signal transduction functions of NOD1 and NOD2 and highlight the new research on the roles of NOD1 and NOD2 in the host defense against chlamydial infection. PMID:27421958

  19. Black Yeasts and Their Filamentous Relatives: Principles of Pathogenesis and Host Defense

    PubMed Central

    Netea, Mihai G.; Mouton, Johan W.; Melchers, Willem J. G.; Verweij, Paul E.; de Hoog, G. Sybren

    2014-01-01

    SUMMARY Among the melanized fungi, the so-called “black yeasts” and their filamentous relatives are particularly significant as agents of severe phaeohyphomycosis, chromoblastomycosis, and mycetoma in humans and animals. The pathogenicity and virulence of these fungi may differ significantly between closely related species. The factors which probably are of significance for pathogenicity include the presence of melanin and carotene, formation of thick cell walls and meristematic growth, presence of yeast-like phases, thermo- and perhaps also osmotolerance, adhesion, hydrophobicity, assimilation of aromatic hydrocarbons, and production of siderophores. Host defense has been shown to rely mainly on the ingestion and elimination of fungal cells by cells of the innate immune system, especially neutrophils and macrophages. However, there is increasing evidence supporting a role of T-cell-mediated immune responses, with increased interleukin-10 (IL-10) and low levels of gamma interferon (IFN-γ) being deleterious during the infection. There are no standardized therapies for treatment. It is therefore important to obtain in vitro susceptibilities of individual patients' fungal isolates in order to provide useful information for selection of appropriate treatment protocols. This article discusses the pathogenesis and host defense factors for these fungi and their severity, chronicity, and subsequent impact on treatment and prevention of diseases in human or animal hosts. PMID:24982320

  20. Geminivirus-encoded TrAP suppressor inhibits the histone methyltransferase SUVH4/KYP to counter host defense

    PubMed Central

    Castillo-González, Claudia; Liu, Xiuying; Huang, Changjun; Zhao, Changjiang; Ma, Zeyang; Hu, Tao; Sun, Feng; Zhou, Yijun; Zhou, Xueping; Wang, Xiu-Jie; Zhang, Xiuren

    2015-01-01

    Transcriptional gene silencing (TGS) can serve as an innate immunity against invading DNA viruses throughout Eukaryotes. Geminivirus code for TrAP protein to suppress the TGS pathway. Here, we identified an Arabidopsis H3K9me2 histone methyltransferase, Su(var)3-9 homolog 4/Kryptonite (SUVH4/KYP), as a bona fide cellular target of TrAP. TrAP interacts with the catalytic domain of KYP and inhibits its activity in vitro. TrAP elicits developmental anomalies phenocopying several TGS mutants, reduces the repressive H3K9me2 mark and CHH DNA methylation, and reactivates numerous endogenous KYP-repressed loci in vivo. Moreover, KYP binds to the viral chromatin and controls its methylation to combat virus infection. Notably, kyp mutants support systemic infection of TrAP-deficient Geminivirus. We conclude that TrAP attenuates the TGS of the viral chromatin by inhibiting KYP activity to evade host surveillance. These findings provide new insight on the molecular arms race between host antiviral defense and virus counter defense at an epigenetic level. DOI: http://dx.doi.org/10.7554/eLife.06671.001 PMID:26344546

  1. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)

    PubMed Central

    Raison, C L; Miller, A H

    2013-01-01

    Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations. These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia. By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function. PMID:22290120

  2. Histone Deacetylases in Herpesvirus Replication and Virus-Stimulated Host Defense

    PubMed Central

    Guise, Amanda J.; Budayeva, Hanna G.; Diner, Benjamin A.; Cristea, Ileana M.

    2013-01-01

    Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based “omic” technologies to infectious disease research, offering a systems biology view of infection. PMID:23807710

  3. The other side of scavenger receptors: pattern recognition for host defense.

    PubMed

    Krieger, M

    1997-10-01

    Scavenger receptors bind modified lipoproteins and may play an important role both in normal and in pathological lipid metabolism. A number of different classes of scavenger receptors have been identified and several of these are multiligand receptors. Studies, both in vitro and in vivo, have indicated that at least some of these scavenger receptors may serve as pattern recognition receptors because they are able to bind a wide variety of pathogens. As a consequence, they may play key roles in innate immunity and host defense. PMID:9335951

  4. A peptide immunization approach to counteract a Staphylococcus aureus protease defense against host immunity.

    PubMed

    Jordan, Robert E; Fernandez, Jeffrey; Brezski, Randall J; Greenplate, Allison R; Knight, David M; Raju, T Shantha; Lynch, A Simon

    2016-04-01

    Pathogens that induce acute and chronic infections, as well as certain cancers, employ numerous strategies to thwart host cellular and humoral immune defenses. One proposed evasion mechanism against humoral immunity is a localized expression of extracellular proteases that cleave the IgG hinge and disable host IgG functions. Host immunity appears to be prepared to counter such a proteolytic tactic by providing a group of autoantibodies, denoted anti-hinge antibodies that specifically bind to cleaved IgGs and provide compensating functional restoration in vitro. These respective counter-measures highlight the complex interrelationships among pathogens and host immunity and suggested to us a possible means for therapeutic intervention. In this study, we combined an investigation of pathogen-mediated proteolysis of host IgGs with an immunization strategy to boost host anti-hinge antibodies. In a Staphylococcus aureus infection model using an artificial tissue cage (wiffle ball) implanted into rabbits, cleaved rabbit IgGs were detected in abundance in the abscesses of untreated animals early after infection. However, in animals previously immunized with peptide analogs of the cleaved IgG hinge to generate substantial anti-hinge antibody titers, S. aureus colony formation was markedly reduced compared to control animals or those similarly immunized with a scrambled peptide sequence. The results of this study demonstrate that extensive local proteolysis of IgGs occurs in a test abscess setting and that immunization to increase host anti-hinge antibodies provided substantial acute protection against bacterial growth. PMID:26905931

  5. Interferon-Inducible CXC Chemokines Directly Contribute to Host Defense against Inhalational Anthrax in a Murine Model of Infection

    PubMed Central

    Crawford, Matthew A.; Burdick, Marie D.; Glomski, Ian J.; Boyer, Anne E.; Barr, John R.; Mehrad, Borna; Strieter, Robert M.; Hughes, Molly A.

    2010-01-01

    Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms. PMID:21124994

  6. NOD2, an Intracellular Innate Immune Sensor Involved in Host Defense and Crohn's Disease

    PubMed Central

    Strober, Warren; Watanabe, Tomohiro

    2013-01-01

    Nucleotide binding oligomerization domain 2 (NOD2) is an intracellular sensor for small peptides derived from the bacterial cell wall component, peptidoglycan. Recent studies have uncovered unexpected functions of NOD2 in innate immune responses such as induction of type I IFN and facilitation of autophagy; moreover, they have disclosed extensive cross-talk between NOD2 and Toll-like receptors which plays an indispensable role both in host defense against microbial infection and in the development of autoimmunity. Of particular interest, polymorphisms of CARD15 encoding NOD2 are associated with Crohn's disease and other autoimmune states such as graft versus host disease. In this review, we summarize recent findings regarding normal functions of NOD2 and discuss the mechanisms by which NOD2 polymorphisms associated with Crohn's disease lead to intestinal inflammation. PMID:21750585

  7. Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells

    PubMed Central

    Upadhyay, Vaibhav; Fu, Yang-Xin

    2014-01-01

    The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review. PMID:24411493

  8. Protective host defense against disseminated candidiasis is impaired in mice expressing human interleukin-37.

    PubMed

    van de Veerdonk, Frank L; Gresnigt, Mark S; Oosting, Marije; van der Meer, Jos W M; Joosten, Leo A B; Netea, Mihai G; Dinarello, Charles A

    2014-01-01

    The effect of the anti-inflammatory cytokine interleukin-37 (IL-37) on host defense against Candida infections remains unknown. We assessed the role of IL-37 in a murine model of disseminated candidiasis using mice transgenic for human IL-37 (hIL-37Tg). Upon exposure to Candida albicans pseudohyphae, macrophages from hIL-37Tg mice release 39% less TNFα compared to cells from wild-type (WT) mice (p = 0.01). In vivo, hIL-37Tg mice displayed a decreased capacity to recruit neutrophils to the site of infection. These defects were associated with increased mortality and organ fungal growth in hIL-37Tg compared to WT mice. We conclude that IL-37 interferes with the innate protective anti-Candida host response by reducing the production of proinflammatory cytokines and suppressing neutrophil recruitment in response to Candida, resulting in an increased susceptibility to disseminated candidiasis. PMID:25620965

  9. Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.

    PubMed

    Jantsch, Jonathan; Schatz, Valentin; Friedrich, Diana; Schröder, Agnes; Kopp, Christoph; Siegert, Isabel; Maronna, Andreas; Wendelborn, David; Linz, Peter; Binger, Katrina J; Gebhardt, Matthias; Heinig, Matthias; Neubert, Patrick; Fischer, Fabian; Teufel, Stefan; David, Jean-Pierre; Neufert, Clemens; Cavallaro, Alexander; Rakova, Natalia; Küper, Christoph; Beck, Franz-Xaver; Neuhofer, Wolfgang; Muller, Dominik N; Schuler, Gerold; Uder, Michael; Bogdan, Christian; Luft, Friedrich C; Titze, Jens

    2015-03-01

    Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection. PMID:25738463

  10. Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense

    PubMed Central

    Jantsch, Jonathan; Schatz, Valentin; Friedrich, Diana; Schröder, Agnes; Kopp, Christoph; Siegert, Isabel; Maronna, Andreas; Wendelborn, David; Linz, Peter; Binger, Katrina J.; Gebhardt, Matthias; Heinig, Matthias; Neubert, Patrick; Fischer, Fabian; Teufel, Stefan; David, Jean-Pierre; Neufert, Clemens; Cavallaro, Alexander; Rakova, Natalia; Küper, Christoph; Beck, Franz-Xaver; Neuhofer, Wolfgang; Muller, Dominik N.; Schuler, Gerold; Uder, Michael; Bogdan, Christian; Luft, Friedrich C.; Titze, Jens

    2015-01-01

    Summary Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na+ concentrations is unknown. We found that Na+ accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na+ storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na+ content in the skin by a high-salt diet boosted activation of macrophages in an Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection. PMID:25738463

  11. Department of Defense Education Activity. An Overview.

    ERIC Educational Resources Information Center

    US Department of Defense, 2004

    2004-01-01

    DoDEA operates 223 public schools in 16 districts located in seven states, Puerto Rico, Guam, and 13 foreign countries to serve the children of military service members and Department of Defense civilian employees. Approximately 104,935 students are enrolled in DoDEA schools, with approximately 73,200 students in the DoDDS system, and…

  12. Pythium infection activates conserved plant defense responses in mosses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The moss Physcomitrella patens (P. patens) is a useful model to study abiotic stress responses since it is highly tolerant to drought, salt and osmotic stress. However, little is known about the defense mechanisms activated in this moss after pathogen assault. Here the induction of defense responses...

  13. Manipulation of Host Quality and Defense by a Plant Virus Improves Performance of Whitefly Vectors.

    PubMed

    Su, Qi; Preisser, Evan L; Zhou, Xiao Mao; Xie, Wen; Liu, Bai Ming; Wang, Shao Li; Wu, Qing Jun; Zhang, You Jun

    2015-02-01

    Pathogen-mediated interactions between insect vectors and their host plants can affect herbivore fitness and the epidemiology of plant diseases. While the role of plant quality and defense in mediating these tripartite interactions has been recognized, there are many ecologically and economically important cases where the nature of the interaction has yet to be characterized. The Bemisia tabaci (Gennadius) cryptic species Mediterranean (MED) is an important vector of tomato yellow leaf curl virus (TYLCV), and performs better on virus-infected tomato than on uninfected controls. We assessed the impact of TYLCV infection on plant quality and defense, and the direct impact of TYLCV infection on MED feeding. We found that although TYLCV infection has a minimal direct impact on MED, the virus alters the nutritional content of leaf tissue and phloem sap in a manner beneficial to MED. TYLCV infection also suppresses herbivore-induced production of plant defensive enzymes and callose deposition. The strongly positive net effect on TYLCV on MED is consistent with previously reported patterns of whitefly behavior and performance, and provides a foundation for further exploration of the molecular mechanisms responsible for these effects and the evolutionary processes that shape them. PMID:26470098

  14. Exploring the Pharmacological Potential of Promiscuous Host-Defense Peptides: From Natural Screenings to Biotechnological Applications

    PubMed Central

    Silva, Osmar N.; Mulder, Kelly C. L.; Barbosa, Aulus E. A. D.; Otero-Gonzalez, Anselmo J.; Lopez-Abarrategui, Carlos; Rezende, Taia M. B.; Dias, Simoni C.; Franco, Octávio L.

    2011-01-01

    In the last few years, the number of bacteria with enhanced resistance to conventional antibiotics has dramatically increased. Most of such bacteria belong to regular microbial flora, becoming a real challenge, especially for immune-depressed patients. Since the treatment is sometimes extremely expensive, and in some circumstances completely inefficient for the most severe cases, researchers are still determined to discover novel compounds. Among them, host-defense peptides (HDPs) have been found as the first natural barrier against microorganisms in nearly all living groups. This molecular class has been gaining attention every day for multiple reasons. For decades, it was believed that these defense peptides had been involved only with the permeation of the lipid bilayer in pathogen membranes, their main target. Currently, it is known that these peptides can bind to numerous targets, as well as lipids including proteins and carbohydrates, from the surface to deep within the cell. Moreover, by using in vivo models, it was shown that HDPs could act both in pathogens and cognate hosts, improving immunological functions as well as acting through multiple pathways to control infections. This review focuses on structural and functional properties of HDP peptides and the additional strategies used to select them. Furthermore, strategies to avoid problems in large-scale manufacture by using molecular and biochemical techniques will also be explored. In summary, this review intends to construct a bridge between academic research and pharmaceutical industry, providing novel insights into the utilization of HDPs against resistant bacterial strains that cause infections in humans. PMID:22125552

  15. The Role of Dectin-2 for Host Defense Against Disseminated Candidiasis

    PubMed Central

    Ifrim, Daniela C.; Quintin, Jessica; Courjol, Flavie; Verschueren, Ineke; van Krieken, J. Han; Koentgen, Frank; Fradin, Chantal; Gow, Neil A.R.; Joosten, Leo A.B.; van der Meer, Jos W.M.; van de Veerdonk, Frank

    2016-01-01

    Despite the fact that Candida albicans is an important human fungal pathogen and Dectin-2 is a major pattern recognition receptor for fungi, our knowledge regarding the role of Dectin-2 for the host defense against disseminated candidiasis is limited. Dectin-2 deficient (Dectin-2−/−) mice were more susceptible to systemic candidiasis, and the susceptibility was mirrored by an elevated fungal load in the kidneys that correlated with the presence of large inflammatory foci. Phagocytosis of Candida by the macrophages lacking the Dectin-2 receptor was moderately decreased, while production of most of the macrophage-derived cytokines from Dectin-2−/− mice with systemic candidiasis was decreased. No striking differences among several Candida mutants defective in mannans could be detected between naïve wild-type and Dectin-2−/− mice, apart from the β-mannan-deficient bmt1Δ/bmt2Δ/bmt5Δ triple mutant, suggesting that β-mannan may partially mask α-mannan detection, which is the major fungal structure recognized by Dectin-2. Deciphering the mechanisms responsible for host defense against the majority of C. albicans strains represents an important step in understanding the pathophysiology of systemic candidiasis, which might lead to the development of novel immunotherapeutic strategies. PMID:27046240

  16. Current and Potential Applications of Host-Defense Peptides and Proteins in Urology

    PubMed Central

    2015-01-01

    The use of antibiotics has become increasingly disfavored as more multidrug resistant pathogens are on the rise. A promising alternative to the use of these conventional drugs includes antimicrobial peptides or host-defense peptides. These peptides typically consist of short amino acid chains with a net cationic charge and a substantial portion of hydrophobic residues. They mainly target the bacterial cell membrane but are also capable of translocating through the membrane and target intracellular components, making it difficult for bacteria to gain resistance as multiple essential cellular processes are being targeted. The use of these peptides in the field of biomedical therapies has been examined, and the different approaches to using them under various settings are constantly being discovered. In this review, we discuss the current and potential applications of these host-defense peptides in the field of urology. Besides the use of these peptides as antimicrobial agents, the value of these biological molecules has recently been expanded to their use as antitumor and anti-kidney-stone agents. PMID:25815308

  17. [Role of neutrophil-derived reactive oxygen species in host defense and inflammation].

    PubMed

    Aratani, Yasuaki; Miura, Noriko; Ohno, Naohito; Suzuki, Kazuo

    2012-01-01

    Neutrophil accumulation is a critical event in the pathogenesis of inflammation. The generation of hypochlorous acid by myeloperoxidase (MPO) in neutrophils is crucial to the host defense response. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for in vivo host defense against fungi. On the other hand, impaired reactive oxygen species (ROS) production by neutrophils has previously been shown to cause an abnormal inflammatory response. In the present study, we have found that MPO-KO mice exhibit more severe pulmonary inflammation than wild-type mice when challenged with an intranasal administration of zymosan. In addition to measuring the kinetics of neutrophil accumulation, we also measured the production of macrophage inflammatory protein-2 (MIP-2) in the lung, and we correlate the degree of neutrophil accumulation with the production of this mediator. Our results demonstrate that MPO regulates the production of MIP-2, which may modulate neutrophil accumulation during lung inflammation. PMID:22728595

  18. The Role of Dectin-2 for Host Defense Against Disseminated Candidiasis.

    PubMed

    Ifrim, Daniela C; Quintin, Jessica; Courjol, Flavie; Verschueren, Ineke; van Krieken, J Han; Koentgen, Frank; Fradin, Chantal; Gow, Neil A R; Joosten, Leo A B; van der Meer, Jos W M; van de Veerdonk, Frank; Netea, Mihai G

    2016-04-01

    Despite the fact that Candida albicans is an important human fungal pathogen and Dectin-2 is a major pattern recognition receptor for fungi, our knowledge regarding the role of Dectin-2 for the host defense against disseminated candidiasis is limited. Dectin-2 deficient (Dectin-2(-/-)) mice were more susceptible to systemic candidiasis, and the susceptibility was mirrored by an elevated fungal load in the kidneys that correlated with the presence of large inflammatory foci. Phagocytosis of Candida by the macrophages lacking the Dectin-2 receptor was moderately decreased, while production of most of the macrophage-derived cytokines from Dectin-2(-/-) mice with systemic candidiasis was decreased. No striking differences among several Candida mutants defective in mannans could be detected between naïve wild-type and Dectin-2(-/-) mice, apart from the β-mannan-deficient bmt1Δ/bmt2Δ/bmt5Δ triple mutant, suggesting that β-mannan may partially mask α-mannan detection, which is the major fungal structure recognized by Dectin-2. Deciphering the mechanisms responsible for host defense against the majority of C. albicans strains represents an important step in understanding the pathophysiology of systemic candidiasis, which might lead to the development of novel immunotherapeutic strategies. PMID:27046240

  19. Priming of the neutrophil respiratory burst: role in host defense and inflammation.

    PubMed

    El-Benna, Jamel; Hurtado-Nedelec, Margarita; Marzaioli, Viviana; Marie, Jean-Claude; Gougerot-Pocidalo, Marie-Anne; Dang, Pham My-Chan

    2016-09-01

    Neutrophils are the major circulating white blood cells in humans. They play an essential role in host defense against pathogens. In healthy individuals, circulating neutrophils are in a dormant state with very low efficiency of capture and arrest on the quiescent endothelium. Upon infection and subsequent release of pro-inflammatory mediators, the vascular endothelium signals to circulating neutrophils to roll, adhere, and cross the endothelial barrier. Neutrophils migrate toward the infection site along a gradient of chemo-attractants, then recognize and engulf the pathogen. To kill this pathogen entrapped inside the vacuole, neutrophils produce and release high quantities of antibacterial peptides, proteases, and reactive oxygen species (ROS). The robust ROS production is also called 'the respiratory burst', and the NADPH oxidase or NOX2 is the enzyme responsible for the production of superoxide anion, leading to other ROS. In vitro, several soluble and particulate agonists induce neutrophil ROS production. This process can be enhanced by prior neutrophil treatment with 'priming' agents, which alone do not induce a respiratory burst. In this review, we will describe the priming process and discuss the beneficial role of controlled neutrophil priming in host defense and the detrimental effect of excessive neutrophil priming in inflammatory diseases. PMID:27558335

  20. Innate antiviral host defense attenuates TGF-β function through IRF3-mediated suppression of Smad signaling

    PubMed Central

    Xu, Pinglong; Bailey-Bucktrout, Samantha; Xi, Ying; Xu, Daqi; Du, Dan; Zhang, Qian; Xiang, Weiwen; Liu, Jianming; Melton, Andrew; Sheppard, Dean; Chapman, Harold A.; Bluestone, Jeffrey A.; Derynck, Rik

    2014-01-01

    Summary TGF-β signaling is essential in many processes, including immune surveillance, and its dysregulation controls various diseases, including cancer, fibrosis, and inflammation. Studying the innate host defense, which functions in most cell types, we found that RLR signaling represses TGF-β responses. This regulation is mediated by activated IRF3, using a dual mechanism of IRF3-directed suppression. Activated IRF3 interacts with Smad3, thus inhibiting TGF-β-induced Smad3 activation, and, in the nucleus, disrupts functional Smad3 transcription complexes by competing with co-regulators. Consequently, IRF3 activation by innate antiviral signaling represses TGF-β-induced growth inhibition, gene regulation and epithelial-mesenchymal transition, and the generation of Treg effector lymphocytes from naïve CD4+ lymphocytes. Conversely, silencing IRF3 expression enhances epithelial-mesenchymal transition, TGF-β-induced Treg cell differentiation upon virus infection, and Treg cell generation in vivo. We present a novel mode of regulation of TGF-β signaling by the antiviral defense, with evidence for its role in immune tolerance and cancer cell behavior. PMID:25526531

  1. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

    PubMed

    Walters, Edgar T

    2014-08-01

    Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain. PMID:25017887

  2. [Evaluation and consideration of BRM-BRM and HDP (host defense potentiators)].

    PubMed

    Chihara, G

    1988-04-01

    It should first be stressed that the term BRM is wrong and unscientific, since this would include potassium cyanide or cancer chemotherapeutics in the strict sense of the term. Therefore, in this article we discuss the evaluation of Host Defence Potentiators (HDP). IL-2 or TNF should not be included as HDP because their action is local and not selective to cancer cells, similar to the case of cancer chemotherapeutics. IL-2 is not useful without the presence of IL-2-responsive cells in the host. The most important facet of the action of HDP is to increase the response of the host to cytokines or other bioactive substances according to the degree of maturation, differentiation or proliferation of responsive cells in the host defence mechanism. Lentinan appears to represent a unique class of HDP, markedly potentiating host resistance to cancer and bacterial, viral and parasitic infections, and shows prominent antitumor activity in syngeneic and autochthonous hosts, suppressing chemical and viral oncogenesis. The most important target of HDP is complete prevention of recurrence after "curative" surgery fundamentally through growth inhibition and regression of a small number of autochthonous tumor cells scattered in the host. Considering the excellent end-point results for phase III advanced and recurrent gastrointestinal and breast cancer, lentinan seems to be the most hopeful drug against cancer recurrence. The development of various new types of MDP mediating host homeostasis in the immune, endocrine and nervous systems and nutritional states is expected. PMID:3382231

  3. Feeding on Host Plants with Different Concentrations and Structures of Pyrrolizidine Alkaloids Impacts the Chemical-Defense Effectiveness of a Specialist Herbivore

    PubMed Central

    Cunha, Beatriz P.; Solferini, Vera N.

    2015-01-01

    Sequestration of chemical defenses from host plants is a strategy widely used by herbivorous insects to avoid predation. Larvae of the arctiine moth Utetheisa ornatrix feeding on unripe seeds and leaves of many species of Crotalaria (Leguminosae) sequester N-oxides of pyrrolizidine alkaloids (PAs) from these host plants, and transfer them to adults through the pupal stage. PAs confer protection against predation on all life stages of U. ornatrix. As U. ornatrix also uses other Crotalaria species as host plants, we evaluated whether the PA chemical defense against predation is independent of host plant use. We fed larvae from hatching to pupation with either leaves or seeds of one of eight Crotalaria species (C. incana, C. juncea, C. micans, C. ochroleuca, C. pallida, C. paulina, C. spectabilis, and C. vitellina), and tested if adults were preyed upon or released by the orb-weaving spider Nephila clavipes. We found that the protection against the spider was more effective in adults whose larvae fed on seeds, which had a higher PA concentration than leaves. The exceptions were adults from larvae fed on C. paulina, C. spectabilis and C. vitellina leaves, which showed high PA concentrations. With respect to the PA profile, we describe for the first time insect-PAs in U. ornatrix. These PAs, biosynthesized from the necine base retronecine of plant origin, or monocrotaline- and senecionine-type PAs sequestered from host plants, were equally active in moth chemical defense, in a dose-dependent manner. These results are also partially explained by host plant phylogeny, since PAs of the host plants do have a phylogenetic signal (clades with high and low PA concentrations in leaves) which is reflected in the adult defense. PMID:26517873

  4. Inbreeding compromises host plant defense gene expression and improves herbivore survival

    PubMed Central

    Portman, Scott L; Kariyat, Rupesh R; Johnston, Michelle A; Stephenson, Andrew G; Marden, James H

    2015-01-01

    Inbreeding commonly occurs in flowering plants and often results in a decline in the plant's defense response. Insects prefer to feed and oviposit on inbred plants more than outbred plants – suggesting that selecting inbred host plants offers them fitness benefits. Until recently, no studies have examined the effects of host plant inbreeding on insect fitness traits such as growth and dispersal ability. In a recent article, we documented that tobacco hornworm (Manduca sexta L.) larvae that fed on inbred horsenettle (Solanum carolinense L.) plants exhibited accelerated larval growth and increased adult flight capacity compared to larvae that fed on outbred plants. Here we report that M. sexta mortality decreased by 38.2% when larvae were reared on inbred horsenettle plants compared to larvae reared on outbreds. Additionally, inbred plants showed a notable reduction in the average relative expression levels of LIPOXYGENEASE-D (LoxD) and 12-OXOPHYTODIENOATE REDUCTASE-3 (OPR3), two genes in the jasmonic acid signaling pathway that are upregulated in response to herbivore damage. Our study presents evidence that furthers our understanding of the biochemical mechanism responsible for differences in insect performance on inbred vs. outbred host plants. PMID:26039489

  5. Acute radiation syndrome (ARS) – treatment of the reduced host defense

    PubMed Central

    Heslet, Lars; Bay, Christiane; Nepper-Christensen, Steen

    2012-01-01

    Background The current radiation threat from the Fukushima power plant accident has prompted rethinking of the contingency plan for prophylaxis and treatment of the acute radiation syndrome (ARS). The well-documented effect of the growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in acute radiation injury has become standard treatment for ARS in the United States, based on the fact that growth factors increase number and functions of both macrophages and granulocytes. Methods Review of the current literature. Results The lungs have their own host defense system, based on alveolar macrophages. After radiation exposure to the lungs, resting macrophages can no longer be transformed, not even during systemic administration of growth factors because G-CSF/GM-CSF does not penetrate the alveoli. Under normal circumstances, locally-produced GM-CSF receptors transform resting macrophages into fully immunocompetent dendritic cells in the sealed-off pulmonary compartment. However, GM-CSF is not expressed in radiation injured tissue due to defervescence of the macrophages. In order to maintain the macrophage’s important role in host defense after radiation exposure, it is hypothesized that it is necessary to administer the drug exogenously in order to uphold the barrier against exogenous and endogenous infections and possibly prevent the potentially lethal systemic infection, which is the main cause of death in ARS. Recommendation Preemptive treatment should be initiated after suspected exposure of a radiation dose of at least <2 Gy by prompt dosing of 250–400 μg GM-CSF/m2 or 5 μg/kg G-CSF administered systemically and concomitant inhalation of GM-CSF < 300 mcg per day for at least 14–21 days. Conclusion The present United States standard for prevention and treatment of ARS standard intervention should consequently be modified into the combined systemic administration of growth factors and

  6. Antipredator defense of biological control agent Oxyops vitiosa is mediated by plant volatiles sequestered from the host plant Melaleuca quinquenervia.

    PubMed

    Wheeler, G S; Massey, L M; Southwell, I A

    2002-02-01

    The weevil Oxyops vitiosa is an Australian species imported to Florida, USA, for the biological control of the invasive weed species Melaleuca quinquenervia. Larvae of this species feed on leaves of their host and produce a shiny orange secretion that covers the integument. When this secretion is applied at physiological concentrations to dog food bait, fire ant consumption and visitation are significantly reduced. Gas chromatographic analysis indicates that the larval secretion qualitatively and quantitatively resembles the terpenoid composition of the host foliage. When the combination of 10 major terpenoids from the O. vitiosa secretion was applied to dog food bait, fire ant consumption and visitation were reduced. When these 10 terpenoids were tested individually, the sesquiterpene viridiflorol was the most active component in decreasing fire ant consumption. Fire ant visitation was initially (15 min after initiation of the study) decreased for dog food bait treated with viridiflorol and the monoterpenes 1,8-cineole and alpha-terpineol. Fire ants continued to avoid the bait treated with viridiflorol at 18 microg/mg dog food for up to 6 hr after the initiation of the experiment. Moreover, ants avoided bait treated with 1.8 microg/mg for up to 3 hr. The concentrations of viridiflorol, 1,8-cineole, and alpha-terpineol in larval washes were about twice that of the host foliage, suggesting that the larvae sequester these plant-derived compounds for defense against generalist predators. PMID:11925069

  7. Non-canonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens

    PubMed Central

    Knodler, Leigh A.; Crowley, Shauna M.; Sham, Ho Pan; Yang, Hyungjun; Wrande, Marie; Ma, Caixia; Ernst, Robert K.; Steele-Mortimer, Olivia; Celli, Jean; Vallance, Bruce A.

    2014-01-01

    Summary Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11 deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human orthologue of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore an epithelial cell intrinsic non-canonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface. PMID:25121752

  8. Regulation of lung immunity and host defense by the intestinal microbiota

    PubMed Central

    Samuelson, Derrick R.; Welsh, David A.; Shellito, Judd E.

    2015-01-01

    Every year in the United States approximately 200,000 people die from pulmonary infections, such as influenza and pneumonia, or from lung disease that is exacerbated by pulmonary infection. In addition, respiratory diseases such as, asthma, affect 300 million people worldwide. Therefore, understanding the mechanistic basis for host defense against infection and regulation of immune processes involved in asthma are crucial for the development of novel therapeutic strategies. The identification, characterization, and manipulation of immune regulatory networks in the lung represents one of the biggest challenges in treatment of lung associated disease. Recent evidence suggests that the gastrointestinal (GI) microbiota plays a key role in immune adaptation and initiation in the GI tract as well as at other distal mucosal sites, such as the lung. This review explores the current research describing the role of the GI microbiota in the regulation of pulmonary immune responses. Specific focus is given to understanding how intestinal “dysbiosis” affects lung health. PMID:26500629

  9. New development in studies of formyl-peptide receptors: critical roles in host defense.

    PubMed

    Li, Liangzhu; Chen, Keqiang; Xiang, Yi; Yoshimura, Teizo; Su, Shaobo; Zhu, Jianwei; Bian, Xiu-wu; Wang, Ji Ming

    2016-03-01

    Formyl-peptide receptors are a family of 7 transmembrane domain, Gi-protein-coupled receptors that possess multiple functions in many pathophysiologic processes because of their expression in a variety of cell types and their capacity to interact with a variety of structurally diverse, chemotactic ligands. Accumulating evidence demonstrates that formyl-peptide receptors are critical mediators of myeloid cell trafficking in the sequential chemotaxis signal relays in microbial infection, inflammation, and immune responses. Formyl-peptide receptors are also involved in the development and progression of cancer. In addition, one of the formyl-peptide receptor family members, Fpr2, is expressed by normal mouse-colon epithelial cells, mediates cell responses to microbial chemotactic agonists, participates in mucosal development and repair, and protects against inflammation-associated tumorigenesis. These novel discoveries greatly expanded the current understanding of the role of formyl-peptide receptors in host defense and as potential molecular targets for the development of therapeutics. PMID:26701131

  10. Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides.

    PubMed

    Li, Hao; Anuwongcharoen, Nuttapat; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have been taken to improve the therapeutic efficacy of HDPs. Amongst these methods, the incorporation of d-amino acids (d-AA) is an approach that has demonstrated consistent success in improving HDPs. Although, virtually all HDP review articles briefly mentioned about the role of d-AA, however it is rather surprising that no systematic review specifically dedicated to this topic exists. Given the impact that d-AA incorporation has on HDPs, this review aims to fill that void with a systematic discussion of the impact of d-AA on HDPs. PMID:27376281

  11. Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides

    PubMed Central

    Li, Hao; Anuwongcharoen, Nuttapat; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E. S.; Nantasenamat, Chanin

    2016-01-01

    Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have been taken to improve the therapeutic efficacy of HDPs. Amongst these methods, the incorporation of d-amino acids (d-AA) is an approach that has demonstrated consistent success in improving HDPs. Although, virtually all HDP review articles briefly mentioned about the role of d-AA, however it is rather surprising that no systematic review specifically dedicated to this topic exists. Given the impact that d-AA incorporation has on HDPs, this review aims to fill that void with a systematic discussion of the impact of d-AA on HDPs. PMID:27376281

  12. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice

    PubMed Central

    Cho, John S.; Pietras, Eric M.; Garcia, Nairy C.; Ramos, Romela Irene; Farzam, David M.; Monroe, Holly R.; Magorien, Julie E.; Blauvelt, Andrew; Kolls, Jay K.; Cheung, Ambrose L.; Cheng, Genhong; Modlin, Robert L.; Miller, Lloyd S.

    2010-01-01

    Staphylococcus aureus is the most common cause of skin and soft tissue infections, and rapidly emerging antibiotic-resistant strains are creating a serious public health concern. If immune-based therapies are to be an alternative to antibiotics, greater understanding is needed of the protective immune response against S. aureus infection in the skin. Although neutrophil recruitment is required for immunity against S. aureus, a role for T cells has been suggested. Here, we used a mouse model of S. aureus cutaneous infection to investigate the contribution of T cells to host defense. We found that mice deficient in γδ but not αβ T cells had substantially larger skin lesions with higher bacterial counts and impaired neutrophil recruitment compared with WT mice. This neutrophil recruitment was dependent upon epidermal Vγ5+ γδ T cell production of IL-17, but not IL-21 and IL-22. Furthermore, IL-17 induction required IL-1, TLR2, and IL-23 and was critical for host defense, since IL-17R–deficient mice had a phenotype similar to that of γδ T cell–deficient mice. Importantly, γδ T cell–deficient mice inoculated with S. aureus and treated with a single dose of recombinant IL-17 had lesion sizes and bacterial counts resembling those of WT mice, demonstrating that IL-17 could restore the impaired immunity in these mice. Our study defines what we believe to be a novel role for IL-17–producing epidermal γδ T cells in innate immunity against S. aureus cutaneous infection. PMID:20364087

  13. Triggering Receptor Expressed on Myeloid Cells (TREM)-2 Impairs Host Defense in Experimental Melioidosis

    PubMed Central

    Weehuizen, Tassili A. F.; Hommes, Tijmen J.; Lankelma, Jacqueline M.; de Jong, Hanna K.; Roelofs, Joris. J.T.H.; de Vos, Alex F.; Colonna, Marco; van der Poll, Tom; Wiersinga, W. Joost

    2016-01-01

    Background Triggering receptor expressed on myeloid cells (TREM) -1 and TREM-2 are key regulators of the inflammatory response that are involved in the clearance of invading pathogens. Melioidosis, caused by the "Tier 1" biothreat agent Burkholderia pseudomallei, is a common form of community-acquired sepsis in Southeast-Asia. TREM-1 has been suggested as a biomarker for sepsis and melioidosis. We aimed to characterize the expression and function of TREM-1 and TREM-2 in melioidosis. Methodology/Principal Findings Wild-type, TREM-1/3 (Trem-1/3-/-) and TREM-2 (Trem-2-/-) deficient mice were intranasally infected with live B. pseudomallei and killed after 24, and/or 72 h for the harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed. Cellular functions were further analyzed by stimulation and/or infection of isolated cells. TREM-1 and TREM-2 expression was increased both in the lung and liver of B. pseudomallei-infected mice. Strikingly, Trem-2-/-, but not Trem-1/3-/-, mice displayed a markedly improved host defense as reflected by a strong survival advantage together with decreased bacterial loads, less inflammation and reduced organ injury. Cellular responsiveness of TREM-2, but not TREM-1, deficient blood and bone-marrow derived macrophages (BMDM) was diminished upon exposure to B. pseudomallei. Phagocytosis and intracellular killing of B. pseudomallei by BMDM and alveolar macrophages were TREM-1 and TREM-2-independent. Conclusions/Significance We found that TREM-2, and to a lesser extent TREM-1, plays a remarkable detrimental role in the host defense against a clinically relevant Gram-negative pathogen in mice: TREM-2 deficiency restricts the inflammatory response, thereby decreasing organ damage and mortality. PMID:27253382

  14. Sequestration of host plant glucosinolates in the defensive hemolymph of the sawfly Athalia rosae.

    PubMed

    Müller, C; Agerbirk, N; Olsen, C E; Boevé, J L; Schaffner, U; Brakefield, P M

    2001-12-01

    Interactions between insects and glucosinolate-containing plant species have been investigated for a long time. Although the glucosinolate-myrosinase system is believed to act as a defense mechanism against generalist herbivores and fungi, several specialist insects use these secondary metabolites for host plant finding and acceptance and can handle them physiologically. However, sequestration of glucosinolates in specialist herbivores has been less well studied. Larvae of the tumip sawfly Athalia rosae feed on several glucosinolate-containing plant species. When larvae are disturbed by antagonists, they release one or more small droplets of hemolymph from their integument. This "reflex bleeding" is used as a defense mechanism. Specific glucosinolate analysis, by conversion to desulfoglucosinolates and analysis of these by high-performance liquid chromatography coupled to diode array UV spectroscopy and mass spectrometry, revealed that larvae incorporate and concentrate the plant's characteristic glucosinolates from their hosts. Extracts of larvae that were reared on Sinapis alba contained sinalbin, even when the larvae were first starved for 22 hr and, thus, had empty guts. Hemolymph was analyzed from larvae that were reared on either S. alba, Brassica nigra, or Barbarea stricta. Leaves were analyzed from the same plants the larvae had fed on. Sinalbin (from S. alba), sinigrin (B. nigra), or glucobarbarin and glucobrassicin (B. stricta) were present in leaves in concentrations less than 1 micromol/g fresh weight, while the same glucosinolates could be detected in the larvae's hemolymph in concentrations between 10 and 31 micromol/g fresh weight, except that glucobrassicin was present only as a trace. In larval feces, only trace amounts of glucosinolates (sinalbin and sinigrin) could be detected. The glucosinolates were likewise found in freshly emerged adults, showing that the sequestered phytochemicals were transferred through the pupal stage. PMID:11789955

  15. Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

    PubMed Central

    Humphreys, Hilary; Greene, Catherine M.; Fitzgerald-Hughes, Deirdre; Devocelle, Marc

    2014-01-01

    Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung. PMID:24277028

  16. Activated chemical defenses suppress herbivory on freshwater red algae.

    PubMed

    Goodman, Keri M; Hay, Mark E

    2013-04-01

    The rapid life cycles of freshwater algae are hypothesized to suppress selection for chemical defenses against herbivores, but this notion remains untested. Investigations of chemical defenses are rare for freshwater macrophytes and absent for freshwater red algae. We used crayfish to assess the palatability of five freshwater red algae relative to a palatable green alga and a chemically defended aquatic moss. We then assessed the roles of structural, nutritional, and chemical traits in reducing palatability. Both native and non-native crayfish preferred the green alga Cladophora glomerata to four of the five red algae. Batrachospermum helminthosum, Kumanoa holtonii, and Tuomeya americana employed activated chemical defenses that suppressed feeding by 30-60 % following damage to algal tissues. Paralemanea annulata was defended by its cartilaginous structure, while Boldia erythrosiphon was palatable. Activated defenses are thought to reduce ecological costs by expressing potent defenses only when actually needed; thus, activation might be favored in freshwater red algae whose short-lived gametophytes must grow and reproduce rapidly over a brief growing season. The frequency of activated chemical defenses found here (three of five species) is 3-20× higher than for surveys of marine algae or aquatic vascular plants. If typical for freshwater red algae, this suggests that (1) their chemical defenses may go undetected if chemical activation is not considered and (2) herbivory has been an important selective force in the evolution of freshwater Rhodophyta. Investigations of defenses in freshwater rhodophytes contribute to among-system comparisons and provide insights into the generality of plant-herbivore interactions and their evolution. PMID:23011851

  17. Plant Defense Response to Fungal Pathogens (II. G-Protein-Mediated Changes in Host Plasma Membrane Redox Reactions).

    PubMed Central

    Vera-Estrella, R.; Higgins, V. J.; Blumwald, E.

    1994-01-01

    Elicitor preparations containing the avr5 gene products from races 4 and 2.3 of Cladosporium fulvum, and tomato (Lycopersicon esculentum L.) cells containing the resistance gene Cf5 were used to investigate the involvement of redox processes in the production of active oxygen species associated with the plant response to the fungal elicitors. Here we demonstrate that certain race-specific elicitors of C. fulvum induced an increase in ferricyanide reduction in enriched plasma membrane fractions of tomato cells. The addition of elicitors to plasma membranes also induced increases in NADH oxidase and NADH-dependent cytochrome c reductase activities, whereas ascorbate peroxidase activity was decreased. These results suggest that changes in the host plasma membrane redox processes, transferring electrons from reducing agents to oxygen, could be involved in the increased production of active oxygen species by the race-specific elicitors. Our results also show that the dephosphorylation of enzymes involved in redox reactions is responsible for the race-specific induced redox activity. The effects of guanidine nucleotide analogs and mastoparan on the activation of plasma membrane redox reactions support the role of GTP-binding proteins in the transduction of signals leading to the activation of the defense response mechanisms of tomato against fungal pathogens. PMID:12232307

  18. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection.

    PubMed

    Gladiator, André; Wangler, Nicolette; Trautwein-Weidner, Kerstin; LeibundGut-Landmann, Salomé

    2013-01-15

    IL-17-mediated immunity has emerged as a crucial host defense mechanism against fungal infections. Although Th cells are generally thought to act as the major source of IL-17 in response to Candida albicans, we show that fungal control is mediated by IL-17-secreting innate lymphoid cells (ILCs) and not by Th17 cells. By using a mouse model of oropharyngeal candidiasis we found that IL-17A and IL-17F, which are both crucial for pathogen clearance, are produced promptly upon infection in an IL-23-dependent manner, and that ILCs in the oral mucosa are the main source for these cytokines. Ab-mediated depletion of ILCs in RAG1-deficient mice or ILC deficiency in retinoic acid-related orphan receptor c(-/-) mice resulted in a complete failure to control the infection. Taken together, our data uncover the cellular basis for the IL-23/IL-17 axis, which acts right at the onset of infection when it is most needed for fungal control and host protection. PMID:23255360

  19. Human Host Defense Peptide LL-37 Stimulates Virulence Factor Production and Adaptive Resistance in Pseudomonas aeruginosa

    PubMed Central

    Strempel, Nikola; Neidig, Anke; Nusser, Michael; Geffers, Robert; Vieillard, Julien; Lesouhaitier, Olivier; Brenner-Weiss, Gerald; Overhage, Joerg

    2013-01-01

    A multitude of different virulence factors as well as the ability to rapidly adapt to adverse environmental conditions are important features for the high pathogenicity of Pseudomonas aeruginosa. Both virulence and adaptive resistance are tightly controlled by a complex regulatory network and respond to external stimuli, such as host signals or antibiotic stress, in a highly specific manner. Here, we demonstrate that physiological concentrations of the human host defense peptide LL-37 promote virulence factor production as well as an adaptive resistance against fluoroquinolone and aminoglycoside antibiotics in P. aeruginosa PAO1. Microarray analyses of P. aeruginosa cells exposed to LL-37 revealed an upregulation of gene clusters involved in the production of quorum sensing molecules and secreted virulence factors (PQS, phenazine, hydrogen cyanide (HCN), elastase and rhamnolipids) and in lipopolysaccharide (LPS) modification as well as an induction of genes encoding multidrug efflux pumps MexCD-OprJ and MexGHI-OpmD. Accordingly, we detected significantly elevated levels of toxic metabolites and proteases in bacterial supernatants after LL-37 treatment. Pre-incubation of bacteria with LL-37 for 2 h led to a decreased susceptibility towards gentamicin and ciprofloxacin. Quantitative Realtime PCR results using a PAO1-pqsE mutant strain present evidence that the quinolone response protein and virulence regulator PqsE may be implicated in the regulation of the observed phenotype in response to LL-37. Further experiments with synthetic cationic antimicrobial peptides IDR-1018, 1037 and HHC-36 showed no induction of pqsE expression, suggesting a new role of PqsE as highly specific host stress sensor. PMID:24349231

  20. Human host defense peptide LL-37 stimulates virulence factor production and adaptive resistance in Pseudomonas aeruginosa.

    PubMed

    Strempel, Nikola; Neidig, Anke; Nusser, Michael; Geffers, Robert; Vieillard, Julien; Lesouhaitier, Olivier; Brenner-Weiss, Gerald; Overhage, Joerg

    2013-01-01

    A multitude of different virulence factors as well as the ability to rapidly adapt to adverse environmental conditions are important features for the high pathogenicity of Pseudomonas aeruginosa. Both virulence and adaptive resistance are tightly controlled by a complex regulatory network and respond to external stimuli, such as host signals or antibiotic stress, in a highly specific manner. Here, we demonstrate that physiological concentrations of the human host defense peptide LL-37 promote virulence factor production as well as an adaptive resistance against fluoroquinolone and aminoglycoside antibiotics in P. aeruginosa PAO1. Microarray analyses of P. aeruginosa cells exposed to LL-37 revealed an upregulation of gene clusters involved in the production of quorum sensing molecules and secreted virulence factors (PQS, phenazine, hydrogen cyanide (HCN), elastase and rhamnolipids) and in lipopolysaccharide (LPS) modification as well as an induction of genes encoding multidrug efflux pumps MexCD-OprJ and MexGHI-OpmD. Accordingly, we detected significantly elevated levels of toxic metabolites and proteases in bacterial supernatants after LL-37 treatment. Pre-incubation of bacteria with LL-37 for 2 h led to a decreased susceptibility towards gentamicin and ciprofloxacin. Quantitative Realtime PCR results using a PAO1-pqsE mutant strain present evidence that the quinolone response protein and virulence regulator PqsE may be implicated in the regulation of the observed phenotype in response to LL-37. Further experiments with synthetic cationic antimicrobial peptides IDR-1018, 1037 and HHC-36 showed no induction of pqsE expression, suggesting a new role of PqsE as highly specific host stress sensor. PMID:24349231

  1. 77 FR 76938 - Defense Federal Acquisition Regulation Supplement: Contracting Activity Updates (DFARS Case 2012...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-31

    ... Agency, the Defense Logistics Agency, the Defense Security Cooperation Agency, the Defense Security... Regulation Supplement: Contracting Activity Updates (DFARS Case 2012-D045) AGENCY: Defense Acquisition.... * * * * * Contracting activity for DoD also means elements designated by the director of a defense agency......

  2. Roles of MAS-related G protein coupled receptor-X2 (MRGPRX2) on mast cell-mediated host defense, pseudoallergic drug reactions and chronic inflammatory diseases

    PubMed Central

    Subramanian, Hariharan; Gupta, Kshitij; Ali, Hydar

    2016-01-01

    Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, contribute to vascular homeostasis, innate/adaptive immunity and wound healing. MCs are, however, best known for their roles in allergic and inflammatory diseases such as anaphylaxis, food allergy, rhinitis, itch, urticaria, atopic dermatitis and asthma. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the largest group of membrane receptor proteins and are the most common targets of drug therapy. Antimicrobial host defense peptides (HDPs), neuropeptides (NPs), major basic protein (MBP), eosinophil peroxidase (EPO) and many FDA approved peptidergic drugs activate human MCs via a novel GPCR known as MAS-related G protein coupled receptor-X2 (MRGPRX2; formerly known as MrgX2). Unique features of MRGPRX2 that distinguish it from other GPCRs include their presence both on plasma membrane and intracellular sites and their selective expression in MCs. In this article, we review the possible roles of MRGPRX2 on host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, itch and chronic inflammatory diseases such as urticaria and asthma. We propose that HDPs that kill microbes directly and activate MCs via MRGPRX2 could serve as novel GPCR targets to modulate host defense against microbial infection. Furthermore, monoclonal antibodies or small molecule inhibitors of MRGPRX2 could be developed for the treatment of MC-dependent allergic and inflammatory disorders. PMID:27448446

  3. Cigarette Smoke Modulates Expression of Human Rhinovirus-Induced Airway Epithelial Host Defense Genes

    PubMed Central

    Proud, David; Hudy, Magdalena H.; Wiehler, Shahina; Zaheer, Raza S.; Amin, Minaa A.; Pelikan, Jonathan B.; Tacon, Claire E.; Tonsaker, Tabitha O.; Walker, Brandie L.; Kooi, Cora; Traves, Suzanne L.; Leigh, Richard

    2012-01-01

    Human rhinovirus (HRV) infections trigger acute exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. The human airway epithelial cell is the primary site of HRV infection and responds to infection with altered expression of multiple genes, the products of which could regulate the outcome to infection. Cigarette smoking aggravates asthma symptoms, and is also the predominant risk factor for the development and progression of COPD. We, therefore, examined whether cigarette smoke extract (CSE) modulates viral responses by altering HRV-induced epithelial gene expression. Primary cultures of human bronchial epithelial cells were exposed to medium alone, CSE alone, purified HRV-16 alone or to HRV-16+ CSE. After 24 h, supernatants were collected and total cellular RNA was isolated. Gene array analysis was performed to examine mRNA expression. Additional experiments, using real-time RT-PCR, ELISA and/or western blotting, validated altered expression of selected gene products. CSE and HRV-16 each induced groups of genes that were largely independent of each other. When compared to gene expression in response to CSE alone, cells treated with HRV+CSE showed no obvious differences in CSE-induced gene expression. By contrast, compared to gene induction in response to HRV-16 alone, cells exposed to HRV+CSE showed marked suppression of expression of a number of HRV-induced genes associated with various functions, including antiviral defenses, inflammation, viral signaling and airway remodeling. These changes were not associated with altered expression of type I or type III interferons. Thus, CSE alters epithelial responses to HRV infection in a manner that may negatively impact antiviral and host defense outcomes. PMID:22808255

  4. Sex-dependent liver colonization of human melanoma in SCID mice--role of host defense mechanisms.

    PubMed

    Dobos, Judit; Mohos, Anita; Tóvári, József; Rásó, Erzsébet; Lőrincz, Tamás; Zádori, Gergely; Tímár, József; Ladányi, Andrea

    2013-04-01

    The possibility that endocrine factors may influence the clinical course of malignant melanoma is suggested by the superior survival data of women. In preclinical models we observed a higher rate of colony formation by human melanoma cells in male compared to female SCID mice, but only in the case of the liver and not in other organs. The gender difference could be seen at an early phase of colony formation. On the other hand, in our human melanoma cell lines we failed to detect steroid receptor protein expression, and treatment with sex hormones did not considerably influence their in vitro behavior. Investigating the possible contribution of host cells to the observed gender difference, we performed in vivo blocking experiments applying pretreatment of the animals with Kupffer cell inhibitor gadolinium chloride and the NK cell inhibitor anti-asialo GM1 antibody. While Kupffer cell blockade enhanced melanoma liver colonization equally in the two sexes, a more prominent increase was observed in female than in male mice in the case of NK cell inhibition. Further supporting the importance of NK cells in the lower liver colonization efficiency of melanoma cells in females, gender difference in colony formation was lost in NSG mice lacking NK activity. Although in humans no organ selectivity of gender difference in melanoma progression has been observed according to data in the literature, our results possibly indicate a contribution of natural host defense mechanisms to gender difference in survival of patients with melanoma or other tumor types as well. PMID:23203681

  5. Macrophages from Patients with Cirrhotic Ascites Showed Function Alteration of Host Defense Receptor

    PubMed Central

    Ahmed, Abdel Motaal M.; Kadaru, Abdel Gadir Y.; Omer, Ibtihal; Musa, Ahmed M.; Enan, Khalid; El Khidir, Isam M.; Williams, Roger

    2014-01-01

    Background Patients with cirrhotic ascites (PCA) are susceptible to spontaneous bacterial peritonitis (SBP) which has increased morbidity and mortality. Since some host defense aspects of peritoneal macrophages (PMф) from PCA are altered this study examined factors related to receptor-mediated phagocytosis. Methods Twelve PCA were studied. PMɸ were isolated from ascitic fluid (AF) samples removed from these patients. Uptake of mannose receptor (MR)-specific ligand, fluorescein isothiocyanate-mannosylated-bovine serum albumin (FITC-man-BSA), by patients' PMɸ and controls, a human monocytic cell line, was measured pre- and post-IL-4 treatment. Phagocytosis of FITC-labeled yeast particles by patients' PMɸ was measured pre- and post-IL-4 treatment. Fluorescence values were obtained using a spectrofuorometer. MRC1 gene was analyzed in blood samples from PCA and controls, healthy donors, using standard polymerase chain reaction (PCR) technique. Results Past SBP episode(s) were reported in 58.3% of patients. Mean AF volume analyzed per patient was 1.3L. PMɸ ratio in cell yield was 53.73% (SD 18.1). Mean uptake absorbance of patients' PMф was 0.0841 (SD 0.077) compared to 0.338 (SD 0.34) of controls, P = 0.023. Following IL-4 treatment absorbance increased to 0.297 (SD 0.28) in patients' PMф (P = 0.018 on paired sample t-test), and to 0.532 (SD 0.398 in controls (P = 0.053 on independent sample t-test). Mean phagocytosis absorbance of patients' PMф was 0.1250 (SD 0.032) before IL-4 treatment compared to 0.2300 (SD 0.104) after (P = 0.026). PCR analysis for MRC1 gene was negative in all PCA samples compared to positive results in all controls. Conclusion Since decreased phagocytosis and MR uptake were enhanced post-IL-4 treatment MR downregulation pre-treatment is plausible. Negative PCR results for MRC1 might suggest an anomaly, but this awaits further ellucidation. These altered host defense findings are relevant to infection pathophysiology, and their

  6. Delayed Hypersensitivity: Indicator of Acquired Failure of Host Defenses in Sepsis and Trauma

    PubMed Central

    Meakins, Jonathan L.; Pietsch, John B.; Bubenick, Oldrich; Kelly, Ralph; Rode, Harold; Gordon, Julius; MacLean, Lloyd D.

    1977-01-01

    Primary failure of host defense mechanisms has been associated with increased infection and mortality. Anergy, the failure of delayed hypersensitivity response, has been shown to identify surgical patients at increased risk for sepsis and related mortality. The anergic and relatively anergic patients whose skin tests failed to improve had a mortality rate of 74.4%, whereas those who improved their responses had a mortality rate of 5.1% (P < 0.001). This study documents abnormalities of neutrophil chemotaxis, T-lymphocyte rosetting in anergic patients and the effect of autologous serum. These abnormalities may account for the increased infection and mortality rates in anergic patients. Skin testing with five standard antigens has identified 110 anergic (A) or relatively anergic (RA) patients in whom neutrophil chemotaxis (CTX) and bactericidal function (NBF), T-lymphocyte rosettes, mixed lymphocyte culture (MLC), cell-mediated lympholysis (CML), and blastogenic factor (BF) were studied. The MLC, CML and BF were normal in the patients studied, and were not clinically helpful. Neutrophil CTX in 19 controls was 117.5 ± 1.6 u whereas in 40 A patients, neutrophils migrated 81.7 ± 2.3 u and in 15 RA patients 97.2 ± 3.8 u (P < 0.01). In 14 patients whose skin tests converted to normal, neutrophil migration improved from 78.2 ± 5.4 u to 107.2 ± 4.0 u (P < 0.01). Incubation of A or control neutrophils in A serum reduced migration in A patients from 93 ± 3.7 u to 86.2 ± 3.5 u (P < 0.01) and in normals from 121.2 ± 1.6 u to 103.6 ± 2.6 u (P < 0.001). The per cent rosette forming cells in 66 A patients was 42.5 ± 3.1 compared to 53.6 ± 2.8 in normal responders (P < 0.02). Incubation of normal lymphocytes in anergic serum further reduced rosetting by 30%. Restoration of delayed hypersensitivity responses and concurrent improvement in cellular and serum components of host defense were correlated with maintenance of adequate nutrition and aggressive surgical drainage

  7. Increased Host Investment in Extrafloral Nectar (EFN) Improves the Efficiency of a Mutualistic Defensive Service

    PubMed Central

    González-Teuber, Marcia; Silva Bueno, Juan Carlos; Heil, Martin; Boland, Wilhelm

    2012-01-01

    Extrafloral nectar (EFN) plays an important role as plant indirect defence through the attraction of defending ants. Like all rewards produced in the context of a mutualism, however, EFN is in danger of being exploited by non-ant consumers that do not defend the plant against herbivores. Here we asked whether plants, by investing more in EFN, can improve their indirect defence, or rather increase the risk of losing this investment to EFN thieves. We used the obligate plant-ant Acacia-Pseudomyrmex system and examined experimentally in the field during the dry and the rainy seasons how variations in EFN secretion are related to (i) ant activity, to (ii) the ant-mediated defence against herbivores and (iii) the exploitation of EFN by non-ant consumers. Extrafloral investment enhanced ant recruitment and was positively related to the ant mediated defence against herbivores. The ant-mediated protection from exploiters also increased in proportion to the nectar sugar concentration. Although the daily peak of EFN production coincided with the highest activity of EFN thieves, Pseudomyrmex ferrugineus ants protected this resource effectively from exploiters. Nevertheless, the defensive effects by ants differed among seasons. During the dry season, plants grew slower and secreted more EFN than in the rainy season, and thus, experienced a higher level of ant-mediated indirect defence. Our results show that an increased plant investment in an indirect defence trait can improve the resulting defensive service against both herbivores and exploiters. EFN secretion by obligate ant-plants represents a defensive trait for which the level of investment correlates positively with the beneficial effects obtained. PMID:23056362

  8. POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes.

    PubMed

    Zhou, Haixia; Brekman, Angelika; Zuo, Wu-Lin; Ou, Xuemei; Shaykhiev, Renat; Agosto-Perez, Francisco J; Wang, Rui; Walters, Matthew S; Salit, Jacqueline; Strulovici-Barel, Yael; Staudt, Michelle R; Kaner, Robert J; Mezey, Jason G; Crystal, Ronald G; Wang, Guoqing

    2016-04-01

    In the process of seeking novel lung host defense regulators by analyzing genome-wide RNA sequence data from normal human airway epithelium, we detected expression of POU domain class 2-associating factor 1 (POU2AF1), a known transcription cofactor previously thought to be expressed only in lymphocytes. Lymphocyte contamination of human airway epithelial samples obtained by bronchoscopy and brushing was excluded by immunohistochemistry staining, the observation of upregulation of POU2AF1 in purified airway basal stem/progenitor cells undergoing differentiation, and analysis of differentiating single basal cell clones. Lentivirus-mediated upregulation of POU2AF1 in airway basal cells induced upregulation of host defense genes, including MX1, IFIT3, IFITM, and known POU2AF1 downstream genes HLA-DRA, ID2, ID3, IL6, and BCL6. Interestingly, expression of these genes paralleled changes of POU2AF1 expression during airway epithelium differentiation in vitro, suggesting POU2AF1 helps to maintain a host defense tone even in pathogen-free condition. Cigarette smoke, a known risk factor for airway infection, suppressed POU2AF1 expression both in vivo in humans and in vitro in human airway epithelial cultures, accompanied by deregulation of POU2AF1 downstream genes. Finally, enhancing POU2AF1 expression in human airway epithelium attenuated the suppression of host defense genes by smoking. Together, these findings suggest a novel function of POU2AF1 as a potential regulator of host defense genes in the human airway epithelium. PMID:26927796

  9. Macrophage Migration Inhibitory Factor Contributes to Host Defense against Acute Trypanosoma cruzi Infection

    PubMed Central

    Reyes, José L.; Terrazas, Luis I.; Espinoza, Bertha; Cruz-Robles, David; Soto, Virgilia; Rivera-Montoya, Irma; Gómez-García, Lorena; Snider, Heidi; Satoskar, Abhay R.; Rodríguez-Sosa, Miriam

    2006-01-01

    Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is involved in the host defense against several pathogens. Here we used MIF−/− mice to determine the role of endogenous MIF in the regulation of the host immune response against Trypanosoma cruzi infection. MIF−/− mice displayed high levels of blood and tissue parasitemia, developed severe heart and skeletal muscle immunopathology, and succumbed to T. cruzi infection faster than MIF+/+ mice. The enhanced susceptibility of MIF−/− mice to T. cruzi was associated with reduced levels of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-12 (IL-12), IL-18, gamma interferon (IFN-γ), and IL-1β, in their sera and reduced production of IL-12, IFN-γ, and IL-4 by spleen cells during the early phase of infection. At all time points, antigen-stimulated splenocytes from MIF+/+ and MIF−/− mice produced comparable levels of IL-10. MIF−/− mice also produced significantly less Th1-associated antigen-specific immunoglobulin G2a (IgG2a) throughout the infection, but both groups produced comparable levels of Th2-associated IgG1. Lastly, inflamed hearts from T. cruzi-infected MIF−/− mice expressed increased transcripts for IFN-γ, but fewer for IL-12 p35, IL-12 p40, IL-23, and inducible nitric oxide synthase, compared to MIF+/+ mice. Taken together, our findings show that MIF plays a role in controlling acute T. cruzi infection. PMID:16714544

  10. Apoptosis as a host defense mechanism in Crassostrea virginica and its modulation by Perkinsus marinus.

    PubMed

    Hughes, Francis M; Foster, Brent; Grewal, Snimar; Sokolova, Inna M

    2010-08-01

    Dermo disease caused by the obligatory intracellular protozoan Perkinsus marinus causes extensive oyster mortalities leading to tremendous losses in the oyster industry and damage to estuarine ecosystems. To better understand the mechanisms of the parasite's evasion of the host immune defense system, we have investigated the molecular mechanisms of P.marinus-induced inhibition of apoptosis in oyster cells as a potential parasite's survival strategy. We found that P. marinus modulates apoptosis of oyster immune cells (hemocytes) in a way that may help the parasite to establish infection. We found an increase in apoptosis in the initial stages of infection in vitro and in vivo, consistent with a host response to this intracellular parasite. During infection with highly virulent strains of P. marinus, this was followed by suppression and a return of apoptosis to basal levels 8-24 h post-infection, strongly indicating the parasite-induced inhibition of the immune response. In contrast, during infections with intermediate or low virulence strains of P. marinus, a transient suppression of apoptosis 4-8 h post-infection was followed by sustained elevation of hemocyte apoptosis at later stages, indicating that hemocytes were able to overcome the parasite-induced suppression and successfully combat the infection. Studies of the mechanisms of P. marinus-induced apoptosis indicated that the early post-infection stimulation of apoptosis is caspase-independent. However, this process can be driven (although to a lesser degree) by the killed parasite, suggesting that oyster hemocytes respond to cell surface molecules of P. marinus. Overall, this study provides novel insights into pathogen-induced modulation of apoptosis and its role in parasite virulence and establishment of infections. PMID:20371290

  11. Iron acquisition from Pseudomonas aeruginosa siderophores by human phagocytes: an additional mechanism of host defense through iron sequestration?

    PubMed

    Britigan, B E; Rasmussen, G T; Olakanmi, O; Cox, C D

    2000-03-01

    Chelation of iron to iron-binding proteins is a strategy of host defense. Some pathogens counter this via the secretion of low-molecular-weight iron-chelating agents (siderophores). Human phagocytes possess a high-capacity mechanism for iron acquisition from low-molecular-weight iron chelates. Efficient acquisition and sequestration of iron bound to bacterial siderophores by host phagocytes could provide a secondary mechanism to limit microbial access to iron. In the present work we report that human neutrophils, macrophages, and myeloid cell lines can acquire iron from the two Pseudomonas aeruginosa siderophores. Analogous to iron acquisition from other low-molecular-weight chelates, iron acquisition from the siderophores is ATP independent, induced by multivalent cationic metals, and unaffected by inhibitors of endocytosis and pinocytosis. In vivo, this process could serve as an additional mechanism of host defense to limit iron availability to invading siderophore-producing microbes. PMID:10678937

  12. Iron Acquisition from Pseudomonas aeruginosa Siderophores by Human Phagocytes: an Additional Mechanism of Host Defense through Iron Sequestration?

    PubMed Central

    Britigan, Bradley E.; Rasmussen, George T.; Olakanmi, Oyebode; Cox, Charles D.

    2000-01-01

    Chelation of iron to iron-binding proteins is a strategy of host defense. Some pathogens counter this via the secretion of low-molecular-weight iron-chelating agents (siderophores). Human phagocytes possess a high-capacity mechanism for iron acquisition from low-molecular-weight iron chelates. Efficient acquisition and sequestration of iron bound to bacterial siderophores by host phagocytes could provide a secondary mechanism to limit microbial access to iron. In the present work we report that human neutrophils, macrophages, and myeloid cell lines can acquire iron from the two Pseudomonas aeruginosa siderophores. Analogous to iron acquisition from other low-molecular-weight chelates, iron acquisition from the siderophores is ATP independent, induced by multivalent cationic metals, and unaffected by inhibitors of endocytosis and pinocytosis. In vivo, this process could serve as an additional mechanism of host defense to limit iron availability to invading siderophore-producing microbes. PMID:10678937

  13. Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense

    PubMed Central

    Rosenberg, Helene F.

    2015-01-01

    The eosinophil-derived neurotoxin (EDN/RNase2) and its divergent orthologs, the mouse eosinophil-associated RNases (mEars), are prominent secretory proteins of eosinophilic leukocytes and are all members of the larger family of RNase A-type ribonucleases. While EDN has broad antiviral activity, targeting RNA viruses via mechanisms that may require enzymatic activity, more recent studies have elucidated how these RNases may generate host defense via roles in promoting leukocyte activation, maturation, and chemotaxis. This review provides an update on recent discoveries, and highlights the versatility of this family in promoting innate immunity. PMID:26184157

  14. A miniature mimic of host defense peptides with systemic antibacterial efficacy

    SciTech Connect

    Sarig, Hadar; Livne, Liran; Held-Kuznetsov, Victoria; Zaknoon, Fadia; Ivankin, Andrey; Gidalevitz, David; Mor, Amram

    2010-08-23

    Oligomers of acylated lysines (OAKs) are synthetic mimics of host defense peptides (HDPs) with promising antimicrobial properties. Here we challenged the OAK concept for its ability to generate both systemically efficient and economically viable lead compounds for fighting multidrug-resistant bacteria. We describe the design and characterization of a miniature OAK composed of only 3 lysyls and 2 acyls (designated C{sub 12({omega}7)}K-{beta}{sub 12}) that preferentially targets gram-positive species by a bacteriostatic mode of action. To gain insight into the mechanism of action, we examined the interaction of OAK with various potential targets, including phospholipid bilayers, using surface plasmon resonance, and Langmuir monolayers, using insertion assays, epifluorescence microscopy, and grazing incidence X-ray diffraction, in a complementary manner. Collectively, the data support the notion that C{sub 12({omega}7)}K-{beta}{sub 12} damages the plasma-membrane architecture similarly to HDPs, that is, following a near-classic 2-step interaction including high-affinity electrostatic adhesion and a subsequent shallow insertion that was limited to the phospholipid head group region. Notably, preliminary acute toxicity and efficacy studies performed with mouse models of infection have consolidated the potential of OAK for treating bacterial infections, including systemic treatments of methicillin-resistant Staphylococcus aureus. Such simple yet robust chemicals might be useful for various antibacterial applications while circumventing potential adverse effects associated with cytolytic compounds.

  15. Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism Against the Siderophilic Bacterium Vibrio vulnificus

    PubMed Central

    Arezes, João; Jung, Grace; Gabayan, Victoria; Valore, Erika; Ruchala, Piotr; Gulig, Paul A.; Ganz, Tomas; Nemeth, Elizabeta; Bulut, Yonca

    2014-01-01

    SUMMARY Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus, and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth, and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia. PMID:25590758

  16. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction.

    PubMed

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de Los Santos, Berta; Arroyo, Francisco T; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

  17. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction

    PubMed Central

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de los Santos, Berta; Arroyo, Francisco T.; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L.

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

  18. Plant defense activators: applications and prospects in cereal crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review addresses the current understanding of the plant immune response and the molecular mechanisms responsible for systemic acquired resistance as well as the phenomenon of "priming" in plant defense. A detailed discussion of the role of salicylic acid in activating the plant transcription c...

  19. Secretory leukocyte protease inhibitor (SLPI), a multifunctional protein in the host defense response.

    PubMed

    Majchrzak-Gorecka, Monika; Majewski, Pawel; Grygier, Beata; Murzyn, Krzysztof; Cichy, Joanna

    2016-04-01

    Secretory leukocyte protease inhibitor (SLPI), a ∼12kDa nonglycosylated cationic protein, is emerging as an important regulator of innate and adaptive immunity and as a component of tissue regenerative programs. First described as an inhibitor of serine proteases such as neutrophil elastase, this protein is increasingly recognized as a molecule that benefits the host via its anti-proteolytic, anti-microbial and immunomodulatory activities. Here, we discuss the diverse functions of SLPI. Moreover, we review several novel layers of SLPI-mediated control that protect the host from excessive/dysregulated inflammation typical of infectious, allergic and autoinflammatory diseases and that support healing responses through affecting cell proliferation, differentiation and apoptosis. PMID:26718149

  20. Herbivore Diet Breadth and Host Plant Defense Mediate the Tri-Trophic Effects of Plant Toxins on Multiple Coccinellid Predators

    PubMed Central

    Katsanis, Angelos; Rasmann, Sergio; Mooney, Kailen A.

    2016-01-01

    Host plant defenses are known to cascade up food chains to influence herbivores and their natural enemies, but how herbivore and predator traits and identity mediate such tri-trophic dynamics is largely unknown. We assessed the influence of plant defense on aphid and coccinellid performance in laboratory trials with low- vs. high-glucosinolate varieties of Brassica napus, a dietary specialist (Brevicoryne brassicae) and generalist (Myzus persicae) aphid, and five species of aphidophagous coccinellids. The performance of the specialist and generalist aphids was similar and unaffected by variation in plant defense. Aphid glucosinolate concentration and resistance to predators differed by aphid species and host plant defense, and these effects acted independently. With respect to aphid species, the dietary generalist aphid (vs. specialist) had 14% lower glucosinolate concentration and coccinellid predators ate three-fold more aphids. With respect to host plant variety, the high-glucosinolate plants (vs. low) increased aphid glucosinolate concentration by 21%, but had relatively weak effects on predation by coccinellids and these effects varied among coccinellid species. In turn, coccinellid performance was influenced by the interactive effects of plant defense and aphid species, as the cascading, indirect effect of plant defense was greater when feeding upon the specialist than generalist aphid. When feeding upon specialist aphids, low- (vs. high-) glucosinolate plants increased coccinellid mass gain by 78% and accelerated development by 14%. In contrast, when feeding upon generalist aphids, low- (vs. high-) glucosinolate plants increased coccinellid mass gain by only 11% and had no detectable effect on development time. These interactive effects of plant defense and aphid diet breadth on predator performance also varied among coccinellid species; the indirect negative effects of plant defenses on predator performance was consistent among the five predators when

  1. Herbivore Diet Breadth and Host Plant Defense Mediate the Tri-Trophic Effects of Plant Toxins on Multiple Coccinellid Predators.

    PubMed

    Katsanis, Angelos; Rasmann, Sergio; Mooney, Kailen A

    2016-01-01

    Host plant defenses are known to cascade up food chains to influence herbivores and their natural enemies, but how herbivore and predator traits and identity mediate such tri-trophic dynamics is largely unknown. We assessed the influence of plant defense on aphid and coccinellid performance in laboratory trials with low- vs. high-glucosinolate varieties of Brassica napus, a dietary specialist (Brevicoryne brassicae) and generalist (Myzus persicae) aphid, and five species of aphidophagous coccinellids. The performance of the specialist and generalist aphids was similar and unaffected by variation in plant defense. Aphid glucosinolate concentration and resistance to predators differed by aphid species and host plant defense, and these effects acted independently. With respect to aphid species, the dietary generalist aphid (vs. specialist) had 14% lower glucosinolate concentration and coccinellid predators ate three-fold more aphids. With respect to host plant variety, the high-glucosinolate plants (vs. low) increased aphid glucosinolate concentration by 21%, but had relatively weak effects on predation by coccinellids and these effects varied among coccinellid species. In turn, coccinellid performance was influenced by the interactive effects of plant defense and aphid species, as the cascading, indirect effect of plant defense was greater when feeding upon the specialist than generalist aphid. When feeding upon specialist aphids, low- (vs. high-) glucosinolate plants increased coccinellid mass gain by 78% and accelerated development by 14%. In contrast, when feeding upon generalist aphids, low- (vs. high-) glucosinolate plants increased coccinellid mass gain by only 11% and had no detectable effect on development time. These interactive effects of plant defense and aphid diet breadth on predator performance also varied among coccinellid species; the indirect negative effects of plant defenses on predator performance was consistent among the five predators when

  2. Anatomy and Physiology of the Urinary Tract: Relation to Host Defense and Microbial Infection

    PubMed Central

    HICKLING, DUANE R.; SUN, TUNG-TIEN; WU, XUE-RU

    2015-01-01

    The urinary tract exits to a body surface area that is densely populated by a wide range of microbes. Yet, under most normal circumstances, it is typically considered sterile, i.e., devoid of microbes, a stark contrast to the gastrointestinal and upper respiratory tracts where many commensal and pathogenic microbes call home. Not surprisingly, infection of the urinary tract over a healthy person’s lifetime is relatively infrequent, occurring once or twice or not at all for most people. For those who do experience an initial infection, the great majority (70% to 80%) thankfully do not go on to suffer from multiple episodes. This is a far cry from the upper respiratory tract infections, which can afflict an otherwise healthy individual countless times. The fact that urinary tract infections are hard to elicit in experimental animals except with inoculum 3–5 orders of magnitude greater than the colony counts that define an acute urinary infection in humans (105 cfu/ml), also speaks to the robustness of the urinary tract defense. How can the urinary tract be so effective in fending off harmful microbes despite its orifice in a close vicinity to that of the microbe-laden gastrointestinal tract? While a complete picture is still evolving, the general consensus is that the anatomical and physiological integrity of the urinary tract is of paramount importance in maintaining a healthy urinary tract. When this integrity is breached, however, the urinary tract can be at a heightened risk or even recurrent episodes of microbial infections. In fact, recurrent urinary tract infections are a significant cause of morbidity and time lost from work and a major challenge to manage clinically. Additionally, infections of the upper urinary tract often require hospitalization and prolonged antibiotic therapy. In this chapter, we provide an overview of the basic anatomy and physiology of the urinary tract with an emphasis on their specific roles in host defense. We also highlight the

  3. Venom of Parasitoid Pteromalus puparum Impairs Host Humoral Antimicrobial Activity by Decreasing Host Cecropin and Lysozyme Gene Expression

    PubMed Central

    Fang, Qi; Wang, Bei-Bei; Ye, Xin-Hai; Wang, Fei; Ye, Gong-Yin

    2016-01-01

    Insect host/parasitoid interactions are co-evolved systems in which host defenses are balanced by parasitoid mechanisms to disable or hide from host immune effectors. Here, we report that Pteromalus puparum venom impairs the antimicrobial activity of its host Pieris rapae. Inhibition zone results showed that bead injection induced the antimicrobial activity of the host hemolymph but that venom inhibited it. The cDNAs encoding cecropin and lysozyme were screened. Relative quantitative PCR results indicated that all of the microorganisms and bead injections up-regulated the transcript levels of the two genes but that venom down-regulated them. At 8 h post bead challenge, there was a peak in the transcript level of the cecropin gene, whereas the peak of lysozyme gene occurred at 24 h. The transcripts levels of the two genes were higher in the granulocytes and fat body than in other tissues. RNA interference decreased the transcript levels of the two genes and the antimicrobial activity of the pupal hemolymph. Venom injections similarly silenced the expression of the two genes during the first 8 h post-treatment in time- and dose-dependent manners, after which the silence effects abated. Additionally, recombinant cecropin and lysozyme had no significant effect on the emergence rate of pupae that were parasitized by P. puparum females. These findings suggest one mechanism of impairing host antimicrobial activity by parasitoid venom. PMID:26907346

  4. Venom of Parasitoid Pteromalus puparum Impairs Host Humoral Antimicrobial Activity by Decreasing Host Cecropin and Lysozyme Gene Expression.

    PubMed

    Fang, Qi; Wang, Bei-Bei; Ye, Xin-Hai; Wang, Fei; Ye, Gong-Yin

    2016-02-01

    Insect host/parasitoid interactions are co-evolved systems in which host defenses are balanced by parasitoid mechanisms to disable or hide from host immune effectors. Here, we report that Pteromalus puparum venom impairs the antimicrobial activity of its host Pieris rapae. Inhibition zone results showed that bead injection induced the antimicrobial activity of the host hemolymph but that venom inhibited it. The cDNAs encoding cecropin and lysozyme were screened. Relative quantitative PCR results indicated that all of the microorganisms and bead injections up-regulated the transcript levels of the two genes but that venom down-regulated them. At 8 h post bead challenge, there was a peak in the transcript level of the cecropin gene, whereas the peak of lysozyme gene occurred at 24 h. The transcripts levels of the two genes were higher in the granulocytes and fat body than in other tissues. RNA interference decreased the transcript levels of the two genes and the antimicrobial activity of the pupal hemolymph. Venom injections similarly silenced the expression of the two genes during the first 8 h post-treatment in time- and dose-dependent manners, after which the silence effects abated. Additionally, recombinant cecropin and lysozyme had no significant effect on the emergence rate of pupae that were parasitized by P. puparum females. These findings suggest one mechanism of impairing host antimicrobial activity by parasitoid venom. PMID:26907346

  5. Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice

    PubMed Central

    Graham, Daniel B.; Robertson, Charles M.; Bautista, Jhoanne; Mascarenhas, Francesca; Diacovo, M. Julia; Montgrain, Vivianne; Lam, Siu Kit; Cremasco, Viviana; Dunne, W. Michael; Faccio, Roberta; Coopersmith, Craig M.; Swat, Wojciech

    2007-01-01

    Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C–γ2 (PLC-γ2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-γ2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav. PMID:17932569

  6. Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice.

    PubMed

    Graham, Daniel B; Robertson, Charles M; Bautista, Jhoanne; Mascarenhas, Francesca; Diacovo, M Julia; Montgrain, Vivianne; Lam, Siu Kit; Cremasco, Viviana; Dunne, W Michael; Faccio, Roberta; Coopersmith, Craig M; Swat, Wojciech

    2007-11-01

    Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C-gamma2 (PLC-gamma2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-gamma2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav. PMID:17932569

  7. Activation of Phospholipase A by Plant Defense Elicitors.

    PubMed Central

    Chandra, S.; Heinstein, P. F.; Low, P. S.

    1996-01-01

    Participation of phospholipase A (PLase A) in plant signal transduction has been documented for auxin stimulation of growth but not for elicitation of any plant defense response. In this paper, we report two independent assays for monitoring PLase A induction in plant cells and have used these assays to evaluate whether transduction of defense-related signals might require PLase A activation. Oligogalacturonic acid, a potent elicitor of the soybean (Glycine max) H2O2 burst, was unable to stimulate endogenous PLase A, suggesting that PLase A activation is not an obligate intermediate in the oligogalacturonic acid-induced burst pathway. In contrast, harpin and an extract from the pathogenic fungus Verticillium dahliae both stimulated the oxidative burst and promoted a rapid increase in PLase A activity. To evaluate the possible role of this inducible PLase A activity in transducing the oxidative burst, we tested the effect of chlorpromazine-HCl, a PLase A inhibitor on elicitor-stimulated burst activity. Pretreatment with chloropromazine was found to inhibit the H2O2 burst triggered by V. dahliae extract at the same concentration at which it blocked PLase A activation. In contrast, neither the harpin- nor oligogalacturonic acid-induced burst was altered by addition of chlorpromazine. These data suggest that PLase A stimulation may be important in certain elicitor-induced oxidative bursts (e.g. V. dahliae) and that other elicitors such as oligogalacturonic acid and harpin must operate through independent signaling intermediates to activate the same defense response. PMID:12226235

  8. Resistance and Susceptibility to Malarial Infection: A Host Defense Strategy against Malaria

    PubMed Central

    BAKIR, Hanaa; YONES, Doaa; GALAL, Lamia; HUSEEIN, Enas

    2015-01-01

    Background: In an effort to understand what limits the virulence of malaria parasites in relation to the host genetic and immunogenic background, we investigated the possibility that the parasite and host genotype crossover interactions constrain virulence. Methods: Two groups of mice from different genotypes were used (C57BL/6 (B6) and DBA/2 mice). The mice were infected with a virulent parasite line Plasmodium yoelii 17XL (P. yoelii 17XL). Parasitemia, hematocrit value and lymphocytes yielded by livers and spleens were evaluated. Fluorescence Activated Cell Sorting (FACS) analysis illustrated phenotypic characterization of lymphocytes. Results: Infection with P. yoelii 17XL did not result in the death of DBA/2 mice. In contrast, B6 mice developed significantly high parasitemia and succumbed to death. Using (FACS) analysis, DBA/2 mice were found to experience a marked expansion of interleukin (IL)-2Rβ+ CD3int cells and γδ T cells in the liver, especially in the recovery phase. The expansion of unconventional T cells (i.e. B220+ T cells) was also marked in DBA/2 mice. Conclusion: The outcome of murine malaria infections depends on the dynamic interplay between the immune-mediator and the genotype of the host. PMID:26811732

  9. Magnetic activity of planet-hosting stars

    NASA Astrophysics Data System (ADS)

    Poppenhaeger, Katja

    2011-05-01

    Magnetic activity in cool stars is a widely observed phenomenon, however it is still far from being understood. How fundamental stellar parameters like mass and rotational period quantitatively cause a stellar magnetic field which manifests itself in features such as spots, flares and high-energy coronal emission is a lively area of research in solar and stellar astrophysics. Especially for planet-hosting stars, stellar activity profiles are very interesting as exoplanets are affected by high-energy radiation, both at the time of planet formation as well as during the further lifetime of a star-planet system. In extreme cases, the atmosphere of a planet very close to its host star can be strongly heated by the stellar X-ray and EUV emission and finally escape the planet's gravitational attraction, so that the atmosphere of the planet evaporates over time. Theoretically, planets can also affect their host star's magnetic activity. In analogy to processes in binary stars which lead to enhanced - both overall and periodically varying - activity levels, also giant planets might influence the stellar activity by tidal or magnetic interaction processes, however on a weaker level than in binaries. Some indications for such interactions exist from chromospheric measurements in stars with Hot Jupiters. In this thesis I investigate the magnetic activity of planet-hosting stars and especially possible effects from star-planet interactions with an emphasis on stellar coronae in X-rays. I tested a complete sample of all known planet-hosting stars within 30 pc distance from the Sun for correlations of stellar X-ray properties with planetary parameters. A significant correlation exists between the stellar X-ray luminosity and the product of planetary mass and inverse semimajor axis. However, this could be traced back to a selection effect introduced by planetary detection methods. For stars in the solar neighborhood, planets are mainly detected by radial velocity shifts in the

  10. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections.

    PubMed

    Han, SeungHye; Mallampalli, Rama K

    2015-05-01

    Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing. Surfactant is enriched with a relatively unique phospholipid, termed dipalmitoylphosphatidylcholine, and four surfactant-associated proteins, SP-A, SP-B, SP-C, and SP-D. The hydrophobic proteins, SP-B and SP-C, together with dipalmitoylphosphatidylcholine, confer surface tension-lowering properties to the material. The more hydrophilic surfactant components, SP-A and SP-D, participate in pulmonary host defense and modify immune responses. Specifically, SP-A and SP-D bind and partake in the clearance of a variety of bacterial, fungal, and viral pathogens and can dampen antigen-induced immune function of effector cells. Emerging data also show immunosuppressive actions of some surfactant-associated lipids, such as phosphatidylglycerol. Conversely, microbial pathogens in preclinical models impair surfactant synthesis and secretion, and microbial proteinases degrade surfactant-associated proteins. Deficiencies of surfactant components are classically observed in the neonatal respiratory distress syndrome, where surfactant replacement therapies have been the mainstay of treatment. However, functional or compositional deficiencies of surfactant are also observed in a variety of acute and chronic lung disorders. Increased surfactant is seen in pulmonary alveolar proteinosis, a disorder characterized by a functional deficiency of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies. Genetic polymorphisms of some surfactant proteins such as SP-C are linked to interstitial pulmonary fibrosis. Here, we briefly review the composition, antimicrobial properties, and relevance of pulmonary surfactant to lung disorders and present its therapeutic implications. PMID:25742123

  11. Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens.

    PubMed

    Rowe, Jared H; Ertelt, James M; Aguilera, Marijo N; Farrar, Michael A; Way, Sing Sing

    2011-07-21

    Although pregnancy confers unique susceptibility to infection, the pregnancy-associated immune defects that erode host defense remain largely undefined. Herein, we demonstrate that expansion of immune-suppressive Foxp3(+) regulatory T cells (Tregs) which occurs physiologically during pregnancy or when experimentally induced in transgenic mice caused enhanced susceptibility to prenatal pathogens including Listeria and Salmonella species. Reciprocally, infection susceptibility was uniformly reduced with Treg ablation. Importantly however, the sustained expansion of maternal Tregs was essential for maintaining immune tolerance to the developing fetus because even partial transient ablation of Foxp3-expressing cells fractured maternal tolerance to fetal antigen and triggered fetal resorption. Interestingly, Foxp3 cell-intrinsic defects in the immune-suppressive cytokine IL-10 alone were sufficient to override Treg-mediated infection susceptibility, while IL-10 was nonessential for sustaining pregnancy. Thus, maternal Treg expansion required for sustaining pregnancy creates naturally occurring holes in host defense that confer prenatal infection susceptibility. PMID:21767812

  12. IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection.

    PubMed

    Nabekura, Tsukasa; Girard, Jean-Philippe; Lanier, Lewis L

    2015-06-15

    NK cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. In this study, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse CMV (MCMV) infection. Although ST2-deficient (Il1rl1 (-/-)) Ly49H(+) NK cells develop normally and differentiate into memory cells after MCMV infection, naive and memory Il1rl1 (-/-) Ly49H(+) NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 Ag-specific proliferation of Ly49H(+) NK cells in vitro. Thus, an IL-33/ST2 signaling axis in NK cells contributes to host defense against MCMV. PMID:25926677

  13. Feeding specialization and host-derived chemical defense in Chrysomeline leaf beetles did not lead to an evolutionary dead end

    PubMed Central

    Termonia, Arnaud; Hsiao, Ting H.; Pasteels, Jacques M.; Milinkovitch, Michel C.

    2001-01-01

    Combination of molecular phylogenetic analyses of Chrysomelina beetles and chemical data of their defensive secretions indicate that two lineages independently developed, from an ancestral autogenous metabolism, an energetically efficient strategy that made the insect tightly dependent on the chemistry of the host plant. However, a lineage (the interrupta group) escaped this subordination through the development of a yet more derived mixed metabolism potentially compatible with a large number of new host-plant associations. Hence, these analyses on leaf beetles document a mechanism that can explain why high levels of specialization do not necessarily lead to “evolutionary dead ends.” PMID:11259651

  14. Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

    PubMed Central

    Suram, Saritha; Silveira, Lori J.; Mahaffey, Spencer; Brown, Gordon D.; Bonventre, Joseph V.; Williams, David L.; Gow, Neil A. R.; Bratton, Donna L.; Murphy, Robert C.; Leslie, Christina C.

    2013-01-01

    The role of Group IVA cytosolic phospholipase A2 (cPLA2α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA2α+/+ than cPLA2α-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2α+/+ than cPLA2α-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2α+/+ and cPLA2α-/- macrophages (3 h) was compared by microarray. cPLA2α+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2α-/- macrophages (≥2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnfα, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifnγ, several IFNγ-inducible GTPases). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2α+/+ macrophages. Representative genes expressed lower in cPLA2α+/+ macrophages (Tnfα, Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation. PMID:23950842

  15. Naturally Produced Defensive Alkenal Compounds Activate TRPA1.

    PubMed

    Blair, Nathaniel T; Philipson, Benjamin I; Richards, Paige M; Doerner, Julia F; Segura, Abraham; Silver, Wayne L; Clapham, David E

    2016-05-01

    (E)-2-alkenals are aldehydes containing an unsaturated bond between the alpha and beta carbons. 2-alkenals are produced by many organisms for defense against predators and secretions containing (E)-2-alkenals cause predators to stop attacking and allow the prey to escape. Chemical ecologists have described many alkenal compounds with 3-20 carbons common, having varied positions of double bonds and substitutions. How do these defensive alkenals act to deter predators? We have tested the effects of (E)-2-alkenals with 6-12 carbons on transient receptor potential channels (TRP) commonly found in sensory neurons. We find that (E)-2-alkenals activate transient receptor potential ankyrin subtype 1 (TRPA1) at low concentrations-EC50s 10-100 µM (in 0 added Ca(2+) external solutions). Other TRP channels were either weakly activated (TRPV1, TRPV3) or insensitive (TRPV2, TRPV4, TRPM8). (E)-2-alkenals may activate TRPA1 by modifying cysteine side chains. However, target cysteines include others beyond the 3 in the amino-terminus implicated in activation, as a channel with cysteines at 621, 641, 665 mutated to serine responded robustly. Related chemicals, including the aldehydes hexanal and decanal, and (E)-2-hexen-1-ol also activated TRPA1, but with weaker potency. Rat trigeminal nerve recordings and behavioral experiments showed (E)-2-hexenal was aversive. Our results suggest that TRPA1 is likely a major target of these commonly used defensive chemicals. PMID:26843529

  16. Bacterial evasion of host immune defense: Yersinia enterocolitica encodes a suppressor for tumor necrosis factor alpha expression.

    PubMed Central

    Beuscher, H U; Rödel, F; Forsberg, A; Röllinghoff, M

    1995-01-01

    The ability of the enteropathogenic Yersinia enterocolitica to survive and proliferate in host tissue depends on a 70-kb plasmid known to encode a number of released Yersinia outer proteins that act as virulence factors by inducing cytotoxicity and inhibiting phagocytosis. This study demonstrates that one of the Yersinia outer proteins, the 41-kDa YopB, suppresses the production of tumor necrosis factor alpha (TNF-alpha), a macrophage-derived cytokine with central roles in the regulation of immune and inflammatory responses to infection. This conclusion is based on several lines of evidence. First, in macrophage cultures, suppression of TNF-alpha mRNA expression was induced by culture supernatant (CS+) of plasmid-bearing yersiniae, the effect which was blocked by anti-YopB antiserum. Second, suppression of TNF-alpha production, but not of interleukin-1 (IL-1) and IL-6, was induced by purified YopB. Third, in Yersinia-infected mice, no increase in TNF-alpha mRNA expression was observed in Peyer's patches, the primary site of bacterial invasion, compared with IL-1 (alpha and beta) mRNA. Finally, administration of anti-YopB antiserum to mice prior to infection with Y. enterocolitica increased TNF activity levels in Peyer's patches and coincided with a reduction in bacterial growth. The results thus provide direct evidence for a secreted eubacterial virulence factor that mediates selective suppression of TNF-alpha production. Although suppression of this single cytokine response is probably not sufficient to facilitate survival of the infecting organisms, the results suggest that suppression of TNF-alpha production by YopB significantly contributes to the evasion of Y. enterocolitica from antibacterial host defense. PMID:7890384

  17. Key Role for Scavenger Receptor B-I in the Integrative Physiology of Host Defense during Bacterial Pneumonia

    PubMed Central

    Gowdy, Kymberly M.; Madenspacher, Jennifer H.; Azzam, Kathleen M.; Gabor, Kristin A.; Janardhan, Kyathanahalli S.; Aloor, Jim J.; Fessler, Michael B.

    2014-01-01

    Scavenger receptor B-I (SR-BI) is a multirecognition receptor that regulates cholesterol trafficking and cardiovascular inflammation. Although it is expressed by neutrophils (PMNs) and lung-resident cells, no role for SR-BI has been defined in pulmonary immunity. Herein, we report that, compared to SR-BI+/+ counterparts, SR-BI−/− mice suffer markedly increased mortality during bacterial pneumonia associated with higher bacterial burden in lung and blood, deficient induction of the stress glucocorticoid corticosterone, higher serum cytokines, and increased organ injury. SR-BI−/− mice had significantly increased PMN recruitment and cytokine production in the infected airspace. This was associated with defective hematopoietic cell-dependent clearance of lipopolysaccharide from the airspace and increased cytokine production by SR-BI−/− macrophages. Corticosterone replacement normalized alveolar neutrophilia but not alveolar cytokines, bacterial burden, or mortality, suggesting that adrenal insufficiency derepresses PMN trafficking to the SR-BI−/− airway in a cytokine-independent manner. Despite enhanced alveolar neutrophilia, SR-BI−/− mice displayed impaired phagocytic killing. Bone marrow chimeras revealed this defect to be independent of the dyslipidemia and adrenal insufficiency of SR-BI−/− mice. During infection, SR-BI−/− PMNs displayed deficient oxidant production and CD11b externalization, and increased surface L-selectin, suggesting defective activation. Taken together, SR-BI coordinates several steps in the integrated neutrophilic host defense response to pneumonia. PMID:25336169

  18. Skin Electroporation of a Plasmid Encoding hCAP-18/LL-37 Host Defense Peptide Promotes Wound Healing

    PubMed Central

    Steinstraesser, Lars; Lam, Martin C; Jacobsen, Frank; Porporato, Paolo E; Chereddy, Kiran Kumar; Becerikli, Mustafa; Stricker, Ingo; Hancock, Robert EW; Lehnhardt, Marcus; Sonveaux, Pierre; Préat, Véronique; Vandermeulen, Gaëlle

    2014-01-01

    Host defense peptides, in particular LL-37, are emerging as potential therapeutics for promoting wound healing and inhibiting bacterial growth. However, effective delivery of the LL-37 peptide remains limiting. We hypothesized that skin-targeted electroporation of a plasmid encoding hCAP-18/LL-37 would promote the healing of wounds. The plasmid was efficiently delivered to full-thickness skin wounds by electroporation and it induced expression of LL-37 in the epithelium. It significantly accelerated reepithelialization of nondiabetic and diabetic wounds and caused a significant VEGFa and interleukin (IL)-6 induction. IL-6 was involved in LL-37–mediated keratinocyte migration in vitro and IL-6 neutralizing antibodies delivered to mice were able to suppress the wound healing activity of the hCAP-18/LL-37 plasmid. In a hindlimb ischemia model, electroporation of the hCAP-18/LL-37 plasmid increased blood perfusion, reduced muscular atrophy, and upregulated the angiogenic chemokines VEGFa and SDF-1a, and their receptors VEGF-R and CXCR-4. These findings demonstrate that a localized gene therapy with LL-37 is a promising approach for the treatment of wounds. PMID:24394186

  19. Multitasking antimicrobial peptides, plant development, and host defense against biotic/abiotic stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crop losses due to pathogens are a major threat to global food security. Plants employ a multilayer defense system against pathogens including use of physical barriers (cell wall), induction of hypersensitive defense response (HR), resistance (R) proteins, and synthesis of antimicrobial peptides (AM...

  20. Small cysteine-rich antifungal proteins from radish: their role in host defense.

    PubMed Central

    Terras, F R; Eggermont, K; Kovaleva, V; Raikhel, N V; Osborn, R W; Kester, A; Rees, S B; Torrekens, S; Van Leuven, F; Vanderleyden, J

    1995-01-01

    Radish seeds have previously been shown to contain two homologous, 5-kD cysteine-rich proteins designated Raphanus sativus-antifungal protein 1 (Rs-AFP1) and Rs-AFP2, both of which exhibit potent antifungal activity in vitro. We now demonstrate that these proteins are located in the cell wall and occur predominantly in the outer cell layers lining different seed organs. Moreover, Rs-AFPs are preferentially released during seed germination after disruption of the seed coat. The amount of released proteins is sufficient to create a microenvironment around the seed in which fungal growth is suppressed. Both the cDNAs and the intron-containing genomic regions encoding the Rs-AFP preproteins were cloned. Transcripts (0.55 kb) hybridizing with an Rs-AFP1 cDNA-derived probe were present in near-mature and mature seeds. Such transcripts as well as the corresponding proteins were barely detectable in healthy uninfected leaves but accumulated systemically at high levels after localized fungal infection. The induced leaf proteins (designated Rs-AFP3 and Rs-AFP4) were purified and shown to be homologous to seed Rs-AFPs and to exert similar antifungal activity in vitro. A chimeric Rs-AFP2 gene under the control of the constitutive cauliflower mosaic virus 35S promoter conferred enhanced resistance to the foliar pathogen Alternaria longipes in transgenic tobacco. The term "plant defensins" is proposed to denote these defense-related proteins. PMID:7780308

  1. Six Hours after Infection, the Metabolic Changes Induced by WSSV Neutralize the Host's Oxidative Stress Defenses.

    PubMed

    Chen, I-Tung; Lee, Der-Yen; Huang, Yun-Tzu; Kou, Guang-Hsiung; Wang, Han-Ching; Chang, Geen-Dong; Lo, Chu-Fang

    2016-01-01

    Levels of intracellular ROS (reactive oxygen species) were significantly increased in hemocytes collected from WSSV-infected shrimp within the first 30-120 min after infection. Measurement of the NADPH/NADP(+) and GSH/GSSG ratios revealed that after a significant imbalance toward the oxidized forms at 2 hpi, redox equilibrium was subsequently restored. Meanwhile, high levels of lactic acid production, elevated NADH/NAD(+) ratios, and metabolic changes in the glycolysis pathway show that the Warburg effect was triggered by the virus. The timing of these changes suggests that WSSV uses this metabolic shift into aerobic glycolysis to counteract the high levels of ROS produced in response to viral infection. We further show that if the Warburg effect is inhibited by chemical inhibition of the PI3K-Akt-mTOR signaling pathway, or if the pentose phosphate pathway is chemically inhibited, then in both cases, the production of intracellular ROS is sustained. We conclude that WSSV uses the PI3K-Akt-mTOR-regulated Warburg effect to restore host redox balance and to counter the ROS produced by the host in response to WSSV infection. We also found that pyruvate kinase activity was inhibited by WSSV. This inhibition is likely to increase the availability of the raw materials essential for WSSV gene expression and replication. PMID:27279169

  2. Variations in hypovirus interactions with the fungal-host RNA-silencing antiviral-defense response.

    PubMed

    Zhang, Xuemin; Shi, Diane; Nuss, Donald L

    2012-12-01

    Hypoviruses Cryphonectria hypovirus 1 (CHV-1)/EP713, CHV-1/Euro7, and CHV-1/EP721, which infect the chestnut blight fungus Cryphonectria parasitica, differ in their degrees of virulence attenuation (hypovirulence), symptom expression, and viral RNA accumulation, even though they share between 90% and 99% amino acid sequence identity. In this report we examine whether this variability is influenced by interactions with the C. parasitica Dicer gene dcl2-dependent RNA-silencing antiviral defense response. The mild symptoms exhibited by strains infected with CHV-1/Euro7 and CHV-1/EP721 relative to those with severe hypovirus CHV-1/EP713 did not correlate with a higher induction of the RNA-silencing pathway. Rather, dcl2 transcripts accumulated to a higher level (∼8-fold) following infection by CHV-1/EP713 than following infection by CHV-1/Euro7 (1.2-fold) or CHV-1/EP721 (1.4-fold). The differences in dcl2 transcript accumulation in response to CHV-1/EP713 and CHV-1/EP721 were unrelated to the suppressor of RNA silencing, p29, encoded by the two viruses. Moreover, the coding strand viral RNA levels increased by 33-, 32-, and 16-fold for CHV-1/EP713, CHV-1/Euro7, and CHV-1/EP721, respectively, in Δdcl2 mutant strains. This indicates that a very robust antiviral RNA-silencing response was induced against all three viruses, even though significant differences in the levels of dcl2 transcript accumulation were observed. Unexpectedly, the severe debilitation previously reported for CHV-1/EP713-infected Δdcl2 mutant strains, and observed here for the CHV-1/Euro7-infected Δdcl2 mutant strains, was not observed with infection by CHV-1/EP721. By constructing chimeric viruses containing portions of CHV-1/EP713 and CHV-1/EP721, it was possible to map the region that is associated with the severe debilitation of the Δdcl2 mutant hosts to a 4.1-kb coding domain located in the central part of the CHV-1/EP713 genome. PMID:22993160

  3. Battle management architectures for active defense against artillery

    NASA Astrophysics Data System (ADS)

    Nugent, John

    2001-08-01

    Rockets, mortars, and artillery (RMA) are widely held, abundant, and inexpensive weapons that historically have been the most lethal 'killers' on the battlefield. The proliferation of non-conventional warheads (chemical and biological) has increased the RMA threat. Recently, new weapons--in particular directed-energy weapons--have shown promise in providing an active defense against RMA. The development and deployment of these advanced weapons is only part of the challenge of providing a total RMA active defense capability. Developing a BMC3I that can support this air battle is also a major challenge. Threat sizes and threat rates of RMA versus traditional air defense threats could easily be higher by one to two orders of magnitude. The implication of this larger threat on the complexity of a BMC3I system is profound. Relative to traditional threats, fighting such an air battle will result in a large demand on sensors to collect information on this dense threat and in a large surge in the dissemination of air picture, control, and status information through the BMC3I network (weapons, sensors, and command posts). A successful BMC3I system must have the architectural features and algorithmic approaches to manage these tasks efficiently. This paper will characterize the magnitude of this problem and discuss architectural and algorithmic challenges.

  4. Physcomitrella patens Activates Defense Responses against the Pathogen Colletotrichum gloeosporioides.

    PubMed

    Reboledo, Guillermo; Del Campo, Raquel; Alvarez, Alfonso; Montesano, Marcos; Mara, Héctor; Ponce de León, Inés

    2015-01-01

    The moss Physcomitrella patens is a suitable model plant to analyze the activation of defense mechanisms after pathogen assault. In this study, we show that Colletotrichum gloeosporioides isolated from symptomatic citrus fruit infects P. patens and cause disease symptoms evidenced by browning and maceration of tissues. After C. gloeosporioides infection, P. patens reinforces the cell wall by the incorporation of phenolic compounds and induces the expression of a Dirigent-protein-like encoding gene that could lead to the formation of lignin-like polymers. C. gloeosporioides-inoculated protonemal cells show cytoplasmic collapse, browning of chloroplasts and modifications of the cell wall. Chloroplasts relocate in cells of infected tissues toward the initially infected C. gloeosporioides cells. P. patens also induces the expression of the defense genes PAL and CHS after fungal colonization. P. patens reporter lines harboring the auxin-inducible promoter from soybean (GmGH3) fused to β-glucuronidase revealed an auxin response in protonemal tissues, cauloids and leaves of C. gloeosporioides-infected moss tissues, indicating the activation of auxin signaling. Thus, P. patens is an interesting plant to gain insight into defense mechanisms that have evolved in primitive land plants to cope with microbial pathogens. PMID:26389888

  5. Physcomitrella patens Activates Defense Responses against the Pathogen Colletotrichum gloeosporioides

    PubMed Central

    Reboledo, Guillermo; del Campo, Raquel; Alvarez, Alfonso; Montesano, Marcos; Mara, Héctor; Ponce de León, Inés

    2015-01-01

    The moss Physcomitrella patens is a suitable model plant to analyze the activation of defense mechanisms after pathogen assault. In this study, we show that Colletotrichum gloeosporioides isolated from symptomatic citrus fruit infects P. patens and cause disease symptoms evidenced by browning and maceration of tissues. After C. gloeosporioides infection, P. patens reinforces the cell wall by the incorporation of phenolic compounds and induces the expression of a Dirigent-protein-like encoding gene that could lead to the formation of lignin-like polymers. C. gloeosporioides-inoculated protonemal cells show cytoplasmic collapse, browning of chloroplasts and modifications of the cell wall. Chloroplasts relocate in cells of infected tissues toward the initially infected C. gloeosporioides cells. P. patens also induces the expression of the defense genes PAL and CHS after fungal colonization. P. patens reporter lines harboring the auxin-inducible promoter from soybean (GmGH3) fused to β-glucuronidase revealed an auxin response in protonemal tissues, cauloids and leaves of C. gloeosporioides-infected moss tissues, indicating the activation of auxin signaling. Thus, P. patens is an interesting plant to gain insight into defense mechanisms that have evolved in primitive land plants to cope with microbial pathogens. PMID:26389888

  6. Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice

    PubMed Central

    Samuelson, D. R.; Assouline, B.; Morre, M.; Shellito, J. E.

    2015-01-01

    Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4+ T lymphocytes are critical for host defense against this infection, but in the absence of CD4+ T lymphocytes, CD8+ T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8+ T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8+ T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-γ)-positive CD8+ central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8+ T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8+ T lymphocytes. PMID:26483405

  7. Neutrophil elastase modulates cytokine expression: contribution to host defense against Pseudomonas aeruginosa-induced pneumonia.

    PubMed

    Benabid, Rym; Wartelle, Julien; Malleret, Laurette; Guyot, Nicolas; Gangloff, Sophie; Lebargy, François; Belaaouaj, Azzaq

    2012-10-12

    There is accumulating evidence that following bacterial infection, the massive recruitment and activation of the phagocytes, neutrophils, is accompanied with the extracellular release of active neutrophil elastase (NE), a potent serine protease. Using NE-deficient mice in a clinically relevant model of Pseudomonas aeruginosa-induced pneumonia, we provide compelling in vivo evidence that the absence of NE was associated with decreased protein and transcript levels of the proinflammatory cytokines TNF-α, MIP-2, and IL-6 in the lungs, coinciding with increased mortality of mutant mice to infection. The implication of NE in the induction of cytokine expression involved at least in part Toll-like receptor 4 (TLR-4). These findings were further confirmed following exposure of cultured macrophages to purified NE. Together, our data suggest strongly for the first time that NE not only plays a direct antibacterial role as it has been previously reported, but released active enzyme can also modulate cytokine expression, which contributes to host protection against P. aeruginosa. In light of our findings, the long held view that considers NE as a prime suspect in P. aeruginosa-associated diseases will need to be carefully reassessed. Also, therapeutic strategies aiming at NE inhibition should take into account the physiologic roles of the enzyme. PMID:22927440

  8. Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling.

    PubMed

    Zhou, Xikun; Ye, Yan; Sun, Yuyang; Li, Xuefeng; Wang, Wenxue; Privratsky, Breanna; Tan, Shirui; Zhou, Zongguang; Huang, Canhua; Wei, Yu-Quan; Birnbaumer, Lutz; Singh, Brij B; Wu, Min

    2015-08-01

    Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca(2+) 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 Ca(2+) entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca(2+) 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 Ca(2+) 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

  9. 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

  10. M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.

    PubMed

    Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R Elaine; Vincent, Isaah S; Burdick, Marie D; Kadl, Alexandra; Mehrad, Borna

    2016-06-15

    Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver. PMID:27183631

  11. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen, Candida albicans

    PubMed Central

    Hise, Amy G.; Tomalka, Jeffrey; Ganesan, Sandhya; Patel, Krupen; Hall, Brian A.; Brown, Gordon D.; Fitzgerald, Katherine A.

    2010-01-01

    SUMMARY Candida albicans is an opportunistic fungal pathogen causing life-threatening mucosal and systemic infections in immunocompromised humans. Using a murine model of mucosal Candida infection we investigated the role of the proinflammatory cytokine IL-1β in host-defense to Candida albicans. We find that the synthesis, processing and release of IL-1β in response to Candida are tightly controlled and first require transcriptional induction, followed by a second signal leading to caspase-1 mediated cleavage of the pro-IL1β cytokine. The known fungal pattern recognition receptorsTLR2 and Dectin-1 regulate IL-1β gene transcription, while the NLRP3 containing pro-inflammatory multiprotein complex, the NLRP3 inflammasome, controls caspase-1 mediated cleavage of pro-IL1β. Furthermore, we show that TLR2, Dectin-1 and NLRP3 are essential for defense against dissemination of mucosal infection and mortality in vivo. Therefore, in addition to sensing bacterial and viral pathogens, the NLRP3 inflammasome senses fungal pathogens and is critical in host defense against Candida. PMID:19454352

  12. Stennis hosts Space Day activities at USM

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Fallon Nettles (left), an Astro Camp counselor at NASA's John C. Stennis Space Center, assists a young fan attending the University of Southern Mississippi football game in Hattiesburg, Miss., on Oct. 17 in launching a balloon 'rocket.' Prior to the game, Stennis Space Center hosted hands-on activities and exhibits for families as part of its first-ever Space Day at USM. The activities were versions of those featured in the daylong and weeklong Astro Camp sessions sponsored by Stennis throughout each year. Stennis Space Center is located in nearby Hancock County and is the nation's premier rocket engine testing facility. The USM activities were part of Stennis' ongoing effort to educate people about the NASA mission and to introduce children and young people to space and space exploration.

  13. Relationships among CFTR expression, HCO3− secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

    PubMed Central

    Shah, Viral S.; Ernst, Sarah; Tang, Xiao Xiao; Karp, Philip H.; Parker, Connor P.; Ostedgaard, Lynda S.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10–50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl− secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3− secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3− at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR+/− or CFTR+/∆F508) expressed CFTR and secreted HCO3− at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3− secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl− secretion, the amount of CFTR is rate-limiting for HCO3− secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers. PMID:27114540

  14. In vitro and ex vivo effects of cyclosporin A on phagocytic host defenses against Aspergillus fumigatus.

    PubMed Central

    Roilides, E; Robinson, T; Sein, T; Pizzo, P A; Walsh, T J

    1994-01-01

    Because cyclosporin A (CsA) is extensively used as an immunosuppressive agent, its effects on phagocytic defenses against Aspergillus fumigatus were studied in vitro and ex vivo. After incubation with 10 to 250 ng of CsA per ml at 37 degrees C for 60 min, polymorphonuclear leukocytes (PMNs) exhibited unaltered superoxide anion (O2-) production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, whereas > or = 500 ng/ml significantly suppressed it (P < 0.01). Moreover, at < 250 ng of CsA per ml, PMNs exhibited no change in their capacity to damage unopsonized hyphae of A. fumigatus compared with controls, whereas at > or = 250 ng/ml, CsA suppressed the function (P < 0.01). Although neither CsA (250 ng/ml) nor hydrocortisone (10 micrograms/ml) suppressed PMN O2- production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, combination of the two agents reduced the function compared with that at the baseline (P < 0.05). Incubation of monocytes with 100 ng of CsA per ml for 1 or 2 days suppressed their antihyphal activity. No essential change in phagocytic activity of monocyte-derived macrophages (MDMs) against A. fumigatus conidia, tested as the percentage of phagocytosing MDMs and average number of MDM-associated conidia, was detected after 2 or 4 days of incubation with 10 to 1,000 ng of CsA per ml. Furthermore, in rabbits treated with CsA (up to 20 mg/kg of body weight per day intravenously for 7 days), neither O2- production and hyphal damage caused by PMNs or monocytes against hyphae nor phagocytosis of conidia by pulmonary alveolar macrophages was significantly suppressed. Thus, these results demonstrated that CsA within therapeutically relevant concentrations does not suppress antifungal activity of phagocytes except that of circulating monocytes. However, it may induce significant immunosuppression of phagocytes' antifungal function at relatively high concentrations in vitro, especially when

  15. Active infrared systems: possible roles in ballistic missile defense?

    NASA Astrophysics Data System (ADS)

    Paleologue, A.

    2006-05-01

    Active Infra-Red (IR) systems developed in the past ten years are now available for missile defense applications. The main purpose of this paper is to describe the advantages an active IR system could offer to a ballistic missile defense (BMD). The active IR system considered in this paper is a LIDAR (LIght Detection And Ranging) system. Historically, the Lincoln Laboratory in the USA began using lasers in the early 1960's. The initial applications included the development of a LIDAR system enabling the measurement of the distance between the earth and the moon in 1962. Satellite tracking using LIDAR began early in 1973. Today, technological developments, with the miniaturization of systems and increased performance levels, have enabled new ambitious projects such as the Discrimination Interceptor Technology Program (DITP) program started in 1998 and the use of LIDAR to help in the discrimination of future exo-atmospheric interceptors within the framework of BMD. The first part of this paper presents the possible contribution of LIDAR to BMD: the main roles, objectives, and strategic advantages. The second part gives a brief overview of the technological features of a generic LIDAR instrument, rapidly addressing laser sources, detectors, optics and electronics. Finally, a modeling of an IR LIDAR system, limited solely to direct detection, and an estimation of performance levels will be presented. A list of possible IR active discriminators will be then presented on the basis of the previous analysis and proposed as new constraints in the design of discrete objects.

  16. Disentangling Detoxification: Gene Expression Analysis of Feeding Mountain Pine Beetle Illuminates Molecular-Level Host Chemical Defense Detoxification Mechanisms

    PubMed Central

    Robert, Jeanne A.; Pitt, Caitlin; Bonnett, Tiffany R.; Yuen, Macaire M. S.; Keeling, Christopher I.; Bohlmann, Jörg; Huber, Dezene P. W.

    2013-01-01

    The mountain pine beetle, Dendroctonus ponderosae, is a native species of bark beetle (Coleoptera: Curculionidae) that caused unprecedented damage to the pine forests of British Columbia and other parts of western North America and is currently expanding its range into the boreal forests of central and eastern Canada and the USA. We conducted a large-scale gene expression analysis (RNA-seq) of mountain pine beetle male and female adults either starved or fed in male-female pairs for 24 hours on lodgepole pine host tree tissues. Our aim was to uncover transcripts involved in coniferophagous mountain pine beetle detoxification systems during early host colonization. Transcripts of members from several gene families significantly increased in insects fed on host tissue including: cytochromes P450, glucosyl transferases and glutathione S-transferases, esterases, and one ABC transporter. Other significantly increasing transcripts with potential roles in detoxification of host defenses included alcohol dehydrogenases and a group of unexpected transcripts whose products may play an, as yet, undiscovered role in host colonization by mountain pine beetle. PMID:24223726

  17. A Comparative Study of Lung Host Defense in Murine Obesity Models. Insights into Neutrophil Function.

    PubMed

    Ubags, Niki D J; Burg, Elianne; Antkowiak, Maryellen; Wallace, Aaron M; Dilli, Estee; Bement, Jenna; Wargo, Matthew J; Poynter, Matthew E; Wouters, Emiel F M; Suratt, Benjamin T

    2016-08-01

    We have shown that obesity-associated attenuation of murine acute lung injury is driven, in part, by blunted neutrophil chemotaxis, yet differences were noted between the two models of obesity studied. We hypothesized that obesity-associated impairment of multiple neutrophil functions contributes to increased risk for respiratory infection but that such impairments may vary between murine models of obesity. We examined the most commonly used murine obesity models (diet-induced obesity, db/db, CPE(fat/fat), and ob/ob) using a Klebsiella pneumoniae pneumonia model and LPS-induced pneumonitis. Marrow-derived neutrophils from uninjured lean and obese mice were examined for in vitro functional responses. All obesity models showed impaired clearance of K. pneumoniae, but in differing temporal patterns. Failure to contain infection in obese mice was seen in the db/db model at both 24 and 48 hours, yet this defect was only evident at 24 hours in CPE(fat/fat) and ob/ob models, and at 48 hours in diet-induced obesity. LPS-induced airspace neutrophilia was decreased in all models, and associated with blood neutropenia in the ob/ob model but with leukocytosis in the others. Obese mouse neutrophils from all models demonstrated impaired chemotaxis, whereas neutrophil granulocyte colony-stimulating factor-mediated survival, LPS-induced cytokine transcription, and mitogen-activated protein kinase and signal transducer and activator of transcription 3 activation in response to LPS and granulocyte colony-stimulating factor, respectively, were variably impaired across the four models. Obesity-associated impairment of host response to lung infection is characterized by defects in neutrophil recruitment and survival. However, critical differences exist between commonly used mouse models of obesity and may reflect variable penetrance of elements of the metabolic syndrome, as well as other factors. PMID:27128821

  18. Effects of parasite pressure on parasite mortality and reproductive output in a rodent-flea system: inferring host defense trade-offs.

    PubMed

    Warburton, Elizabeth M; Kam, Michael; Bar-Shira, Enav; Friedman, Aharon; Khokhlova, Irina S; Koren, Lee; Asfur, Mustafa; Geffen, Eli; Kiefer, Daniel; Krasnov, Boris R; Degen, A Allan

    2016-09-01

    Evaluating host resistance via parasite fitness helps place host-parasite relationships within evolutionary and ecological contexts; however, few studies consider both these processes simultaneously. We investigated how different levels of parasite pressure affect parasite mortality and reproductive success in relationship to host defense efforts, using the rodent Gerbillus nanus and the flea Xenopsylla conformis as a host-parasite system. Fifteen immune-naïve male rodents were infested with 20, 50, or 100 fleas for four weeks. During this time number of new imagoes produced per adult flea (our flea reproductive output metric), flea mortality, and change in circulating anti-flea immunoglobulin G (our measure of adaptive immune defense) were monitored. Three hypotheses guided this work: (1) increasing parasite pressure would heighten host defenses; (2) parasite mortality would increase and parasite reproductive output would decrease with increasing investment in host defense; and (3) hosts under high parasite pressure could invest in behavioral and/or immune responses. We predicted that at high infestation levels (a) parasite mortality would increase; (b) flea reproductive output per individual would decrease; and (c) host circulating anti-flea antibody levels would increase. The hypotheses were partially supported. Flea mortality significantly increased and flea reproductive output significantly decreased as flea pressure increased. Host adaptive immune defense did not significantly change with increasing flea pressure. Therefore, we inferred that investment in host behavioral defense, either alone or in combination with density-dependent effects, may be more efficient at increasing flea mortality and decreasing flea reproductive output than antibody production during initial infestation in this system. PMID:27130319

  19. Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae

    PubMed Central

    Jeong, Dong-Gu; Seo, Jin-Hee; Heo, Seung-Ho; Choi, Yang-Kyu

    2015-01-01

    Streptococcus pneumoniae is a major human pathogen that is involved in community-acquired pneumonia. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that activates immune responses against infection, invasion, injury, or inflammation. To study the role of TNF-α during S. pneumoniae infection, a murine pneumococcal pneumonia model was used. We intranasally infected C57BL/6J wild-type (WT) and TNF-α knockout (KO) mice with S. pneumoniae D39 serotype 2. In TNF-α KO mice, continuous and distinct loss of body weight, and low survival rates were observed. Bacterial counts in the lungs and blood of TNF-α KO mice were significantly higher than those in WT mice. Histopathological lesions in the spleen of TNF-α KO mice were more severe than those in WT mice. In TNF-α KO mice, severe depletion of white pulp was observed and the number of apoptotic cells was significantly increased. Interferon-gamma (IFN-γ), IL-12p70 and IL-10 levels in serum were significantly increased in TNF-α KO mice. TNF-α is clearly involved in the regulation of S. pneumoniae infections. Early death and low survival rates of TNF-α KO mice were likely caused by a combination of impaired bacterial clearance and damage to the spleen. Our findings suggest that TNF-α plays a critical role in protecting the host from systemic S. pneumoniae infection. PMID:26155202

  20. Evidence for alteration of fungal endophyte community assembly by host defense compounds.

    PubMed

    Saunders, Megan; Kohn, Linda Myra

    2009-01-01

    * Plant defense compounds are common stressors encountered by endophytes. Fungi readily evolve tolerance to these compounds, yet few studies have addressed the influence of intraspecific variation in defense compound production on endophyte colonization. We compared the influence of defense compound production on the composition of fungal endophyte communities in replicated field experiments. * Maize (Zea mays) produces benzoxazinoids (BXs), compounds with antifungal byproducts persistent in the environment. Fungi were isolated from leaf and root tissue of two maize genotypes that produce BXs, and a natural mutant that does not. Isolates representing the species recovered were tested for tolerance to 2-benzoxazolinone (BOA), a toxic BX byproduct. * In seedling roots and mature leaves, the community proportion with low BOA tolerance was significantly greater in BX nonproducers than producers. Mean isolation frequency of Fusarium species was up to 35 times higher in mature leaves of BX producers than nonproducers. * Fungal species with relatively high tolerance to BOA are more abundant in BX producing than BX nonproducing maize. Production of BXs may increase colonization by Fusarium species in maize, including agents of animal toxicosis and yield-reducing disease in maize. Overall, results indicate that production of defense compounds can significantly alter endophyte community assembly. PMID:19170900

  1. A new lysozyme from the eastern oyster, Crassostrea virginica, and a possible evolutionary pathway for i-type lysozymes in bivalves from host defense to digestion

    PubMed Central

    2010-01-01

    Background Lysozymes are enzymes that lyse bacterial cell walls, an activity widely used for host defense but also modified in some instances for digestion. The biochemical and evolutionary changes between these different functional forms has been well-studied in the c-type lysozymes of vertebrates, but less so in the i-type lysozymes prevalent in most invertebrate animals. Some bivalve molluscs possess both defensive and digestive lysozymes. Results We report a third lysozyme from the oyster Crassostrea virginica, cv-lysozyme 3. The chemical properties of cv-lysozyme 3 (including molecular weight, isoelectric point, basic amino acid residue number, and predicted protease cutting sites) suggest it represents a transitional form between lysozymes used for digestion and immunity. The cv-lysozyme 3 protein inhibited the growth of bacteria (consistent with a defensive function), but semi-quantitative RT-PCR suggested the gene was expressed mainly in digestive glands. Purified cv-lysozyme 3 expressed maximum muramidase activity within a range of pH (7.0 and 8.0) and ionic strength (I = 0.005-0.01) unfavorable for either cv-lysozyme 1 or cv-lysozyme 2 activities. The topology of a phylogenetic analysis of cv-lysozyme 3 cDNA (full length 663 bp, encoding an open reading frame of 187 amino acids) is also consistent with a transitional condition, as cv-lysozyme 3 falls at the base of a monophyletic clade of bivalve lysozymes identified from digestive glands. Rates of nonsynonymous substitution are significantly high at the base of this clade, consistent with an episode of positive selection associated with the functional transition from defense to digestion. Conclusion The pattern of molecular evolution accompanying the shift from defensive to digestive function in the i-type lysozymes of bivalves parallels those seen for c-type lysozymes in mammals and suggests that the lysozyme paralogs that enhance the range of physiological conditions for lysozyme activity may provide

  2. Active, Non-Intrusive Inspection Technologies for Homeland Defense

    SciTech Connect

    James L. Jones

    2003-06-01

    Active, non-intrusive inspection or interrogation technologies have been used for 100 years - with the primary focus being radiographic imaging. During the last 50 years, various active interrogation systems have been investigated and most have revealed many unique and interesting capabilities and advantages that have already benefited the general public. Unfortunately, except for medical and specific industrial applications, these unique capabilities have not been widely adopted, largely due to the complexity of the technology, the overconfident reliance on passive detection systems to handle most challenges, and the unrealistic public concerns regarding radiation safety issues for a given active inspection deployment. The unique homeland security challenges facing the United States today are inviting more "out-of-the-box" solutions and are demanding the effective technological solutions that only active interrogation systems can provide. While revolutionary new solutions are always desired, these technology advancements are rare, and when found, usually take a long time to fully understand and implement for a given application. What's becoming more evident is that focusing on under-developed, but well-understood, active inspection technologies can provide many of the needed "out-of-the-box" solutions. This paper presents a brief historical overview of active interrogation. It identifies some of the major homeland defense challenges being confronted and the commercial and research technologies presently available and being pursued. Finally, the paper addresses the role of the Idaho National Engineering and Environmental Laboratory and its partner, the Idaho Accelerator Center at Idaho State University, in promoting and developing active inspection technologies for homeland defense.

  3. Immunomodulation of Fungal β-Glucan in Host Defense Signaling by Dectin-1

    PubMed Central

    Batbayar, Sainkhuu; Lee, Dong Hee; Kim, Ha Won

    2012-01-01

    During the course of evolution, animals encountered the harmful effects of fungi, which are strong pathogens. Therefore, they have developed powerful mechanisms to protect themselves against these fungal invaders. β-Glucans are glucose polymers of a linear β(1,3)-glucan backbone with β(1,6)-linked side chains. The immunostimulatory and antitumor activities of β-glucans have been reported; however, their mechanisms have only begun to be elucidated. Fungal and particulate β-glucans, despite their large size, can be taken up by the M cells of Peyer's patches, and interact with macrophages or dendritic cells (DCs) and activate systemic immune responses to overcome the fungal infection. The sampled β-glucans function as pathogen-associated molecular patterns (PAMPs) and are recognized by pattern recognition receptors (PRRs) on innate immune cells. Dectin-1 receptor systems have been incorporated as the PRRs of β-glucans in the innate immune cells of higher animal systems, which function on the front line against fungal infection, and have been exploited in cancer treatments to enhance systemic immune function. Dectin-1 on macrophages and DCs performs dual functions: internalization of β-glucan-containing particles and transmittance of its signals into the nucleus. This review will depict in detail how the physicochemical nature of β-glucan contributes to its immunostimulating effect in hosts and the potential uses of β-glucan by elucidating the dectin-1 signal transduction pathway. The elucidation of β-glucan and its signaling pathway will undoubtedly open a new research area on its potential therapeutic applications, including as immunostimulants for antifungal and anti-cancer regimens. PMID:24009832

  4. Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications

    PubMed Central

    Wu, William K.K.; Wang, Guangshun; Coffelt, Seth B.; Betancourt, Aline M.; Lee, Chung W.; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J.Y.; Cho, Chi H.

    2010-01-01

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does it eliminate pathogenic microbes directly, LL-37 also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. While overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide. PMID:20521250

  5. Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications.

    PubMed

    Wu, William K K; Wang, Guangshun; Coffelt, Seth B; Betancourt, Aline M; Lee, Chung W; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J Y; Cho, Chi H

    2010-10-15

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide. PMID:20521250

  6. Amoebal Endosymbiont Neochlamydia Genome Sequence Illuminates the Bacterial Role in the Defense of the Host Amoebae against Legionella pneumophila

    PubMed Central

    Ishida, Kasumi; Sekizuka, Tsuyoshi; Hayashida, Kyoko; Matsuo, Junji; Takeuchi, Fumihiko; Kuroda, Makoto; Nakamura, Shinji; Yamazaki, Tomohiro; Yoshida, Mitsutaka; Takahashi, Kaori; Nagai, Hiroki; Sugimoto, Chihiro; Yamaguchi, Hiroyuki

    2014-01-01

    Previous work has shown that the obligate intracellular amoebal endosymbiont Neochlamydia S13, an environmental chlamydia strain, has an amoebal infection rate of 100%, but does not cause amoebal lysis and lacks transferability to other host amoebae. The underlying mechanism for these observations remains unknown. In this study, we found that the host amoeba could completely evade Legionella infection. The draft genome sequence of Neochlamydia S13 revealed several defects in essential metabolic pathways, as well as unique molecules with leucine-rich repeats (LRRs) and ankyrin domains, responsible for protein-protein interaction. Neochlamydia S13 lacked an intact tricarboxylic acid cycle and had an incomplete respiratory chain. ADP/ATP translocases, ATP-binding cassette transporters, and secretion systems (types II and III) were well conserved, but no type IV secretion system was found. The number of outer membrane proteins (OmcB, PomS, 76-kDa protein, and OmpW) was limited. Interestingly, genes predicting unique proteins with LRRs (30 genes) or ankyrin domains (one gene) were identified. Furthermore, 33 transposases were found, possibly explaining the drastic genome modification. Taken together, the genomic features of Neochlamydia S13 explain the intimate interaction with the host amoeba to compensate for bacterial metabolic defects, and illuminate the role of the endosymbiont in the defense of the host amoebae against Legionella infection. PMID:24747986

  7. OsRDR6 plays role in host defense against double-stranded RNA virus, Rice Dwarf Phytoreovirus

    PubMed Central

    Hong, Wei; Qian, Dan; Sun, Runhong; Jiang, Lin; Wang, Yu; Wei, Chunhong; Zhang, Zhongkai; Li, Yi

    2015-01-01

    RNAi is a major antiviral defense response in plant and animal model systems. RNA-dependent RNA polymerase 6 (RDR6) is an essential component of RNAi, which plays an important role in the resistance against viruses in the model plants. We found previously that rice RDR6 (OsRDR6) functioned in the defense against Rice stripe virus (RSV), and Rice Dwarf Phytoreovirus (RDV) infection resulted in down-regulation of expression of RDR6. Here we report our new findings on the function of OsRDR6 against RDV. Our result showed that down-regulation of OsRDR6 through the antisense (OsRDR6AS) strategy increased rice susceptibility to RDV infection while over-expression of OsRDR6 had no effect on RDV infection. The accumulation of RDV vsiRNAs was reduced in the OsRDR6AS plants. In the OsRDR6 over-expressed plants, the levels of OsRDR6 RNA transcript and protein were much higher than that in the control plants. Interestingly, the accumulation level of OsRDR6 protein became undetectable after RDV infection. This finding indicated that the translation and/or stability of OsRDR6 protein were negatively impacted upon RDV infection. This new finding provides a new light on the function of RDR6 in plant defense response and the cross-talking between factors encoded by host plant and double-stranded RNA viruses. PMID:26165755

  8. Review: The intersection of surfactant homeostasis and innate host defense of the lung: lessons from newborn infants.

    PubMed

    Whitsett, Jeffrey A

    2010-06-01

    The study of pulmonary surfactant, directed towards prevention and treatment of respiratory distress syndrome in preterm infants, led to the identification of novel proteins/genes that determine the synthesis, packaging, secretion, function, and catabolism of alveolar surfactant. The surfactant proteins, SP-A, SP-B, SP-C, and SP-D, and the surfactant lipid associated transporter, ABCA3, play critical roles in surfactant homeostasis. The study of their structure and function provided insight into a system that integrates the biophysical need to reduce surface tension in the alveoli and the innate host defenses required to maintain pulmonary structure and function after birth. Alveolar homeostasis depends on the intrinsic, multifunctional structures of the surfactant-associated proteins and the shared transcriptional regulatory modules that determine both the expression of genes involved in surfactant production as well as those critical for host defense. Identification of the surfactant proteins and the elucidation of the genetic networks regulating alveolar homeostasis have provided the basis for understanding and diagnosing rare and common pulmonary disorders, including respiratory distress syndrome, inherited disorders of surfactant homeostasis, and pulmonary alveolar proteinosis. PMID:20351134

  9. Temporal and Spatial Resolution of Activated Plant Defense Responses in Leaves of Nicotiana benthamiana Infected with Dickeya dadantii

    PubMed Central

    Pérez-Bueno, María L.; Granum, Espen; Pineda, Mónica; Flors, Víctor; Rodriguez-Palenzuela, Pablo; López-Solanilla, Emilia; Barón, Matilde

    2016-01-01

    The necrotrophic bacteria Dickeya dadantii is the causal agent of soft-rot disease in a broad range of hosts. The model plant Nicotiana benthamiana, commonly used as experimental host for a very broad range of plant pathogens, is susceptible to infection by D. dadantii. The inoculation with D. dadantii at high dose seems to overcome the plant defense capacity, inducing maceration and death of the tissue, although restricted to the infiltrated area. By contrast, the output of the defense response to low dose inoculation is inhibition of maceration and limitation in the growth, or even eradication, of bacteria. Responses of tissue invaded by bacteria (neighboring the infiltrated areas after 2–3 days post-inoculation) included: (i) inhibition of photosynthesis in terms of photosystem II efficiency; (ii) activation of energy dissipation as non-photochemical quenching in photosystem II, which is related to the activation of plant defense mechanisms; and (iii) accumulation of secondary metabolites in cell walls of the epidermis (lignins) and the apoplast of the mesophyll (phytoalexins). Infiltrated tissues showed an increase in the content of the main hormones regulating stress responses, including abscisic acid, jasmonic acid, and salicylic acid. We propose a mechanism involving the three hormones by which N. benthamiana could activate an efficient defense response against D. dadantii. PMID:26779238

  10. Dual ligand/receptor interactions activate urothelial defenses against uropathogenic E. coli

    PubMed Central

    Liu, Yan; Mémet, Sylvie; Saban, Ricardo; Kong, Xiangpeng; Aprikian, Pavel; Sokurenko, Evgeni; Sun, Tung-Tien; Wu, Xue-Ru

    2015-01-01

    During urinary tract infection (UTI), the second most common bacterial infection, dynamic interactions take place between uropathogenic E. coli (UPEC) and host urothelial cells. While significant strides have been made in the identification of the virulence factors of UPEC, our understanding of how the urothelial cells mobilize innate defenses against the invading UPEC remains rudimentary. Here we show that mouse urothelium responds to the adhesion of type 1-fimbriated UPEC by rapidly activating the canonical NF-κB selectively in terminally differentiated, superficial (umbrella) cells. This activation depends on a dual ligand/receptor system, one between FimH adhesin and uroplakin Ia and another between lipopolysaccharide and Toll-like receptor 4. When activated, all the nuclei (up to 11) of a multinucleated umbrella cell are affected, leading to significant amplification of proinflammatory signals. Intermediate and basal cells of the urothelium undergo NF-κB activation only if the umbrella cells are detached or if the UPEC persistently express type 1-fimbriae. Inhibition of NF-κB prevents the urothelium from clearing the intracellular bacterial communities, leading to prolonged bladder colonization by UPEC. Based on these data, we propose a model of dual ligand/receptor system in innate urothelial defenses against UPEC. PMID:26549759

  11. Expression Profiling of R Gene-Mediated Host Defense Against Aphid Feeding in Wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The greenbug, Schizaphis graminum (Rondani), is an important aphid pest of wheat in the southern High Plains of the U.S. The single dominant gene, Gb3 confers consistent and durable resistance against prevailing greenbug biotypes in wheat fields. However, molecular mechanisms of R gene mediated host...

  12. NVLAP activities at Department of Defense calibration laboratories

    SciTech Connect

    Schaeffer, D.M.

    1993-12-31

    There are 367 active radiological instrument calibration laboratories within the U.S. Department of Defense (DoD). Each of the four services in DoD manages, operates, and certifies the technical proficiency and competency of those laboratories under their cognizance. Each service has designated secondary calibration laboratories to trace all calibration source standards to the National Institute of Standards and Technology. Individual service radiological calibration programs and capabilities, present and future, are described, as well as the measurement quality assurance (MQA) processes for their traceability. National Voluntary Laboratory Accreditation Program (NVLAP) programs for dosimetry systems are briefly summarized. Planned NVLAP accreditation of secondary laboratories is discussed in the context of current technical challenges and future efforts.

  13. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    PubMed Central

    Morash, Michael G.; Douglas, Susan E.; Robotham, Anna; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. Cytotoxicities were assessed in vitro using cell-based assays and in vivo using zebrafish embryos. Morphological changes were assessed by both transmission and scanning electron microscopy, and functional assays were performed on zebrafish embryos to investigate the mechanism of cell death. A total of 14 peptides were virtually inactive against HL60 human leukemia cells, whereas 12 caused >50% death at ≤32 μg/ml. Morphological changes characteristic of oncosis were evident by electron microscopy after only 1 minute of treatment with 32 μg/ml of variant NRC-03. Only two peptides were hemolytic. Four peptides showed no toxicity towards zebrafish embryos at the highest concentration tested (25 μM; ∼64 μg/ml) and one peptide was highly toxic, killing 4-hour-post-fertilization (hpf) embryos immediately after exposure to 1 μM peptide. Four other peptides killed embryos after 24 hours of exposure at 1 μM. Most peptides caused mortality at one or more developmental stages only after continuous exposure (24 hours) with higher lethal doses (≥5 μM). Pleurocidin NRC-03 bound to embryos and induced the release of superoxide, caused an increase in the number of TUNEL-positive nuclei, and caused membrane damage and the loss of embryonic epithelial integrity, marked by the exclusion of cells from the outer epithelium and the appearance of F-actin within the circumferential cells of the repair site. Our results indicate that specific pleurocidin variants are attractive cancer

  14. Activation of Intestinal Epithelial Stat3 Orchestrates Tissue Defense during Gastrointestinal Infection

    PubMed Central

    Wittkopf, Nadine; Pickert, Geethanjali; Billmeier, Ulrike; Mahapatro, Mousumi; Wirtz, Stefan; Martini, Eva; Leppkes, Moritz; Neurath, Markus Friedrich; Becker, Christoph

    2015-01-01

    Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line-defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium – a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIIIγ and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function. PMID:25799189

  15. NLRC4-driven interleukin-1β production discriminates between pathogenic and commensal bacteria and promotes host intestinal defense

    PubMed Central

    Franchi, Luigi; Kamada, Nobuhiko; Nakamura, Yuumi; Burberry, Aaron; Kuffa, Peter; Suzuki, Shiho; Shaw, Michael H.; Kim, Yun-Gi; Núñez, Gabriel

    2012-01-01

    Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we report that intestinal phagocytes are anergic to Toll-like receptor ligands or commensals, but constitutively express pro-interleukin-1β (proIL-1β). Upon infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produce mature IL-1β through the NLRC4 inflammasome, but not tumor necrosis factor or IL-6. Mice deficient in NLRC4 or IL-1 receptor on a Balb/c background were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. Increased lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment, and poor intestinal pathogen clearance. Thus, NLRC4-dependent IL-1β production by intestinal phagocytes represents a specific response discriminating pathogenic from commensal bacteria and contributes to host defense in the intestine. PMID:22484733

  16. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense.

    PubMed

    Franchi, Luigi; Kamada, Nobuhiko; Nakamura, Yuumi; Burberry, Aaron; Kuffa, Peter; Suzuki, Shiho; Shaw, Michael H; Kim, Yun-Gi; Núñez, Gabriel

    2012-05-01

    Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1β (pro-IL-1β). After infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produced mature IL-1β through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1β by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine. PMID:22484733

  17. Chlamydial Lung Infection Induces Transient IL-9 Production Which Is Redundant for Host Defense against Primary Infection

    PubMed Central

    Peng, Ying; Gao, Xiaoling; Yang, Jie; Shekhar, Sudhanshu; Wang, Shuhe; Fan, Yijun; Yang, Xi

    2015-01-01

    IL-9/Th9 responses are recently found to be important for innate and adaptive immunity particularly in parasitic infections. To date, the study on the role of IL-9 in bacterial infections is limited and the reported data are contradictory. One reported function of IL-9/Th9 is to modulate Th1/Th17 responses. Since our and others’ previous work has shown a critical role of Th1 and Th17 cells in host defense against chlamydial lung infection, we here examined the role of IL-9 responses in Chlamydia muridarum (Cm) lung infection, particularly its effect on Th1 and Th17 responses and outcome infection. Our data showed quick but transient IL-9 production in the lung following infection, peaking at day 3 and back to baseline around day 7. CD4+ T cell was the major source of IL-9 production in the lung infection. Blockade of endogenous IL-9 using neutralizing antibody failed to change Interferon-γ (IFN-γ) and IL-17 production by cultured spleen mononuclear cells isolated from Cm infected mice. Similarly, in vivo neutralization of IL-9 failed to show significant effect on T cell (Th1 and Th17) and antibody responses (IgA, IgG1 and IgG2a). Consistently, the neutralization of IL-9 had no significant effect on disease process, including body weight change, bacterial burden and histopathological score. The data suggest that IL-9 production following chlamydial lung infection is redundant for host defense against the intracellular bacteria. PMID:25646821

  18. Pseudomonas fluorescens induces strain-dependent and strain-independent host plant responses in defense networks, primary metabolism and photosynthesis

    SciTech Connect

    Pelletier, Dale A; Morrell-Falvey, Jennifer L; Karve, Abhijit A; Lu, Tse-Yuan S; Tschaplinski, Timothy J; Tuskan, Gerald A; Chen, Jay; Martin, Madhavi Z; Jawdy, Sara; Weston, David; Doktycz, Mitchel John; Schadt, Christopher Warren

    2012-01-01

    Colonization of plants by nonpathogenic Pseudomonas fluorescens strains can confer enhanced defense capacity against a broad spectrum of pathogens. Few studies, however, have linked defense pathway regulation to primary metabolism and physiology. In this study, physiological data, metabolites, and transcript profiles are integrated to elucidate how molecular networks initiated at the root-microbe interface influence shoot metabolism and whole-plant performance. Experiments with Arabidopsis thaliana were performed using the newly identified P. fluorescens GM30 or P. fluorescens Pf-5 strains. Co-expression networks indicated that Pf-5 and GM30 induced a subnetwork specific to roots enriched for genes participating in RNA regulation, protein degradation, and hormonal metabolism. In contrast, only GM30 induced a subnetwork enriched for calcium signaling, sugar and nutrient signaling, and auxin metabolism, suggesting strain dependence in network architecture. In addition, one subnetwork present in shoots was enriched for genes in secondary metabolism, photosynthetic light reactions, and hormone metabolism. Metabolite analysis indicated that this network initiated changes in carbohydrate and amino acid metabolism. Consistent with this, we observed strain-specific responses in tryptophan and phenylalanine abundance. Both strains reduced host plant carbon gain and fitness, yet provided a clear fitness benefit when plants were challenged with the pathogen P. syringae DC3000.

  19. Localization and developmental expression of two chicken host defense peptides: cathelicidin-2 and avian β-defensin 9.

    PubMed

    Cuperus, Tryntsje; van Dijk, Albert; Dwars, R Marius; Haagsman, Henk P

    2016-08-01

    In the first weeks of life young chickens are highly susceptible to infectious diseases due to immaturity of the immune system. Little is known about the expression of host defense peptides (HDPs) during this period. In this study we examined the expression pattern of two chicken HDPs, the cathelicidin CATH-2 and the β-defensin AvBD9 by immunohistochemistry in a set of organs from embryonic day 12 until four weeks posthatch. AvBD9 was predominantly found in enteroendocrine cells throughout the intestine, the first report of in vivo HDP expression in this cell type, and showed stable expression levels during development. CATH-2 was exclusively found in heterophils which decreased after hatch in most of the examined organs including spleen, bursa and small intestine. In the lung CATH-2 expression was biphasic and peaked at the first day posthatch. In short, CATH-2 and AvBD9 appear to be expressed in cell types strategically located to respond to infectious stimuli, suggesting these peptides play a role in embryonic and early posthatch defense. PMID:26972737

  20. CD4+ T-cell subsets and host defense in the lung

    PubMed Central

    Kolls, Jay K.

    2012-01-01

    Summary CD4+ T-helper subsets are lineages of T cells that have effector function in the lung and control critical aspects of lung immunity. Depletion of these cells experimentally or by drugs or human immunodeficiency virus (HIV) infection in humans leads to the development of opportunistic infections as well as increased rates of bacteremia with certain bacterial pneumonias. Recently, it has been proposed that CD4+ T-cell subsets may also be excellent targets for mucosal vaccination to prevent pulmonary infections in susceptible hosts. Here we review recent findings that increase our understanding of T-cell subsets and their effector cytokines in the context of pulmonary infection. PMID:23405903

  1. Lactobacillus rhamnosus Ingestion Promotes Innate Host Defense in an Enteric Parasitic Infection

    PubMed Central

    McClemens, Jessica; Kim, Janice J.; Wang, Huaqing; Mao, Yu-Kang; Collins, Matthew; Kunze, Wolfgang; Bienenstock, John

    2013-01-01

    Enteric parasite infections around the world are a huge economic burden and decrease the quality of life for many people. The use of beneficial bacteria has attracted attention for their potential therapeutic applications in various diseases. However, the effects of beneficial bacteria in enteric parasitic infections remain largely unexplored. We investigated the effects of ingestion of Lactobacillus rhamnosus (JB-1) in a model of enteric nematode (Trichuris muris) infection. C57BL/6 (resistant to infection), AKR (susceptible to infection), interleukin 10 (IL-10) knockout (KO), and mucin Muc2 KO mice were infected with T. muris and treated orally with probiotic JB-1 or medium. The mice were sacrificed on various days postinfection to examine goblet cells, epithelial cell proliferation, cytokines, and worm burdens. Treatment with JB-1 significantly enhanced worm expulsion in resistant C57BL/6 mice, and this was associated with increases in IL-10 levels, goblet cell numbers, and epithelial cell proliferation. Beneficial effects of JB-1 were absent in IL-10 KO and resistant mice treated with γ-irradiated bacteria. Live JB-1 treatment also expedited worm expulsion in Muc2 KO mice and, more importantly, in AKR mice (susceptible to infection). Injection of IL-10 directly into the colonic tissue of uninfected mice induced goblet cell hyperplasia. These findings demonstrate that JB-1 modulates goblet cell biology and promotes parasite expulsion via an IL-10-mediated pathway and provide novel insights into probiotic effects on innate defense in nematode infection. PMID:23536695

  2. Role of Nucleotide-Binding Oligomerization Domain-Containing (NOD) 2 in Host Defense during Pneumococcal Pneumonia

    PubMed Central

    Hommes, Tijmen J.; van Lieshout, Miriam H.; van ‘t Veer, Cornelis; Florquin, Sandrine; Bootsma, Hester J.; Hermans, Peter W.; de Vos, Alex F.; van der Poll, Tom

    2015-01-01

    Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Nucleotide-binding oligomerization domain-containing (NOD) 2 is a pattern recognition receptor located in the cytosol of myeloid cells that is able to detect peptidoglycan fragments of S. pneumoniae. We here aimed to investigate the role of NOD2 in the host response during pneumococcal pneumonia. Phagocytosis of S. pneumoniae was studied in NOD2 deficient (Nod2-/-) and wild-type (Wt) alveolar macrophages and neutrophils in vitro. In subsequent in vivo experiments Nod2-/- and Wt mice were inoculated with serotype 2 S. pneumoniae (D39), an isogenic capsule locus deletion mutant (D39Δcps) or serotype 3 S. pneumoniae (6303) via the airways, and bacterial growth and dissemination and the lung inflammatory response were evaluated. Nod2-/- alveolar macrophages and blood neutrophils displayed a reduced capacity to internalize pneumococci in vitro. During pneumonia caused by S. pneumoniae D39 Nod2-/- mice were indistinguishable from Wt mice with regard to bacterial loads in lungs and distant organs, lung pathology and neutrophil recruitment. While Nod2-/- and Wt mice also had similar bacterial loads after infection with the more virulent S. pneumoniae 6303 strain, Nod2-/- mice displayed a reduced bacterial clearance of the normally avirulent unencapsulated D39Δcps strain. These results suggest that NOD2 does not contribute to host defense during pneumococcal pneumonia and that the pneumococcal capsule impairs recognition of S. pneumoniae by NOD2. PMID:26673231

  3. NODULES WITH ACTIVATED DEFENSE 1 is required for maintenance of rhizobial endosymbiosis in Medicago truncatula.

    PubMed

    Wang, Chao; Yu, Haixiang; Luo, Li; Duan, Liujian; Cai, Liuyang; He, Xinxing; Wen, Jiangqi; Mysore, Kirankumar S; Li, Guoliang; Xiao, Aifang; Duanmu, Deqiang; Cao, Yangrong; Hong, Zonglie; Zhang, Zhongming

    2016-10-01

    The symbiotic interaction between legume plants and rhizobia results in the formation of root nodules, in which symbiotic plant cells host and harbor thousands of nitrogen-fixing rhizobia. Here, a Medicago truncatula nodules with activated defense 1 (nad1) mutant was identified using reverse genetics methods. The mutant phenotype was characterized using cell and molecular biology approaches. An RNA-sequencing technique was used to analyze the transcriptomic reprogramming of nad1 mutant nodules. In the nad1 mutant plants, rhizobial infection and propagation in infection threads are normal, whereas rhizobia and their symbiotic plant cells become necrotic immediately after rhizobia are released from infection threads into symbiotic cells of nodules. Defense-associated responses were detected in nad1 nodules. NAD1 is specifically present in root nodule symbiosis plants with the exception of Morus notabilis, and the transcript is highly induced in nodules. NAD1 encodes a small uncharacterized protein with two predicted transmembrane helices and is localized at the endoplasmic reticulum. Our data demonstrate a positive role for NAD1 in the maintenance of rhizobial endosymbiosis during nodulation. PMID:27245091

  4. Sustained mitogen-activated protein kinase activation reprograms defense metabolism and phosphoprotein profile in Arabidopsis thaliana

    PubMed Central

    Lassowskat, Ines; Böttcher, Christoph; Eschen-Lippold, Lennart; Scheel, Dierk; Lee, Justin

    2014-01-01

    Mitogen-activated protein kinases (MAPKs) target a variety of protein substrates to regulate cellular signaling processes in eukaryotes. In plants, the number of identified MAPK substrates that control plant defense responses is still limited. Here, we generated transgenic Arabidopsis thaliana plants with an inducible system to simulate in vivo activation of two stress-activated MAPKs, MPK3, and MPK6. Metabolome analysis revealed that this artificial MPK3/6 activation (without any exposure to pathogens or other stresses) is sufficient to drive the production of major defense-related metabolites, including various camalexin, indole glucosinolate and agmatine derivatives. An accompanying (phospho)proteome analysis led to detection of hundreds of potential phosphoproteins downstream of MPK3/6 activation. Besides known MAPK substrates, many candidates on this list possess typical MAPK-targeted phosphosites and in many cases, the corresponding phosphopeptides were detected by mass spectrometry. Notably, several of these putative phosphoproteins have been reported to be associated with the biosynthesis of antimicrobial defense substances (e.g., WRKY transcription factors and proteins encoded by the genes from the “PEN” pathway required for penetration resistance to filamentous pathogens). Thus, this work provides an inventory of candidate phosphoproteins, including putative direct MAPK substrates, for future analysis of MAPK-mediated defense control. (Proteomics data are available with the identifier PXD001252 via ProteomeXchange, http://proteomecentral.proteomexchange.org). PMID:25368622

  5. A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom Authors

    PubMed Central

    Marichal, Thomas; Starkl, Philipp; Reber, Laurent L.; Kalesnikoff, Janet; Oettgen, Hans C.; Tsai, Mindy; Metz, Martin; Galli, Stephen J.

    2014-01-01

    Summary Allergies are widely considered to be misdirected type 2 immune responses, in which IgE antibodies are produced against any of a broad range of seemingly harmless antigens. However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response which increased their resistance to subsequent challenge with potentially lethal amounts of the venom. Our data indicate that IgE antibodies and the high affinity IgE receptor, FcεRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances. PMID:24210352

  6. Analysis of putative apoplastic effectors from the nematode, Globodera rostochiensis, and identification of an expansin-like protein that can induce and suppress host defenses.

    PubMed

    Ali, Shawkat; Magne, Maxime; Chen, Shiyan; Côté, Olivier; Stare, Barbara Gerič; Obradovic, Natasa; Jamshaid, Lubna; Wang, Xiaohong; Bélair, Guy; Moffett, Peter

    2015-01-01

    The potato cyst nematode, Globodera rostochiensis, is an important pest of potato. Like other pathogens, plant parasitic nematodes are presumed to employ effector proteins, secreted into the apoplast as well as the host cytoplasm, to alter plant cellular functions and successfully infect their hosts. We have generated a library of ORFs encoding putative G. rostochiensis putative apoplastic effectors in vectors for expression in planta. These clones were assessed for morphological and developmental effects on plants as well as their ability to induce or suppress plant defenses. Several CLAVATA3/ESR-like proteins induced developmental phenotypes, whereas predicted cell wall-modifying proteins induced necrosis and chlorosis, consistent with roles in cell fate alteration and tissue invasion, respectively. When directed to the apoplast with a signal peptide, two effectors, an ubiquitin extension protein (GrUBCEP12) and an expansin-like protein (GrEXPB2), suppressed defense responses including NB-LRR signaling induced in the cytoplasm. GrEXPB2 also elicited defense response in species- and sequence-specific manner. Our results are consistent with the scenario whereby potato cyst nematodes secrete effectors that modulate host cell fate and metabolism as well as modifying host cell walls. Furthermore, we show a novel role for an apoplastic expansin-like protein in suppressing intra-cellular defense responses. PMID:25606855

  7. Analysis of Putative Apoplastic Effectors from the Nematode, Globodera rostochiensis, and Identification of an Expansin-Like Protein That Can Induce and Suppress Host Defenses

    PubMed Central

    Ali, Shawkat; Magne, Maxime; Chen, Shiyan; Côté, Olivier; Stare, Barbara Gerič; Obradovic, Natasa; Jamshaid, Lubna; Wang, Xiaohong; Bélair, Guy; Moffett, Peter

    2015-01-01

    The potato cyst nematode, Globodera rostochiensis, is an important pest of potato. Like other pathogens, plant parasitic nematodes are presumed to employ effector proteins, secreted into the apoplast as well as the host cytoplasm, to alter plant cellular functions and successfully infect their hosts. We have generated a library of ORFs encoding putative G. rostochiensis putative apoplastic effectors in vectors for expression in planta. These clones were assessed for morphological and developmental effects on plants as well as their ability to induce or suppress plant defenses. Several CLAVATA3/ESR-like proteins induced developmental phenotypes, whereas predicted cell wall-modifying proteins induced necrosis and chlorosis, consistent with roles in cell fate alteration and tissue invasion, respectively. When directed to the apoplast with a signal peptide, two effectors, an ubiquitin extension protein (GrUBCEP12) and an expansin-like protein (GrEXPB2), suppressed defense responses including NB-LRR signaling induced in the cytoplasm. GrEXPB2 also elicited defense response in species- and sequence-specific manner. Our results are consistent with the scenario whereby potato cyst nematodes secrete effectors that modulate host cell fate and metabolism as well as modifying host cell walls. Furthermore, we show a novel role for an apoplastic expansin-like protein in suppressing intra-cellular defense responses. PMID:25606855

  8. The biphasic virulence activities of gingipains: activation and inactivation of host proteins.

    PubMed

    Imamura, Takahisa; Travis, James; Potempa, Jan

    2003-12-01

    Gingipains are trypsin-like cysteine proteinases produced by Porphyromonas gingivalis, a major causative bacterium of adult periodontitis. Rgps (HRgpA and RgpB) and Kgp are specific for -Arg-Xaa- and -Lys-Xaa- peptide bonds, respectively. HRgpA and Kgp are non-covalent complexes containing separate catalytic and adhesion/hemagglutinin domains, while RgpB has only a catalytic domain with a primary structure essentially identical to that of the cata-lytic subunit of HRgpA. The multiple virulence activities of gingipains are reviewed in view of the biphasic mechanisms: activation and inactivation of host proteins. Rgps enhanced vascular permeability through prekallikrein activation or direct bradykinin release in combination with Kgp. This Rgp action is potentially associated with gingival edema and crevicular fluid production. Rgps activate the blood coagulation system, leading to progression of inflammation and consequent alveolar bone loss in the periodontitis site. Rgps also activate protease-activated receptors and induce platelet aggregation, which, together with the coagulation-inducing activity, may explain an emerging link between periodontitis and cardiovascular disease. Kgp is the most potent fibrinogen/fibrin degrading enzyme of the three gingipains in human plasma, being involved in the bleeding tendency at the diseased gingiva. Gingipains stimulate expression of matrix metalloproteinases (MMPs) in fibroblasts and activate secreted latent MMPs that can destroy periodontal tissues. Gingipains degrade cytokines, components of the complement system and several receptors, including macrophage CD14, T cell CD4 and CD8, thus perturbing the host-defense systems and thereby facilitating sustained colonization of P. gingivalis. Gingipains are potent virulence factors of P. gingivalis, and in many regards their pathogenic activities constitute new mechanisms of bacterial virulence. PMID:14683429

  9. Phospholipase A2 Activity Triggers the Wound-Activated Chemical Defense in the Diatom Thalassiosira rotula

    PubMed Central

    Pohnert, Georg

    2002-01-01

    The activation of oxylipin-based chemical defense in the diatom Thalassiosira rotula is initiated by phospholipases that act immediately after cell damage. This lipase activity is responsible for the preferential release of free mono- and polyunsaturated fatty acids. Among these, eicosatetraenoic- and eicosapentaenoic acid are further converted by lipoxygenases to reactive defensive metabolites such as the antiproliferative α,β,γ,δ-unsaturated aldehydes 2,4-decadienal and 2,4,7-decatrienal. We show that mainly saturated free fatty acids are present in the intact diatom T. rotula, whereas the amount of free polyunsaturated eicosanoids is drastically increased in the first minutes after wounding. Using fluorescent probes, the main enzyme activity responsible for initiation of the aldehyde-generating lipase/lipoxygenase/hydroperoxide lyase cascade was characterized as a phospholipase A2. All enzymes involved in this specific defensive reaction are active in seawater over several minutes. Thus, the mechanism allows the unicellular algae to overcome restrictions arising out of potential dilution of defensive metabolites. Only upon predation are high local concentrations of aldehydes formed in the vicinity of the herbivores, whereas in times of low stress, cellular resources can be invested in the formation of eicosanoid-rich phospholipids. In contrast to higher plants, which use lipases acting on galactolipids to release C18 fatty acids for production of leaf-volatile aldehydes, diatoms rely on phospholipids and the transformation of C20 fatty acids to form 2,4-decadienal and 2,4,7-decatrienal as an activated defense. PMID:12011342

  10. An insecticidal compound produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition.

    PubMed

    Ullah, Ihsan; Khan, Abdul Latif; Ali, Liaqat; Khan, Abdur Rahim; Waqas, Muhammad; Lee, In-Jung; Shin, Jae-Ho

    2014-01-01

    A bioassay-guided column chromatographic strategy was adopted in the present study to fractionate the culture extract of Photorhabdus temperata M1021 to identify potential insecticidal and antimicrobial compounds. An ethyl acetate (EtOAc) culture extract of P. temperata was assayed against Galleria mellonella larvae through intra-hemocoel injection and exhibited 100% insect mortality within 60 h. The EtOAc fraction and an isolated compound exhibited phenoloxidase (PO) inhibition of up to 60% and 63%, respectively. The compound was identified as 1,2-benzenedicarboxylic acid (phthalic acid, PA) by gas chromatography-mass spectrometry and nuclear magnetic resonance. PA exhibited insecticidal activity against G. mellonella in a dose-dependent manner, and 100% insect mortality was observed at 108 h after injection of 1 M PA. In a PO inhibition assay, 0.5 and 1 M concentrations of PA were found to inhibit PO activity by 74% and 82%, respectively; and in a melanotic nodule formation assay, nodule formation was significantly inhibited (27 and 10 nodules) by PA (0.5 and 1 M, respectively). PA was furthermore found to have substantial antioxidant activity and maximum antioxidant activity was 64.7% for 0.5 M PA as compare to control. Antibacterial activity was assessed by The MIC values ranged from 0.1 M to 0.5 M of PA. This study reports a multifunctional PA, a potential insecticidal agent, could a factor of insect mortality along with other toxins produced by P. temperata M1021. PMID:25514230

  11. Orientations of psychotic activity in defensive pathological organizations.

    PubMed

    Williams, Paul

    2014-06-01

    The author reviews some clinical experiences of the treatment of personality disordered patients suffering from internal domination of ego functioning by a defensive pathological organization. In particular, the function and purpose of perverse, sadistic attacks by the organization on the ego are considered and questions pertaining to technique are raised. It is suggested that different forms of sadistic, subjugating activity by pathological organizations may denote differences in intent borne of the type and severity of the psychopathology of the individual. Patients with severe narcissistic psychopathology for whom object contact has become associated with the arousal of intense psychotic anxieties seem more likely to be subjected to an invasive, annihilatory imperative by the pathological organization, the purpose of which appears to be to obliterate the experience of contact with any differentiated object, to avoid emotion and to use coercion to enforce a primitive identification by the ego with the psychotic organization in the mind. Certain patients with less severe narcissistic psychopathology, yet for whom object contact can also be associated with the arousal of psychotic anxieties due to intense or persistent conflict with the object, sometimes expressed as organized sadomasochistic clinging to a punishing and punished object (for example, in certain borderline or depressed patients) exhibit sadistic attacks that serve less to annihilate object contact and more to intrusively control and punish the object. Observations of these phenomena have been made by a number of psychoanalysts in recent decades and these contributions are discussed. This paper is addressed primarily to the implications for technique with such patients, particularly a need for triangulation of their experiences of oppression in order to loosen the controls over the ego by the pathological organization. PMID:24620792

  12. Effects of inhalation of organic chemical air contaminants on murine lung host defenses

    SciTech Connect

    Aranyi, C.; O'Shea, W.J.; Graham, J.A.; Miller, F.J.

    1986-05-01

    The potential health hazards of exposure to threshold limit value (TLV) concentrations of acetaldehyde, acrolein, propylene oxide, chloroform, methyl chloroform, carbon tetrachloride, allyl chloride, methylene chloride, ethylene trichloride, perchloroethylene, benzene, phenol, monochlorobenzene, and benzyl chloride, compounds which may be present in the ambient or work room atmosphere were investigated. The effects of single and multiple 3-hr inhalation exposures were evaluated in mice by monitoring changes in their susceptibility to experimentally induced streptococcus aerosol infection and pulmonary bactericidal activity to inhaled Klebsiella pneumoniae. When significant changes in these parameters were found, further exposures were performed at reduced vapor concentrations until the no-measurable-effect level was reached. Multiple exposures on 5 consecutive days were then performed at this concentration. Significant increases in susceptibility to respiratory streptococcus infection were observed after single 3-hr exposure to TLV concentrations of methylene chloride, perchloroethylene, and ethylene trichloride. For methylene chloride and perchloroethylene, these exposure conditions also resulted in significantly decreased pulmonary bactericidal activity.

  13. The Host Defense Peptide Cathelicidin Is Required for NK Cell-Mediated Suppression of Tumor Growth

    PubMed Central

    Büchau, Amanda S.; Morizane, Shin; Trowbridge, Janet; Schauber, Jürgen; Kotol, Paul; Bui, Jack D.; Gallo, Richard L.

    2010-01-01

    Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide, although it is now clear that it fulfills a variety of immune functions beyond microbial killing. Recent data have suggested contrasting roles for cathelicidin in tumor development. Because its role in tumor surveillance is not well understood, we investigated the requirement of cathelicidin in controlling transplantable tumors in mice. Cathelicidin was observed to be abundant in tumor-infiltrating NK1.1+ cells in mice. The importance of this finding was demonstrated by the fact that cathelicidin knockout mice (Camp−/−) permitted faster tumor growth than wild type controls in two different xenograft tumor mouse models (B16.F10 and RMA-S). Functional in vitro analyses found that NK cells derived from Camp−/− versus wild type mice showed impaired cytotoxic activity toward tumor targets. These findings could not be solely attributed to an observed perforin deficiency in freshly isolated Camp−/− NK cells, because this deficiency could be partially restored by IL-2 treatment, whereas cytotoxic activity was still defective in IL-2-activated Camp−/− NK cells. Thus, we demonstrate a previously unrecognized role of cathelicidin in NK cell antitumor function. PMID:19949065

  14. The Baculovirus Uses a Captured Host Phosphatase to Induce Enhanced Locomotory Activity in Host Caterpillars

    PubMed Central

    Katsuma, Susumu; Koyano, Yasue; Kang, WonKyung; Kokusho, Ryuhei; Kamita, Shizuo George; Shimada, Toru

    2012-01-01

    The baculovirus is a classic example of a parasite that alters the behavior or physiology of its host so that progeny transmission is maximized. Baculoviruses do this by inducing enhanced locomotory activity (ELA) that causes the host caterpillars to climb to the upper foliage of plants. We previously reported that this behavior is not induced in silkworms that are infected with a mutant baculovirus lacking its protein tyrosine phosphatase (ptp) gene, a gene likely captured from an ancestral host. Here we show that the product of the ptp gene, PTP, associates with baculovirus ORF1629 as a virion structural protein, but surprisingly phosphatase activity associated with PTP was not required for the induction of ELA. Interestingly, the ptp knockout baculovirus showed significantly reduced infectivity of larval brain tissues. Collectively, we show that the modern baculovirus uses the host-derived phosphatase to establish adequate infection for ELA as a virion-associated structural protein rather than as an enzyme. PMID:22496662

  15. Protein Tyrosine Phosphatase-1B Negatively Impacts Host Defense against Pseudomonas aeruginosa Infection.

    PubMed

    Yue, Lei; Xie, Zhongping; Li, Hua; Pang, Zheng; Junkins, Robert D; Tremblay, Michel L; Chen, Xiaochun; Lin, Tong-Jun

    2016-05-01

    Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated cytokines and chemokines, including chemokine ligand 5 (regulated on activation normal T cell expressed and secreted), CXCL10 (interferon γ-inducible protein 10), and interferon-β production. Further studies reveal that PTP1B deficiency leads to increased interferon regulatory factor 7 (IRF7) expression and activation. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-IRF7 interaction. This novel PTP1B-IRF7-interferon-stimulated response elements pathway may have broader implications in Toll-like receptor-mediated innate immunity. PMID:27105736

  16. A systematic study of host defense processes in badly injured patients.

    PubMed Central

    Polk, H C; George, C D; Wellhausen, S R; Cost, K; Davidson, P R; Regan, M P; Borzotta, A P

    1986-01-01

    A prospective study of factors predisposing to infection in badly injured patients has disclosed: the dominant roles of two specific parameters: monocyte antigen presenting capacity, and opsonic capacity of diluted serum; the potential value of further assessment of: the predictive value of plots of activated T-cells/total T-cells versus monocyte antigen presenting capacity, the apparent protective effect of the ability to sharply increase specific IgM in response to infection, and the apparent protective effect of cytomegalovirus (CMV) infection in the first 28 days after injury against major bacterial infection; the lack of value of analysis of other T- and B-cell subsets in such patients; and the need to clarify CMV and transfusion status with respect to interpretation of such data. The specific role of variable transfusion and of specific serum immunoglobulins will require further and more discriminating study. PMID:3019260

  17. NK cells and type 1 innate lymphoid cells: partners in host defense.

    PubMed

    Spits, Hergen; Bernink, Jochem H; Lanier, Lewis

    2016-06-21

    Innate lymphoid cells (ILCs) are effectors and regulators of innate immunity and tissue modeling and repair. Researchers have identified subsets of ILCs with differing functional activities, capacities to produce cytokines and transcription factors required for development and function. Natural killer (NK) cells represent the prototypical member of the ILC family. Together with ILC1s, NK cells constitute group 1 ILCs, which are characterized by their capacity to produce interferon-γ and their functional dependence on the transcription factor T-bet. NK cells and ILC1s are developmentally distinct but share so many features that they are difficult to distinguish, particularly under conditions of infection and inflammation. Here we review current knowledge of NK cells and the various ILC1 subsets. PMID:27328005

  18. Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

    PubMed Central

    Li, Yitang; Jia, Yonghui; Pichavant, Muriel; Loison, Fabien; Sarraj, Bara; Kasorn, Anongnard; You, Jian; Robson, Bryanne E.; Umetsu, Dale T.; Mizgerd, Joseph P.; Ye, Keqiang

    2009-01-01

    Neutropenia and related infections are the most important dose-limiting toxicities in anticancer chemotherapy and radiotherapy. In this study, we explored a new strategy for augmenting host defense in neutropenia-related pneumonia. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3′-phosphatase that hydrolyzes PtdIns(3,4,5)P3. In myeloid-specific PTEN knockout mice, significantly more neutrophils were recruited to the inflamed lungs during neutropenia-associated pneumonia. Using an adoptive transfer technique, we demonstrated that this enhancement could be caused directly by PTEN depletion in neutrophils. In addition, disruption of PTEN increased the recruitment of macrophages and elevated proinflammatory cytokines/chemokine levels in the inflamed lungs, which could also be responsible for the enhanced neutrophil recruitment. Depleting PTEN also significantly delayed apoptosis and enhanced the bacteria-killing capability of the recruited neutrophils. Finally, we provide direct evidence that enhancement of neutrophil function by elevating PtdIns(3,4,5)P3 signaling can alleviate pneumonia-associated lung damage and decrease pneumonia-elicited mortality. Collectively, these results not only provide insight into the mechanism of action of PTEN and PtdIns(3,4,5)P3 signaling pathway in modulating neutrophil function during lung infection and inflammation, but they also establish PTEN and related pathways as potential therapeutic targets for treating neutropenia-associated pneumonia. PMID:19286998

  19. Host-defense and trefoil factor family peptides in skin secretions of the Mawa clawed frog Xenopus boumbaensis (Pipidae).

    PubMed

    Conlon, J Michael; Mechkarska, Milena; Kolodziejek, Jolanta; Leprince, Jérôme; Coquet, Laurent; Jouenne, Thierry; Vaudry, Hubert; Nowotny, Norbert; King, Jay D

    2015-10-01

    Peptidomic analysis of norepinephrine-stimulated skin secretions from the octoploid Mawa clawed frog Xenopus boumbaensis Loumont, 1983 led to the identification and characterization of 15 host-defense peptides belonging to the magainin (two peptides), peptide glycine-leucine-amide (PGLa; three peptides), xenopsin precursor fragment (XPF; three peptides), caerulein precursor fragment (CPF; two peptides), and caerulein precursor fragment-related peptide (CPF-RP; five peptides) families. In addition, caerulein and three peptides with structural similarity to the trefoil factor family (TFF) peptides, xP2 and xP4 from Xenopus laevis were also present in the secretions. Consistent with data from comparisons of the nucleotides sequence of mitochondrial and nuclear genes, the primary structures of the peptides suggest a close phylogenetic relationship between X. boumbaensis and the octoploid frogs Xenopus amieti and Xenopus andrei. As the three species occupy disjunct ranges within Cameroon, it is suggested that they diverged from a common ancestor by allopatric speciation. PMID:25849343

  20. Inhalable particles and pulmonary host defense: in vivo and in vitro effects of ambient air and combustion particles.

    PubMed

    Hatch, G E; Boykin, E; Graham, J A; Lewtas, J; Pott, F; Loud, K; Mumford, J L

    1985-02-01

    The ability of particulate air pollutants (and possible constituents) to alter pulmonary host defenses was examined using an in vitro alveolar macrophage cytotoxicity assay and an in vivo bacterial infectivity screening test which employed intratracheal injection of the particles. A wide range of response between particles was seen at the 1.0-mg/ml level in vitro and the 0.1-mg/mouse level in vivo. A sample of fluidized-bed coal fly ash, bentonite, asbestos, some ambient air particles, and heavy metal oxides greatly increased susceptibility to pulmonary bacterial infection. Most coal fly ash samples and some air particles caused moderate increases in infectivity, while diesel particulates, volcanic ash, and crystalline silica caused only small increases. Cytotoxic effects on macrophages in vitro were observed with most of the particles. The in vivo and in vitro assays produced a similar ranking of toxicity; however, not all particles that were highly cytotoxic were potent in increasing bacterial infectivity. Increased toxicity measurable by either assay often appeared to be associated with small size or with the presence of metal in the particles. PMID:3967645

  1. Achyrocline satureioides (Lam.) D.C. Hydroalcoholic Extract Inhibits Neutrophil Functions Related to Innate Host Defense

    PubMed Central

    Barioni, Eric Diego; Machado, Isabel Daufenback; Rodrigues, Stephen Fernandes de Paula; Ferraz-de-Paula, Viviane; Wagner, Theodoro Marcel; Cogliati, Bruno; Corrêa dos Santos, Matheus; Machado, Marina da Silva; de Andrade, Sérgio Faloni; Niero, Rivaldo; Farsky, Sandra Helena Poliselli

    2013-01-01

    Achyrocline satureioides (Lam.) D.C. is a herb native to South America, and its inflorescences are popularly employed to treat inflammatory diseases. Here, the effects of the in vivo actions of the hydroalcoholic extract obtained from inflorescences of A. satureioides on neutrophil trafficking into inflamed tissue were investigated. Male Wistar rats were orally treated with A. satureioides extract, and inflammation was induced one hour later by lipopolysaccharide injection into the subcutaneous tissue. The number of leukocytes and the amount of chemotactic mediators were quantified in the inflammatory exudate, and adhesion molecule and toll-like receptor 4 (TLR-4) expressions and phorbol-myristate-acetate- (PMA-) stimulated oxidative burst were quantified in circulating neutrophils. Leukocyte-endothelial interactions were quantified in the mesentery tissue. Enzymes and tissue morphology of the liver and kidney were evaluated. Treatment with A. satureioides extract reduced neutrophil influx and secretion of leukotriene B4 and CINC-1 in the exudates, the number of rolling and adhered leukocytes in the mesentery postcapillary venules, neutrophil L-selectin, β2-integrin and TLR-4 expression, and oxidative burst, but did not cause an alteration in the morphology and activities of liver and kidney. Together, the data show that A. satureioides extract inhibits neutrophil functions related to the innate response and does not cause systemic toxicity. PMID:23476704

  2. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense.

    PubMed

    Garaude, Johan; Acín-Pérez, Rebeca; Martínez-Cano, Sarai; Enamorado, Michel; Ugolini, Matteo; Nistal-Villán, Estanislao; Hervás-Stubbs, Sandra; Pelegrín, Pablo; Sander, Leif E; Enríquez, José A; Sancho, David

    2016-09-01

    Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection. PMID:27348412

  3. Role of primary human alveolar epithelial cells in host defense against Francisella tularensis infection.

    PubMed

    Gentry, Megan; Taormina, Joanna; Pyles, Richard B; Yeager, Linsey; Kirtley, Michelle; Popov, Vsevolod L; Klimpel, Gary; Eaves-Pyles, Tonyia

    2007-08-01

    Francisella tularensis, an intracellular pathogen, is highly virulent when inhaled. Alveolar epithelial type I (ATI) and type II (ATII) cells line the majority of the alveolar surface and respond to inhaled pathogenic bacteria via cytokine secretion. We hypothesized that these cells contribute to the lung innate immune response to F. tularensis. Results demonstrated that the live vaccine strain (LVS) contacted ATI and ATII cells by 2 h following intranasal inoculation of mice. In culture, primary human ATI or ATII cells, grown on transwell filters, were stimulated on the apical (AP) surface with virulent F. tularensis Schu 4 or LVS. Basolateral (BL) conditioned medium (CM), collected 6 and 24 h later, was added to the BL surfaces of transwell cultures of primary human pulmonary microvasculature endothelial cells (HPMEC) prior to the addition of polymorphonuclear leukocytes (PMNs) or dendritic cells (DCs) to the AP surface. HPMEC responded to S4- or LVS-stimulated ATII, but not ATI, CM as evidenced by PMN and DC migration. Analysis of the AP and BL ATII CM revealed that both F. tularensis strains induced various levels of a variety of cytokines via NF-kappaB activation. ATII cells pretreated with an NF-kappaB inhibitor prior to F. tularensis stimulation substantially decreased interleukin-8 secretion, which did not occur through Toll-like receptor 2, 2/6, 4, or 5 stimulation. These data indicate a crucial role for ATII cells in the innate immune response to F. tularensis. PMID:17502386

  4. Role of Primary Human Alveolar Epithelial Cells in Host Defense against Francisella tularensis Infection▿

    PubMed Central

    Gentry, Megan; Taormina, Joanna; Pyles, Richard B.; Yeager, Linsey; Kirtley, Michelle; Popov, Vsevolod L.; Klimpel, Gary; Eaves-Pyles, Tonyia

    2007-01-01

    Francisella tularensis, an intracellular pathogen, is highly virulent when inhaled. Alveolar epithelial type I (ATI) and type II (ATII) cells line the majority of the alveolar surface and respond to inhaled pathogenic bacteria via cytokine secretion. We hypothesized that these cells contribute to the lung innate immune response to F. tularensis. Results demonstrated that the live vaccine strain (LVS) contacted ATI and ATII cells by 2 h following intranasal inoculation of mice. In culture, primary human ATI or ATII cells, grown on transwell filters, were stimulated on the apical (AP) surface with virulent F. tularensis Schu 4 or LVS. Basolateral (BL) conditioned medium (CM), collected 6 and 24 h later, was added to the BL surfaces of transwell cultures of primary human pulmonary microvasculature endothelial cells (HPMEC) prior to the addition of polymorphonuclear leukocytes (PMNs) or dendritic cells (DCs) to the AP surface. HPMEC responded to S4- or LVS-stimulated ATII, but not ATI, CM as evidenced by PMN and DC migration. Analysis of the AP and BL ATII CM revealed that both F. tularensis strains induced various levels of a variety of cytokines via NF-κB activation. ATII cells pretreated with an NF-κB inhibitor prior to F. tularensis stimulation substantially decreased interleukin-8 secretion, which did not occur through Toll-like receptor 2, 2/6, 4, or 5 stimulation. These data indicate a crucial role for ATII cells in the innate immune response to F. tularensis. PMID:17502386

  5. Aphanomyces euteiches cell wall fractions containing novel glucan-chitosaccharides induce defense genes and nuclear calcium oscillations in the plant host Medicago truncatula.

    PubMed

    Nars, Amaury; Lafitte, Claude; Chabaud, Mireille; Drouillard, Sophie; Mélida, Hugo; Danoun, Saïda; Le Costaouëc, Tinaig; Rey, Thomas; Benedetti, Julie; Bulone, Vincent; Barker, David George; Bono, Jean-Jacques; Dumas, Bernard; Jacquet, Christophe; Heux, Laurent; Fliegmann, Judith; Bottin, Arnaud

    2013-01-01

    N-acetylglucosamine-based saccharides (chitosaccharides) are components of microbial cell walls and act as molecular signals during host-microbe interactions. In the legume plant Medicago truncatula, the perception of lipochitooligosaccharide signals produced by symbiotic rhizobia and arbuscular mycorrhizal fungi involves the Nod Factor Perception (NFP) lysin motif receptor-like protein and leads to the activation of the so-called common symbiotic pathway. In rice and Arabidopsis, lysin motif receptors are involved in the perception of chitooligosaccharides released by pathogenic fungi, resulting in the activation of plant immunity. Here we report the structural characterization of atypical chitosaccharides from the oomycete pathogen Aphanomyces euteiches, and their biological activity on the host Medicago truncatula. Using a combination of biochemical and biophysical approaches, we show that these chitosaccharides are linked to β-1,6-glucans, and contain a β-(1,3;1,4)-glucan backbone whose β-1,3-linked glucose units are substituted on their C-6 carbon by either glucose or N-acetylglucosamine residues. This is the first description of this type of structural motif in eukaryotic cell walls. Glucan-chitosaccharide fractions of A. euteiches induced the expression of defense marker genes in Medicago truncatula seedlings independently from the presence of a functional Nod Factor Perception protein. Furthermore, one of the glucan-chitosaccharide fractions elicited calcium oscillations in the nucleus of root cells. In contrast to the asymmetric oscillatory calcium spiking induced by symbiotic lipochitooligosaccharides, this response depends neither on the Nod Factor Perception protein nor on the common symbiotic pathway. These findings open new perspectives in oomycete cell wall biology and elicitor recognition and signaling in legumes. PMID:24086432

  6. Aphanomyces euteiches Cell Wall Fractions Containing Novel Glucan-Chitosaccharides Induce Defense Genes and Nuclear Calcium Oscillations in the Plant Host Medicago truncatula

    PubMed Central

    Nars, Amaury; Lafitte, Claude; Chabaud, Mireille; Drouillard, Sophie; Mélida, Hugo; Danoun, Saïda; Le Costaouëc, Tinaig; Rey, Thomas; Benedetti, Julie; Bulone, Vincent; Barker, David George; Bono, Jean-Jacques; Dumas, Bernard; Jacquet, Christophe; Heux, Laurent; Fliegmann, Judith; Bottin, Arnaud

    2013-01-01

    N-acetylglucosamine-based saccharides (chitosaccharides) are components of microbial cell walls and act as molecular signals during host-microbe interactions. In the legume plant Medicago truncatula, the perception of lipochitooligosaccharide signals produced by symbiotic rhizobia and arbuscular mycorrhizal fungi involves the Nod Factor Perception (NFP) lysin motif receptor-like protein and leads to the activation of the so-called common symbiotic pathway. In rice and Arabidopsis, lysin motif receptors are involved in the perception of chitooligosaccharides released by pathogenic fungi, resulting in the activation of plant immunity. Here we report the structural characterization of atypical chitosaccharides from the oomycete pathogen Aphanomyces euteiches, and their biological activity on the host Medicago truncatula. Using a combination of biochemical and biophysical approaches, we show that these chitosaccharides are linked to β-1,6-glucans, and contain a β-(1,3;1,4)-glucan backbone whose β-1,3-linked glucose units are substituted on their C-6 carbon by either glucose or N-acetylglucosamine residues. This is the first description of this type of structural motif in eukaryotic cell walls. Glucan-chitosaccharide fractions of A. euteiches induced the expression of defense marker genes in Medicago truncatula seedlings independently from the presence of a functional Nod Factor Perception protein. Furthermore, one of the glucan-chitosaccharide fractions elicited calcium oscillations in the nucleus of root cells. In contrast to the asymmetric oscillatory calcium spiking induced by symbiotic lipochitooligosaccharides, this response depends neither on the Nod Factor Perception protein nor on the common symbiotic pathway. These findings open new perspectives in oomycete cell wall biology and elicitor recognition and signaling in legumes. PMID:24086432

  7. Phyllotreta striolata flea beetles use host plant defense compounds to create their own glucosinolate-myrosinase system.

    PubMed

    Beran, Franziska; Pauchet, Yannick; Kunert, Grit; Reichelt, Michael; Wielsch, Natalie; Vogel, Heiko; Reinecke, Andreas; Svatoš, Aleš; Mewis, Inga; Schmid, Daniela; Ramasamy, Srinivasan; Ulrichs, Christian; Hansson, Bill S; Gershenzon, Jonathan; Heckel, David G

    2014-05-20

    The ability of a specialized herbivore to overcome the chemical defense of a particular plant taxon not only makes it accessible as a food source but may also provide metabolites to be exploited for communication or chemical defense. Phyllotreta flea beetles are adapted to crucifer plants (Brassicales) that are defended by the glucosinolate-myrosinase system, the so-called "mustard-oil bomb." Tissue damage caused by insect feeding brings glucosinolates into contact with the plant enzyme myrosinase, which hydrolyzes them to form toxic compounds, such as isothiocyanates. However, we previously observed that Phyllotreta striolata beetles themselves produce volatile glucosinolate hydrolysis products. Here, we show that P. striolata adults selectively accumulate glucosinolates from their food plants to up to 1.75% of their body weight and express their own myrosinase. By combining proteomics and transcriptomics, a gene responsible for myrosinase activity in P. striolata was identified. The major substrates of the heterologously expressed myrosinase were aliphatic glucosinolates, which were hydrolyzed with at least fourfold higher efficiency than aromatic and indolic glucosinolates, and β-O-glucosides. The identified beetle myrosinase belongs to the glycoside hydrolase family 1 and has up to 76% sequence similarity to other β-glucosidases. Phylogenetic analyses suggest species-specific diversification of this gene family in insects and an independent evolution of the beetle myrosinase from other insect β-glucosidases. PMID:24799680

  8. Plant Defense Mechanisms Are Activated during Biotrophic and Necrotrophic Development of Colletotricum graminicola in Maize1[W][OA

    PubMed Central

    Vargas, Walter A.; Martín, José M. Sanz; Rech, Gabriel E.; Rivera, Lina P.; Benito, Ernesto P.; Díaz-Mínguez, José M.; Thon, Michael R.; Sukno, Serenella A.

    2012-01-01

    Hemibiotrophic plant pathogens first establish a biotrophic interaction with the host plant and later switch to a destructive necrotrophic lifestyle. Studies of biotrophic pathogens have shown that they actively suppress plant defenses after an initial microbe-associated molecular pattern-triggered activation. In contrast, studies of the hemibiotrophs suggest that they do not suppress plant defenses during the biotrophic phase, indicating that while there are similarities between the biotrophic phase of hemibiotrophs and biotrophic pathogens, the two lifestyles are not analogous. We performed transcriptomic, histological, and biochemical studies of the early events during the infection of maize (Zea mays) with Colletotrichum graminicola, a model pathosystem for the study of hemibiotrophy. Time-course experiments revealed that mRNAs of several defense-related genes, reactive oxygen species, and antimicrobial compounds all begin to accumulate early in the infection process and continue to accumulate during the biotrophic stage. We also discovered the production of maize-derived vesicular bodies containing hydrogen peroxide targeting the fungal hyphae. We describe the fungal respiratory burst during host infection, paralleled by superoxide ion production in specific fungal cells during the transition from biotrophy to a necrotrophic lifestyle. We also identified several novel putative fungal effectors and studied their expression during anthracnose development in maize. Our results demonstrate a strong induction of defense mechanisms occurring in maize cells during C. graminicola infection, even during the biotrophic development of the pathogen. We hypothesize that the switch to necrotrophic growth enables the fungus to evade the effects of the plant immune system and allows for full fungal pathogenicity. PMID:22247271

  9. Active-passive bistatic surveillance for long range air defense

    NASA Astrophysics Data System (ADS)

    Wardrop, B.; Molyneux-Berry, M. R. B.

    1992-06-01

    A hypothetical mobile support receiver capable of working within existing and future air defense networks as a means to maintain essential surveillance functions is considered. It is shown how multibeam receiver architecture supported by digital signal processing can substantially improve surveillance performance against chaff and jamming threats. A dual-mode support receiver concept is proposed which is based on the state-of-the-art phased-array technology, modular processing in industry standard hardware and existing networks.

  10. Active-passive bistatic surveillance for long range air defense

    SciTech Connect

    Wardrop, B.; Molyneux-Berry, M.R.B. )

    1992-06-01

    A hypothetical mobile support receiver capable of working within existing and future air defense networks as a means to maintain essential surveillance functions is considered. It is shown how multibeam receiver architecture supported by digital signal processing can substantially improve surveillance performance against chaff and jamming threats. A dual-mode support receiver concept is proposed which is based on the state-of-the-art phased-array technology, modular processing in industry standard hardware and existing networks. 20 refs.

  11. Leaf-mining by Phyllonorycter blancardella reprograms the host-leaf transcriptome to modulate phytohormones associated with nutrient mobilization and plant defense.

    PubMed

    Zhang, Hui; Dugé de Bernonville, Thomas; Body, Mélanie; Glevarec, Gaëlle; Reichelt, Michael; Unsicker, Sybille; Bruneau, Maryline; Renou, Jean-Pierre; Huguet, Elisabeth; Dubreuil, Géraldine; Giron, David

    2016-01-01

    Phytohormones have long been hypothesized to play a key role in the interactions between plant-manipulating organisms and their host-plants such as insect-plant interactions that lead to gall or 'green-islands' induction. However, mechanistic understanding of how phytohormones operate in these plant reconfigurations is lacking due to limited information on the molecular and biochemical phytohormonal modulation following attack by plant-manipulating insects. In an attempt to fill this gap, the present study provides an extensive characterization of how the leaf-miner Phyllonorycter blancardella modulates the major phytohormones and the transcriptional activity of plant cells in leaves of Malus domestica. We show here, that cytokinins strongly accumulate in mined tissues despite a weak expression of plant cytokinin-related genes. Leaf-mining is also associated with enhanced biosynthesis of jasmonic acid precursors but not the active form, a weak alteration of the salicylic acid pathway and a clear inhibition of the abscisic acid pathway. Our study consolidates previous results suggesting that insects may produce and deliver cytokinins to the plant as a strategy to manipulate the physiology of the leaf to create a favorable nutritional environment. We also demonstrate that leaf-mining by P. blancardella leads to a strong reprogramming of the plant phytohormonal balance associated with increased nutrient mobilization, inhibition of leaf senescence and mitigation of plant direct and indirect defense. PMID:26068004

  12. Characterization of Oyster Voltage-Dependent Anion Channel 2 (VDAC2) Suggests Its Involvement in Apoptosis and Host Defense

    PubMed Central

    Li, Yingxiang; Zhang, Linlin; Qu, Tao; Li, Li; Zhang, Guofan

    2016-01-01

    Genomic and transcriptomic studies have revealed a sophisticated and powerful apoptosis regulation network in oyster, highlighting its adaptation to sessile life in a highly stressful intertidal environment. However, the functional molecular basis of apoptosis remains largely unexplored in oysters. In this study, we focused on a representative apoptotic gene encoding voltage-dependent anion channel 2 (VDAC2), a porin that abounds at the mitochondrial outer membrane. This is the first report on the identification and characterization of a VDAC gene in the Pacific oyster, Crassostrea gigas (CgVDAC2). The full length of CgVDAC2 was 1,738 bp with an open reading frame of 843 bp that encoded a protein of 281 amino acids. A four-element eukaryotic porin signature motif, a conserved ATP binding motif, and a VKAKV-like sequence were identified in the predicted CgVDAC2. Expression pattern analysis in different tissues and developmental stages as well as upon infection by ostreid herpesvirus 1 revealed the energy supply-related and immunity-related expression of CgVDAC2. CgVDAC2 was co-localized with mitochondria when it was transiently transfected into HeLa cells. Overexpression of CgVDAC2 in HEK293T cells suppressed the UV irradiation-induced apoptosis by inhibiting the pro-apoptotic function of CgBak. RNA interference induced reduction in CgVDAC2 expression showed a promoted apoptosis level upon UV light irradiation in hemocytes. The yeast two-hybrid system and co-immunoprecipitation assay indicated a direct interaction between CgVDAC2 and the pro-apoptotic protein CgBak. This study revealed the function of VDAC2 in oyster and provided new insights into its involvement in apoptosis modulation and host defense in mollusks. PMID:26727366

  13. The acute and sub-chronic exposures of goldfish to naphthenic acids induce different host defense responses.

    PubMed

    Hagen, Mariel O; Garcia-Garcia, Erick; Oladiran, Ayoola; Karpman, Matthew; Mitchell, Scott; El-Din, Mohamed Gamal; Martin, Jonathan W; Belosevic, Miodrag

    2012-03-01

    Naphthenic acids (NAs) are believed to be the major toxic component in oil sands process-affected water (OSPW) produced by the oil sands mining industry in Northern Alberta, Canada. We recently reported that oral exposure to NAs alters mammalian immune responses, but the effect of OSPW or NAs on the immune mechanisms of aquatic organisms has not been fully elucidated. We analyzed the effects of acute and sub-chronic NAs exposures on goldfish immune responses by measuring the expression of three pro-inflammatory cytokine genes, antimicrobial functions of macrophages, and host defense after challenge with a protozoan pathogen (Trypanosoma carassii). One week after NAs exposure, fish exhibited increased expression of pro-inflammatory cytokines (IFNγ, IL-1β1, TNF-α2) in the gills, kidney and spleen. Primary macrophages from fish exposed to NAs for one week, exhibited increased production of nitric oxide and reactive oxygen intermediates. Goldfish exposed for one week to 20 mg/L NAs were more resistant to infection by T. carassii. In contrast, sub-chronic exposure of goldfish (12 weeks) to NAs resulted in decreased expression of pro-inflammatory cytokines in the gills, kidney and spleen. The sub-chronic exposure to NAs reduced the ability of goldfish to control the T. carassii infection, exemplified by a drastic increase in fish mortality and increased blood parasite loads. This is the first report analyzing the effects of OSPW contaminants on the immune system of aquatic vertebrates. We believe that the bioassays depicted in this work will be valuable tools for analyzing the efficacy of OSPW remediation techniques and assessment of diverse environmental pollutants. PMID:22227375

  14. Characterization of Oyster Voltage-Dependent Anion Channel 2 (VDAC2) Suggests Its Involvement in Apoptosis and Host Defense.

    PubMed

    Li, Yingxiang; Zhang, Linlin; Qu, Tao; Li, Li; Zhang, Guofan

    2016-01-01

    Genomic and transcriptomic studies have revealed a sophisticated and powerful apoptosis regulation network in oyster, highlighting its adaptation to sessile life in a highly stressful intertidal environment. However, the functional molecular basis of apoptosis remains largely unexplored in oysters. In this study, we focused on a representative apoptotic gene encoding voltage-dependent anion channel 2 (VDAC2), a porin that abounds at the mitochondrial outer membrane. This is the first report on the identification and characterization of a VDAC gene in the Pacific oyster, Crassostrea gigas (CgVDAC2). The full length of CgVDAC2 was 1,738 bp with an open reading frame of 843 bp that encoded a protein of 281 amino acids. A four-element eukaryotic porin signature motif, a conserved ATP binding motif, and a VKAKV-like sequence were identified in the predicted CgVDAC2. Expression pattern analysis in different tissues and developmental stages as well as upon infection by ostreid herpesvirus 1 revealed the energy supply-related and immunity-related expression of CgVDAC2. CgVDAC2 was co-localized with mitochondria when it was transiently transfected into HeLa cells. Overexpression of CgVDAC2 in HEK293T cells suppressed the UV irradiation-induced apoptosis by inhibiting the pro-apoptotic function of CgBak. RNA interference induced reduction in CgVDAC2 expression showed a promoted apoptosis level upon UV light irradiation in hemocytes. The yeast two-hybrid system and co-immunoprecipitation assay indicated a direct interaction between CgVDAC2 and the pro-apoptotic protein CgBak. This study revealed the function of VDAC2 in oyster and provided new insights into its involvement in apoptosis modulation and host defense in mollusks. PMID:26727366

  15. Molecular insights into a molluscan transferrin homolog identified from disk abalone (Haliotis discus discus) evidencing its detectable role in host antibacterial defense.

    PubMed

    Herath, H M L P B; Elvitigala, Don Anushka Sandaruwan; Godahewa, G I; Whang, Ilson; Lee, Jehee

    2015-11-01

    The basic function of transferrin is to bind iron (III) ions in the medium and to deliver them to the locations where they are required for metabolic processes. It also takes part in the host immune defense mainly via its ability to bind to iron (III) ions. Hence, transferrin is also identified as an important acute-phase protein in host immunity. Abalones are major shellfish aquaculture crops that are susceptible to a range of marine microbial infections. Since transferrin is known to be a major player in innate immunity, in the present study we sought to identify, and molecularly and functionally characterize a transferrin-like gene from disk abalone (Haliotis discus discus) named as AbTrf. AbTrf consisted of a 2187-bp open reading frame (ORF) which encodes a 728 amino acid (aa) protein. The putative amino acid sequence of AbTrf harbored N- and C-terminal transferrin-like domains, active sites for iron binding, and conserved cysteine residues. A constitutive tissue specific AbTrf expression pattern was detected by qPCR in abalones where mantle and muscle showed high AbTrf expression levels. Three immune challenge experiments were conducted using Vibrio parahaemolyticus, Listeria monocytogenes and LPS as stimuli and, subsequently, AbTrf mRNA expression levels were quantified in gill and hemocytes in a time-course manner. The mRNA expression was greatly induced in both tissues in response to both challenges. Evidencing the functional property of transferrins, recombinant AbTrf N-terminal domain (AbTrf-N) showed dose-dependent iron (III) binding activity detected by chrome azurol S (CAS) assay system. Moreover, recombinant AbTrf-N could significantly inhibit the growth of iron-dependent bacterium, Escherichia coli in a dose-dependent manner. However, AbTrf-N was unable to show any detectable bacteriostatic activity against iron-independent bacterium Lactobacillus plantarum (L. plantarum) even at its highest concentration. Collectively, our results suggest that Ab

  16. Host-pathogen interactions between the human innate immune system and Candida albicans—understanding and modeling defense and evasion strategies

    PubMed Central

    Dühring, Sybille; Germerodt, Sebastian; Skerka, Christine; Zipfel, Peter F.; Dandekar, Thomas; Schuster, Stefan

    2015-01-01

    The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given. PMID:26175718

  17. The Bark-Beetle-Associated Fungus, Endoconidiophora polonica, Utilizes the Phenolic Defense Compounds of Its Host as a Carbon Source.

    PubMed

    Wadke, Namita; Kandasamy, Dineshkumar; Vogel, Heiko; Lah, Ljerka; Wingfield, Brenda D; Paetz, Christian; Wright, Louwrance P; Gershenzon, Jonathan; Hammerbacher, Almuth

    2016-06-01

    Norway spruce (Picea abies) is periodically attacked by the bark beetle Ips typographus and its fungal associate, Endoconidiophora polonica, whose infection is thought to be required for successful beetle attack. Norway spruce produces terpenoid resins and phenolics in response to fungal and bark beetle invasion. However, how the fungal associate copes with these chemical defenses is still unclear. In this study, we investigated changes in the phenolic content of Norway spruce bark upon E. polonica infection and the biochemical factors mediating these changes. Although genes encoding the rate-limiting enzymes in Norway spruce stilbene and flavonoid biosynthesis were actively transcribed during fungal infection, there was a significant time-dependent decline of the corresponding metabolites in fungal lesions. In vitro feeding experiments with pure phenolics revealed that E. polonica transforms both stilbenes and flavonoids to muconoid-type ring-cleavage products, which are likely the first steps in the degradation of spruce defenses to substrates that can enter the tricarboxylic acid cycle. Four genes were identified in E. polonica that encode catechol dioxygenases carrying out these reactions. These enzymes catalyze the cleavage of phenolic rings with a vicinal dihydroxyl group to muconoid products accepting a wide range of Norway spruce-produced phenolics as substrates. The expression of these genes and E. polonica utilization of the most abundant spruce phenolics as carbon sources both correlated positively with fungal virulence in several strains. Thus, the pathways for the degradation of phenolic compounds in E. polonica, initiated by catechol dioxygenase action, are important to the infection, growth, and survival of this bark beetle-vectored fungus and may play a major role in the ability of I. typographus to colonize spruce trees. PMID:27208235

  18. Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature.

    PubMed

    Foxman, Ellen F; Storer, James A; Vanaja, Kiran; Levchenko, Andre; Iwasaki, Akiko

    2016-07-26

    Most strains of rhinovirus (RV), the common cold virus, replicate better at cool temperatures found in the nasal cavity (33-35 °C) than at lung temperature (37 °C). Recent studies found that although 37 °C temperature suppressed RV growth largely by engaging the type 1 IFN response in infected epithelial cells, a significant temperature dependence to viral replication remained in cells devoid of IFN induction or signaling. To gain insight into IFN-independent mechanisms limiting RV replication at 37 °C, we studied RV infection in human bronchial epithelial cells and H1-HeLa cells. During the single replication cycle, RV exhibited temperature-dependent replication in both cell types in the absence of IFN induction. At 37 °C, earlier signs of apoptosis in RV-infected cells were accompanied by reduced virus production. Furthermore, apoptosis of epithelial cells was enhanced at 37 °C in response to diverse stimuli. Dynamic mathematical modeling and B cell lymphoma 2 (BCL2) overexpression revealed that temperature-dependent host cell death could partially account for the temperature-dependent growth observed during RV amplification, but also suggested additional mechanisms of virus control. In search of a redundant antiviral pathway, we identified a role for the RNA-degrading enzyme RNAseL. Simultaneous antagonism of apoptosis and RNAseL increased viral replication and dramatically reduced temperature dependence. These findings reveal two IFN-independent mechanisms active in innate defense against RV, and demonstrate that even in the absence of IFNs, temperature-dependent RV amplification is largely a result of host cell antiviral restriction mechanisms operating more effectively at 37 °C than at 33 °C. PMID:27402752

  19. Peptidomic analysis of the extensive array of host-defense peptides in skin secretions of the dodecaploid frog Xenopus ruwenzoriensis (Pipidae).

    PubMed

    Coquet, Laurent; Kolodziejek, Jolanta; Jouenne, Thierry; Nowotny, Norbert; King, Jay D; Conlon, J Michael

    2016-09-01

    The Uganda clawed frog Xenopus ruwenzoriensis with a karyotype of 2n=108 is one of the very few vertebrates with dodecaploid status. Peptidomic analysis of norepinephrine-stimulated skin secretions from this species led to the isolation and structural characterization of 23 host-defense peptides belonging to the following families: magainin (3 peptides), peptide glycine-leucine-amide (PGLa; 6 peptides), xenopsin precursor fragment (XPF; 3 peptides), caerulein precursor fragment (CPF; 8 peptides), and caerulein precursor fragment-related peptide (CPF-RP; 3 peptides). In addition, the secretions contained caerulein, identical to the peptide from Xenopus laevis, and two peptides that were identified as members of the trefoil factor family (TFF). The data indicate that silencing of the host-defense peptide genes following polyploidization has been appreciable and non-uniform. Consistent with data derived from comparison of nucleotide sequences of mitochrondrial and nuclear genes, cladistic analyses based upon the primary structures of the host-defense peptides provide support for an evolutionary scenario in which X. ruwenzoriensis arose from an allopolyploidization event involving an octoploid ancestor of the present-day frogs belonging to the Xenopus amieti species group and a tetraploid ancestor of Xenopus pygmaeus. PMID:27290612

  20. Role of Granulocyte Macrophage Colony-Stimulating Factor in Host Defense Against Pulmonary Cryptococcus neoformans Infection during Murine Allergic Bronchopulmonary Mycosis

    PubMed Central

    Chen, Gwo-Hsiao; Olszewski, Michal A.; McDonald, Roderick A.; Wells, Jason C.; Paine, Robert; Huffnagle, Gary B.; Toews, Galen B.

    2007-01-01

    We investigated the role of granulocyte macrophage colony-stimulating factor (GM-CSF) in host defense in a murine model of pulmonary cryptococcosis induced by intratracheal inoculation of Cryptococcus neoformans. Pulmonary C. neoformans infection of C57BL/6 mice is an established model of an allergic bronchopulmonary mycosis. Our objective was to determine whether GM-CSF regulates the pulmonary Th2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in GM-CSF knockout (GM−/−) mice, resulting in increased pulmonary burden of fungi between weeks 3 and 5. GM-CSF was required for the early influx of macrophages and CD4 and CD8 T cells into the lungs but was not required later in the infection. Lack of GM-CSF also resulted in reduced eosinophil recruitment and delayed recruitment of mononuclear cells into the airspace. Macrophages from GM+/+ mice showed numerous hallmarks of alternatively activated macrophages: higher numbers of intracellular cryptococci, YM1 crystals, and induction of CCL17. These hallmarks are absent in macrophages from GM−/− mice. Mucus-producing goblet cells were abundantly present within the bronchial epithelial layer in GM+/+ mice but not in GM−/− mice at week 5 after infection. Production of both Th1 and Th2 cytokines was impaired in the absence of GM-CSF, consistent with both reduced C. neoformans clearance and absence of allergic lung pathology. PMID:17322386

  1. Survival to Parasitoids in an Insect Hosting Defensive Symbionts: A Multivariate Approach to Polymorphic Traits Affecting Host Use by Its Natural Enemy

    PubMed Central

    Bilodeau, Emilie; Guay, Jean-Frédéric; Turgeon, Julie; Cloutier, Conrad

    2013-01-01

    Insect parasitoids and their insect hosts represent a wide range of parasitic trophic relations that can be used to understand the evolution of biotic diversity on earth. Testing theories of coevolution between hosts and parasites is based on factors directly involved in host susceptibility and parasitoid virulence. We used controlled encounters with potential hosts of the Aphidius ervi wasp to elucidate behavioral and other phenotypic traits of host Acyrthosiphon pisum that most contribute to success or failure of parasitism. The host aphid is at an advanced stage of specialization on different crop plants, and exhibits intra-population polymorphism for traits of parasitoid avoidance and resistance based on clonal variation of color morph and anti-parasitoid bacterial symbionts. Randomly selected aphid clones from alfalfa and clover were matched in 5 minute encounters with wasps of two parasitoid lineages deriving from hosts of each plant biotype in a replicated transplant experimental design. In addition to crop plant affiliation (alfalfa, clover), aphid clones were characterized for color morph (green, pink), Hamiltonella defensa and Regiella insecticola symbionts, and frequently used behaviors in encounters with A. ervi wasps. A total of 12 explanatory variables were examined using redundancy analysis (RDA) to predict host survival or failure to A. ervi parasitism. Aphid color was the best univariate predictor, but was poorly predictive in the RDA model. In contrast, aphid host plant and symbionts were not significant univariate predictors, but significant predictors in the multivariate model. Aphid susceptibility to wasp acceptance as reflected in host attacks and oviposition clearly differed from its suitability to parasitism and progeny development. Parasitoid progeny were three times more likely to survive on clover than alfalfa host aphids, which was compensated by behaviorally adjusting eggs invested per host. Strong variation of the predictive power of

  2. Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage.

    PubMed

    Cervellati, Carlo; Sticozzi, Claudia; Romani, Arianna; Belmonte, Giuseppe; De Rasmo, Domenico; Signorile, Anna; Cervellati, Franco; Milanese, Chiara; Mastroberardino, Pier Giorgio; Pecorelli, Alessandra; Savelli, Vinno; Forman, Henry J; Hayek, Joussef; Valacchi, Giuseppe

    2015-10-01

    A strong correlation between oxidative stress (OS) and Rett syndrome (RTT), a rare neurodevelopmental disorder affecting females in the 95% of the cases, has been well documented although the source of OS and the effect of a redox imbalance in this pathology has not been yet investigated. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have demonstrated in RTT cells high levels of H2O2 and HNE protein adducts. These findings correlated with the constitutive activation of NADPH-oxidase (NOX) and that was prevented by a NOX inhibitor and iron chelator pre-treatment, showing its direct involvement. In parallel, we demonstrated an increase in mitochondrial oxidant production, altered mitochondrial biogenesis and impaired proteasome activity in RTT samples. Further, we found that the key cellular defensive enzymes: glutathione peroxidase, superoxide dismutase and thioredoxin reductases activities were also significantly lower in RTT. Taken all together, our findings suggest that the systemic OS levels in RTT can be a consequence of both: increased endogenous oxidants as well as altered mitochondrial biogenesis with a decreased activity of defensive enzymes that leads to posttranslational oxidant protein modification and a proteasome activity impairment. PMID:26189585

  3. Chemoproteomic profiling of host and pathogen enzymes active in cholera

    PubMed Central

    Hatzios, Stavroula K.; Hubbard, Troy; Sasabe, Jumpei; Munera, Diana; Clark, Lars; Bachovchin, Daniel A.; Qadri, Firdausi; Ryan, Edward T.; Davis, Brigid M.; Weerapana, Eranthie; Waldor, Matthew K.

    2016-01-01

    Activity-based protein profiling (ABPP) is a chemoproteomic tool for detecting active enzymes in complex biological systems. We used ABPP to identify secreted bacterial and host serine hydrolases that are active in animals infected with the cholera pathogen Vibrio cholerae. Four V. cholerae proteases were consistently active in infected rabbits, and one, VC0157 (renamed IvaP), was also active in human cholera stool. Inactivation of IvaP influenced the activity of other secreted V. cholerae and rabbit enzymes in vivo, while genetic disruption of all four proteases increased the abundance and binding of an intestinal lectin—intelectin—to V. cholerae in infected rabbits. Intelectin also bound to other enteric bacterial pathogens, suggesting it may constitute a previously unrecognized mechanism of bacterial surveillance in the intestine that is inhibited by pathogen-secreted proteases. Our work demonstrates the power of activity-based proteomics to reveal host-pathogen enzymatic dialogue in an animal model of infection. PMID:26900865

  4. Jasmonic acid and salicylic acid activate a common defense system in rice

    PubMed Central

    Tamaoki, Daisuke; Seo, Shigemi; Yamada, Shoko; Kano, Akihito; Miyamoto, Ayumi; Shishido, Hodaka; Miyoshi, Seika; Taniguchi, Shiduku; Akimitsu, Kazuya; Gomi, Kenji

    2013-01-01

    Jasmonic acid (JA) and salicylic acid (SA) play important roles in plant defense systems. JA and SA signaling pathways interact antagonistically in dicotyledonous plants, but, the status of crosstalk between JA and SA signaling is unknown in monocots. Our rice microarray analysis showed that more than half of the genes upregulated by the SA analog BTH are also upregulated by JA, suggesting that a major portion of the SA-upregulated genes are regulated by JA-dependent signaling in rice. A common defense system that is activated by both JA and SA is thus proposed which plays an important role in pathogen defense responses in rice. PMID:23518581

  5. Enteropathogenic Escherichia coli inhibits type I interferon- and RNase L-mediated host defense to disrupt intestinal epithelial cell barrier function.

    PubMed

    Long, Tiha M; Nisa, Shahista; Donnenberg, Michael S; Hassel, Bret A

    2014-07-01

    Enteropathogenic Escherichia coli (EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function. PMID:24733098

  6. Role of PMK-1/p38 MAPK defense in Caenorhabditis elegans against Klebsiella pneumoniae infection during host-pathogen interaction.

    PubMed

    Kamaladevi, Arumugam; Balamurugan, Krishnaswamy

    2015-07-01

    The present study reports that Klebsiella pneumoniae (KP) killed the Caenorhabditis elegans as a consequence of an accumulation and proliferation of the pathogen inside the worms' intestine. The real-time PCR analysis of the genes responsible for vulval development (let-23) and egg laying (lin-29) in KP infected C. elegans confirmed the reproductive defects provoked by KP at the molecular level. In addition, the genetic analysis in N2 wild type, tol-1, sek-1 and pmk-1 mutants unveiled that KP attenuates the toll-dependent p38 mitogen-activated protein kinase (p38 MAPK) by chiefly inhibiting the production of antimicrobial factors such as nlp-29, lys-1 and C-type lectins. Conclusively, the surrendering of the host immune system appears to be attenuated by the toll-dependent p38 MAPK pathway regulation in C. elegans. PMID:25819035

  7. The Nod1, Nod2, and Rip2 Axis Contributes to Host Immune Defense against Intracellular Acinetobacter baumannii Infection

    PubMed Central

    Bist, Pradeep; Dikshit, Neha; Koh, Tse Hsien; Mortellaro, Alessandra; Tan, Thuan Tong

    2014-01-01

    Acinetobacter baumannii is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling A. baumannii are not well understood. Although viewed as an extracellular pathogen, A. baumannii can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against A. baumannii is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of A. baumannii by human airway epithelial cells in vitro. A. baumannii infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of A. baumannii in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of A. baumannii infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for A. baumannii infection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to A. baumannii infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of A. baumannii infection through the production of β-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of A. baumannii and may contribute to the development of effective immune therapeutics and vaccines against A. baumannii. PMID:24366254

  8. Lectin Activation in Giardia lamblia by Host Protease: A Novel Host-Parasite Interaction

    NASA Astrophysics Data System (ADS)

    Lev, Boaz; Ward, Honorine; Keusch, Gerald T.; Pereira, Miercio E. A.

    1986-04-01

    A lectin in Giardia lamblia was activated by secretions from the human duodenum, the environment where the parasite lives. Incubation of the secretions with trypsin inhibitors prevented the appearance of lectin activity, implicating proteases as the activating agent. Accordingly, lectin activation was also produced by crystalline trypsin and Pronase; other proteases tested were ineffective. When activated, the lectin agglutinated intestinal cells to which the parasite adheres in vivo. The lectin was most specific to mannose-6-phosphate and apparently was bound to the plasma membrane. Activation of a parasite lectin by a host protease represents a novel mechanism of hostparasite interaction and may contribute to the affinity of Giardia lamblia to the infection site.

  9. Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice.

    PubMed

    Nakamura, Shigeki; Iwanaga, Naoki; Seki, Masafumi; Fukudome, Kenji; Oshima, Kazuhiro; Miyazaki, Taiga; Izumikawa, Koichi; Yanagihara, Katsunori; Miyazaki, Yoshitsugu; Mukae, Hiroshi; Kohno, Shigeru

    2016-07-01

    Chronic lower respiratory tract infection with Pseudomonas aeruginosa is difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response to Pseudomonas infection in mice. We implanted sterile plastic tubes precoated with P. aeruginosa in the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assays in vitro using UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G(+) neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P < 0.05). Depletion of CD4(+) T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function. PMID:27091927

  10. Analysis of Active Sensor Discrimination Requirements for Various Defense Missile Defense Scenarios Final Report 1999(99-ERD-080)

    SciTech Connect

    Ledebuhr, A.G.; Ng, L.C.; Gaughan, R.J.

    2000-02-15

    During FY99, we have explored and analyzed a combined passive/active sensor concept to support the advanced discrimination requirements for various missile defense scenario. The idea is to combine multiple IR spectral channels with an imaging LIDAR (Light Detection and Ranging) behind a common optical system. The imaging LIDAR would itself consist of at least two channels; one at the fundamental laser wavelength (e.g., the 1.064 {micro}m for Nd:YAG) and one channel at the frequency doubled (at 532 nm for Nd:YAG). two-color laser output would, for example, allow the longer wavelength for a direct detection time of flight ranger and an active imaging channel at the shorter wavelength. The LIDAR can function as a high-resolution 2D spatial image either passively or actively with laser illumination. Advances in laser design also offer three color (frequency tripled) systems, high rep-rate operation, better pumping efficiencies that can provide longer distance acquisition, and ranging for enhanced discrimination phenomenology. New detector developments can enhance the performance and operation of both LIDAR channels. A real time data fusion approach that combines multi-spectral IR phenomenology with LIDAR imagery can improve both discrimination and aim-point selection capability.

  11. Determination of host RNA helicases activity in viral replication

    PubMed Central

    Sharma, Amit; Boris-Lawrie, Kathleen

    2016-01-01

    RNA helicases are encoded by all eukaryotic and prokaryotic cells and a minority of viruses. Activity of RNA helicases is necessary for all steps in the expression of cells and viruses and the host innate response to virus infection. Their vast functional repertoire is attributable to the core ATPase-dependent helicase domain in conjunction with flanking domains that are interchangeable and engage viral and cellular cofactors. Here, we address the important issue of host RNA helicases that are necessary for replication of a virus. The chapter covers approaches to identification and characterization of candidate helicases and methods to define the biochemical and biophysical parameters of specificity and functional activity of the enzymes. We discuss the context of cellular RNA helicase activity and virion-associated RNA helicases. The methodology and choice of controls fosters the assessment of the virologic scope of RNA helicases across divergent cell lineages and viral replication cycles. PMID:22713331

  12. TRANSGENIC EXPRESSION OF THE ERWINIA AMYLOVORA (FIRE BLIGHT) EFFECTOR PROTEIN EOP1 SUPRESSES HOST BASAL DEFENSE MECHANISMS IN MALUS (APPLE)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Erwinia amylovora (Ea) is the causative agent of fire blight, a devastating disease of apple and pear. Like many other plant and animal bacterial pathogens Ea utilizes a type three secretion system (TTSS) to deliver effector proteins into plant host cells. Once inside the host cell, effector protei...

  13. Arginase II Restricts Host Defense to Helicobacter pylori by Attenuating Inducible Nitric Oxide Synthase Translation in Macrophages

    PubMed Central

    Lewis, Nuruddeen D.; Asim, Mohammad; Barry, Daniel P.; Singh, Kshipra; de Sablet, Thibaut; Boucher, Jean-Luc; Gobert, Alain P.; Chaturvedi, Rupesh; Wilson, Keith T.

    2010-01-01

    Helicobacter pylori infection of the stomach causes peptic ulcer disease and gastric cancer. Despite eliciting a vigorous immune response, the bacterium persists for the life of the host. An important antimicrobial mechanism is the production of NO derived from inducible NO synthase (iNOS). We have reported that macrophages can kill H. pylori in vitro by an NO-dependent mechanism, but supraphysiologic levels of the iNOS substrate L-arginine are required. Because H. pylori induces arginase activity in macrophages, we determined if this restricts NO generation by reducing L-arginine availability. Inhibition of arginase with S-(2-boronoethyl)-L-cysteine (BEC) significantly enhanced NO generation in H. pylori-stimulated RAW 264.7 macrophages by enhancing iNOS protein translation but not iNOS mRNA levels. This effect resulted in increased killing of H. pylori that was attenuated with an NO scavenger. In contrast, inhibition of arginase in macrophages activated by the colitis-inducing bacterium Citrobacter rodentium increased NO without affecting iNOS levels. H. pylori upregulated levels of arginase II (Arg2) mRNA and protein, which localized to mitochondria, whereas arginase I was not induced. Increased iNOS protein and NO levels were also demonstrated by small interfering RNA knockdown of Arg2 and in peritoneal macrophages from C57BL/6 Arg2−/− mice. In H. pylori-infected mice, treatment with BEC or deletion of Arg2 increased iNOS protein levels and NO generation in gastric macrophages, but treatment of Arg2−/− mice with BEC had no additional effect. These studies implicate Arg2 in the immune evasion of H. pylori by causing intracellular depletion of L-arginine and thus reduction of NO-dependent bactericidal activity. PMID:20097867

  14. Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Chan, Liana C.; Chaili, Siyang; Filler, Scott G.; Barr, Kevin; Wang, Huiyuan; Kupferwasser, Deborah; Edwards, John E.; Xiong, Yan Q.; Ibrahim, Ashraf S.; Miller, Lloyd S.; Schmidt, Clint S.; Hennessey, John P.

    2015-01-01

    Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to S. aureus, particularly methicillin-resistant S. aureus (MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection. PMID:26351278

  15. Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection

    PubMed Central

    Abboud, Georges; Tahiliani, Vikas; Desai, Pritesh; Varkoly, Kyle; Driver, John; Hutchinson, Tarun E.

    2015-01-01

    immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus. PMID:26468539

  16. Geodetic activities of the Department of Defense under IGY programs

    SciTech Connect

    Williams, O.W.; Daugherty, K.I.

    1983-10-16

    Attention is given to the U.S. Department of Defence (DOD) activities that contributed to the International Geophysical Year's active, passive, and cooperative satellite programs. The DOD continues to support the deployment, enhancement, and application of novel technology in such areas as satellite altimetry, gravity radiometry, inertial surveying, interferometry, airborne gravimetry, inertial surveying, and CCD and laser methods for geodetic astronomy. Also noted are such major department initiatives as the Global Positioning System, which will become operational toward the end of this decade.

  17. Smuggling across the border: how arthropod-borne pathogens evade and exploit the host defense system of the skin.

    PubMed

    Bernard, Quentin; Jaulhac, Benoit; Boulanger, Nathalie

    2014-05-01

    The skin is a critical barrier between hosts and pathogens in arthropod-borne diseases. It harbors many resident cells and specific immune cells to arrest or limit infections by secreting inflammatory molecules or by directly killing pathogens. However, some pathogens are able to use specific skin cells and arthropod saliva for their initial development, to hide from the host immune system, and to establish persistent infection in the vertebrate host. A better understanding of the initial mechanisms taking place in the skin should allow the development of new strategies to fight these vector-borne pathogens that are spread worldwide and are of major medical importance. PMID:24552683

  18. Chemoproteomic profiling of host and pathogen enzymes active in cholera.

    PubMed

    Hatzios, Stavroula K; Abel, Sören; Martell, Julianne; Hubbard, Troy; Sasabe, Jumpei; Munera, Diana; Clark, Lars; Bachovchin, Daniel A; Qadri, Firdausi; Ryan, Edward T; Davis, Brigid M; Weerapana, Eranthie; Waldor, Matthew K

    2016-04-01

    Activity-based protein profiling (ABPP) is a chemoproteomic tool for detecting active enzymes in complex biological systems. We used ABPP to identify secreted bacterial and host serine hydrolases that are active in animals infected with the cholera pathogen Vibrio cholerae. Four V. cholerae proteases were consistently active in infected rabbits, and one, VC0157 (renamed IvaP), was also active in human choleric stool. Inactivation of IvaP influenced the activity of other secreted V. cholerae and rabbit enzymes in vivo, and genetic disruption of all four proteases increased the abundance of intelectin, an intestinal lectin, and its binding to V. cholerae in infected rabbits. Intelectin also bound to other enteric bacterial pathogens, suggesting that it may constitute a previously unrecognized mechanism of bacterial surveillance in the intestine that is inhibited by pathogen-secreted proteases. Our work demonstrates the power of activity-based proteomics to reveal host-pathogen enzymatic dialog in an animal model of infection. PMID:26900865

  19. Cortical multineuronal activity in dogs with defensive instrumental conditioned reflex.

    PubMed

    Dolbakyan, E E; Merzhanova, G Kh; Tveritskaya, I N

    1990-01-01

    For the first time in dogs with semi-microelectrodes chronically implanted in the motor and somatosensory region of the cortex, background multineuronal activity (MNA) was recorded over the long term followed by an amplitudinal discrimination from the MNA of impulse series presumably belonging to cells of large, medium, and small size was performed. The presence of close synergistic functional connections, particularly significant during the avoidance conditioned reflex and its extinction, was established by determining the correlation coefficient (CC) between the impulse flows of these neurons. In trained animals the highest CC values were observed between neurons with a small and medium spike amplitude. The network properties of identified neurons were studied by constructing histograms of cross interval relationships. The connections established were of primarily a unilateral, excitatory character. PMID:2077444

  20. Fiscal Year 1985 Congressional budget request. Volume 1. Atomic energy defense activities

    SciTech Connect

    Not Available

    1984-02-01

    Contents include: summaries of estimates by appropriation, savings from management initiatives, staffing by subcommittee, staffing appropriation; appropriation language; amounts available for obligation; estimates by major category; program overview; weapons activities; verification and control technology; materials production; defense waste and by-products management; nuclear safeguards and security; security investigations; and naval reactors development.

  1. An Effector-Targeted Protease Contributes to Defense against Phytophthora infestans and Is under Diversifying Selection in Natural Hosts1[W

    PubMed Central

    Kaschani, Farnusch; Shabab, Mohammed; Bozkurt, Tolga; Shindo, Takayuki; Schornack, Sebastian; Gu, Christian; Ilyas, Muhammad; Win, Joe; Kamoun, Sophien; van der Hoorn, Renier A.L.

    2010-01-01

    Since the leaf apoplast is a primary habitat for many plant pathogens, apoplastic proteins are potent, ancient targets for apoplastic effectors secreted by plant pathogens. So far, however, only a few apoplastic effector targets have been identified and characterized. Here, we discovered that the papain-like cysteine protease C14 is a new common target of EPIC1 and EPIC2B, two apoplastic, cystatin-like proteins secreted by the potato (Solanum tuberosum) late blight pathogen Phytophthora infestans. C14 is a secreted protease of tomato (Solanum lycopersicum) and potato typified by a carboxyl-terminal granulin domain. The EPIC-C14 interaction occurs at a wide pH range and is stronger than the previously described interactions of EPICs with tomato defense proteases PIP1 and RCR3. The selectivity of the EPICs is also different when compared with the AVR2 effector of the fungal tomato pathogen Cladosporium fulvum, which targets PIP1 and RCR3, and only at apoplastic pH. Importantly, silencing of C14 increased susceptibility to P. infestans, demonstrating that this protease plays a role in pathogen defense. Although C14 is under conservative selection in tomato, it is under diversifying selection in wild potato species (Solanum demissum, Solanum verrucosum, and Solanum stoliniferum) that are the natural hosts of P. infestans. These data reveal a novel effector target in the apoplast that contributes to immunity and is under diversifying selection, but only in the natural host of the pathogen. PMID:20940351

  2. Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4.

    PubMed

    Qiu, Zhijuan; Cervantes, Jorge L; Cicek, Basak B; Mukherjee, Subhajit; Venkatesh, Madhukumar; Maher, Leigh A; Salazar, Juan C; Mani, Sridhar; Khanna, Kamal M

    2016-01-01

    The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr(-/-) mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr(-/-) mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr(-/-) mice. Mechanistically, the heightened inflammation in Pxr(-/-) mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection. PMID:27550658

  3. Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

    PubMed Central

    Qiu, Zhijuan; Cervantes, Jorge L.; Cicek, Basak B.; Mukherjee, Subhajit; Venkatesh, Madhukumar; Maher, Leigh A.; Salazar, Juan C.; Mani, Sridhar; Khanna, Kamal M.

    2016-01-01

    The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr−/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr−/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr−/− mice. Mechanistically, the heightened inflammation in Pxr−/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection. PMID:27550658

  4. Active defense scheme against DDoS based on mobile agent and network control in network confrontation

    NASA Astrophysics Data System (ADS)

    Luo, Rong; Li, Junshan; Ye, Xia; Wang, Rui

    2013-03-01

    In order to effective defend DDoS attacks in network confrontation, an active defense scheme against DDoS is built based on Mobile Agent and network control. A distributed collaborative active defense model is constructed by using mobile agent technology and encapsulating a variety of DDoS defense techniques. Meanwhile the network control theory is applied to establish a network confrontation's control model for DDoS to control the active defense process. It provides a new idea to solve the DDoS problem.

  5. The immunology of host defence peptides: beyond antimicrobial activity.

    PubMed

    Hancock, Robert E W; Haney, Evan F; Gill, Erin E

    2016-05-01

    Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications. PMID:27087664

  6. Role of Toll-like receptors in lung innate defense against invasive aspergillosis. Distinct impact in immunocompetent and immunocompromized hosts.

    PubMed

    Chignard, Michel; Balloy, Viviane; Sallenave, Jean-Michel; Si-Tahar, Mustapha

    2007-09-01

    Toll-like receptors are key to pathogen recognition by a host and to the subsequent triggering of an innate immune response. Experimental and clinical evidence shows that defects in Toll-like receptors or in signaling pathways downstream from these receptors render hosts susceptible to various types of infection, including aspergillosis. Patients receiving an immunosuppressive regimen, including corticosteroid therapy or cytotoxic chemotherapy, are also susceptible to infections. Aspergillus fumigatus is an opportunistic pathogen that infects the lungs of immunosuppressed hosts. Here, we review the evidence that experimental inactivation of various Toll-like receptors and of their signaling pathways may worsen cases of invasive pulmonary aspergillosis. Moreover, the literature clearly indicates that the type of immunosuppression is very important, as it influences whether or not Toll-like receptors contribute to infection. The involvement of Toll-like receptors, based on the immunological status of the patient, should be considered if an immunosuppressive treatment must be administered. PMID:17604224

  7. Human and Animal Isolates of Yersinia enterocolitica Show Significant Serotype-Specific Colonization and Host-Specific Immune Defense Properties

    PubMed Central

    Schaake, Julia; Kronshage, Malte; Uliczka, Frank; Rohde, Manfred; Knuuti, Tobias; Strauch, Eckhard; Fruth, Angelika; Wos-Oxley, Melissa

    2013-01-01

    Yersinia enterocolitica is a human pathogen that is ubiquitous in livestock, especially pigs. The bacteria are able to colonize the intestinal tract of a variety of mammalian hosts, but the severity of induced gut-associated diseases (yersiniosis) differs significantly between hosts. To gain more information about the individual virulence determinants that contribute to colonization and induction of immune responses in different hosts, we analyzed and compared the interactions of different human- and animal-derived isolates of serotypes O:3, O:5,27, O:8, and O:9 with murine, porcine, and human intestinal cells and macrophages. The examined strains exhibited significant serotype-specific cell binding and entry characteristics, but adhesion and uptake into different host cells were not host specific and were independent of the source of the isolate. In contrast, survival and replication within macrophages and the induced proinflammatory response differed between murine, porcine, and human macrophages, suggesting a host-specific immune response. In fact, similar levels of the proinflammatory cytokine macrophage inflammatory protein 2 (MIP-2) were secreted by murine bone marrow-derived macrophages with all tested isolates, but the equivalent interleukin-8 (IL-8) response of porcine bone marrow-derived macrophages was strongly serotype specific and considerably lower in O:3 than in O:8 strains. In addition, all tested Y. enterocolitica strains caused a considerably higher level of secretion of the anti-inflammatory cytokine IL-10 by porcine than by murine macrophages. This could contribute to limiting the severity of the infection (in particular of serotype O:3 strains) in pigs, which are the primary reservoir of Y. enterocolitica strains pathogenic to humans. PMID:23959720

  8. A Role for the Anti-Viral Host Defense Mechanism in the Phylogenetic Divergence in Baculovirus Evolution.

    PubMed

    Nagamine, Toshihiro; Sako, Yasushi

    2016-01-01

    Although phylogenic analysis often suggests co-evolutionary relationships between viruses and host organisms, few examples have been reported at the microevolutionary level. Here, we show a possible example in which a species-specific anti-viral response may drive phylogenic divergence in insect virus evolution. Two baculoviruses, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and Bombyx mori nucleopolyhedrovirus (BmNPV), have a high degree of DNA sequence similarity, but exhibit non-overlapping host specificity. In our study of their host-range determination, we found that BmNPV replication in B. mori cells was prevented by AcMNPV-P143 (AcP143), but not BmNPV-P143 (BmP143) or a hybrid P143 protein from a host-range expanded phenotype. This suggests that AcMNPV resistance in B. mori cells depends on AcP143 recognition and that BmNPV uses BmP143 to escapes this recognition. Based on these data, we propose an insect-baculovirus co-evolution scenario in which an ancestor of silkworms exploited an AcMNPV-resistant mechanism; AcMNPV counteracted this resistance via P143 mutations, resulting in the birth of BmNPV. PMID:27244571

  9. A Role for the Anti-Viral Host Defense Mechanism in the Phylogenetic Divergence in Baculovirus Evolution

    PubMed Central

    Nagamine, Toshihiro; Sako, Yasushi

    2016-01-01

    Although phylogenic analysis often suggests co-evolutionary relationships between viruses and host organisms, few examples have been reported at the microevolutionary level. Here, we show a possible example in which a species-specific anti-viral response may drive phylogenic divergence in insect virus evolution. Two baculoviruses, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and Bombyx mori nucleopolyhedrovirus (BmNPV), have a high degree of DNA sequence similarity, but exhibit non-overlapping host specificity. In our study of their host-range determination, we found that BmNPV replication in B. mori cells was prevented by AcMNPV-P143 (AcP143), but not BmNPV-P143 (BmP143) or a hybrid P143 protein from a host-range expanded phenotype. This suggests that AcMNPV resistance in B. mori cells depends on AcP143 recognition and that BmNPV uses BmP143 to escapes this recognition. Based on these data, we propose an insect-baculovirus co-evolution scenario in which an ancestor of silkworms exploited an AcMNPV-resistant mechanism; AcMNPV counteracted this resistance via P143 mutations, resulting in the birth of BmNPV. PMID:27244571

  10. Oligopeptide elicitor-mediated defense gene activation in cultured parsley cells.

    PubMed Central

    Hahlbrock, K; Scheel, D; Logemann, E; Nürnberger, T; Parniske, M; Reinold, S; Sacks, W R; Schmelzer, E

    1995-01-01

    We have used suspension-cultured parsley cells (Petroselinum crispum) and an oligopeptide elicitor derived from a surface glycoprotein of the phytopathogenic fungus Phytophthora megasperma f.sp. glycinea to study the signaling pathway from elicitor recognition to defense gene activation. Immediately after specific binding of the elicitor by a receptor in the plasma membrane, large and transient increases in several inorganic ion fluxes (Ca2+, H+, K+, Cl-) and H2O2 formation are the first detectable plant cell responses. These are rapidly followed by transient changes in the phosphorylation status of various proteins and by the activation of numerous defense-related genes, concomitant with the inactivation of several other, non-defense-related genes. A great diversity of cis-acting elements and trans-acting factors appears to be involved in elicitor-mediated gene regulation, similar to the apparently complex nature of the signal transduced intracellularly. With few exceptions, all individual defense responses analyzed in fungus-infected parsley leaves have been found to be closely mimicked in elicitor-treated, cultured parsley cells, thus validating the use of the elicitor/cell culture system as a valuable model system for these types of study. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:7753777

  11. Low Structural Variation in the Host-Defense Peptide Repertoire of the Dwarf Clawed Frog Hymenochirus boettgeri (Pipidae)

    PubMed Central

    Matthijs, Severine; Ye, Lumeng; Stijlemans, Benoit; Cornelis, Pierre; Bossuyt, Franky; Roelants, Kim

    2014-01-01

    The skin secretion of many amphibians contains peptides that are able to kill a broad range of microorganisms (antimicrobial peptides: AMPs) and potentially play a role in innate immune defense. Similar to the toxin arsenals of various animals, amphibian AMP repertoires typically show major structural variation, and previous studies have suggested that this may be the result of diversifying selection in adaptation to a diverse spectrum of pathogens. Here we report on transcriptome analyses that indicate a very different pattern in the dwarf clawed frog H. boettgeri. Our analyses reveal a diverse set of transcripts containing two to six tandem repeats, together encoding 14 distinct peptides. Five of these have recently been identified as AMPs, while three more are shown here to potently inhibit the growth of gram-negative bacteria, including multi-drug resistant strains of the medically important Pseudomonas aeruginosa. Although the number of predicted peptides is similar to the numbers of related AMPs in Xenopus and Silurana frog species, they show significantly lower structural variation. Selection analyses confirm that, in contrast to the AMPs of other amphibians, the H. boettgeri peptides did not evolve under diversifying selection. Instead, the low sequence variation among tandem repeats resulted from purifying selection, recent duplication and/or concerted gene evolution. Our study demonstrates that defense peptide repertoires of closely related taxa, after diverging from each other, may evolve under differential selective regimes, leading to contrasting patterns of structural diversity. PMID:24466037

  12. AN ULTRAVIOLET INVESTIGATION OF ACTIVITY ON EXOPLANET HOST STARS

    SciTech Connect

    Shkolnik, Evgenya L.

    2013-03-20

    Using the far-UV (FUV) and near-UV (NUV) photometry from the NASA Galaxy Evolution Explorer (GALEX), we searched for evidence of increased stellar activity due to tidal and/or magnetic star-planet interactions (SPI) in the 272 known FGK planetary hosts observed by GALEX. With the increased sensitivity of GALEX, we are able probe systems with lower activity levels and at larger distances than what has been done to date with X-ray satellites. We compared samples of stars with close-in planets (a < 0.1 AU) to those with far-out planets (a > 0.5 AU) and looked for correlations of excess activity with other system parameters. This statistical investigation found no clear correlations with a, M{sub p} , or M{sub p} /a, in contrast to some X-ray and Ca II studies. However, there is tentative evidence (at a level of 1.8{sigma}) that stars with radial-velocity-(RV)-detected close-in planets are more FUV-active than stars with far-out planets, in agreement with several published X-ray and Ca II results. The case is strengthened to a level of significance to 2.3{sigma} when transit-detected close-in planets are included. This is most likely because the RV-selected sample of stars is significantly less active than the field population of comparable stars, while the transit-selected sample is similarly active. Given the factor of 2-3 scatter in fractional FUV luminosity for a given stellar effective temperature, it is necessary to conduct a time-resolved study of the planet hosts in order to better characterize their UV variability and generate a firmer statistical result.

  13. Modulation of plasma membrane H+-ATPase activity differentially activates wound and pathogen defense responses in tomato plants.

    PubMed Central

    Schaller, A; Oecking, C

    1999-01-01

    Systemin is an important mediator of wound-induced defense gene activation in tomato plants, and it elicits a rapid alkalinization of the growth medium of cultured Lycopersicon peruvianum cells. A possible mechanistic link between proton fluxes across the plasma membrane and the induction of defense genes was investigated by modulating plasma membrane H+-ATPase activity. Inhibitors of H+-ATPase (erythrosin B, diethyl stilbestrol, and vanadate) were found to alkalinize the growth medium of L. peruvianum cell cultures and to induce wound response genes in whole tomato plants. Conversely, an activator of the H+-ATPase (fusicoccin) acidified the growth medium of L. peruvianum cell cultures and suppressed systemin-induced medium alkalinization. Likewise, in fusicoccin-treated tomato plants, the wound- and systemin-triggered accumulation of wound-responsive mRNAs was found to be suppressed. However, fusicoccin treatment of tomato plants led to the accumulation of salicylic acid and the expression of pathogenesis-related genes. Apparently, the wound and pathogen defense signaling pathways are differentially regulated by changes in the proton electrochemical gradient across the plasma membrane. In addition, alkalinization of the L. peruvianum cell culture medium was found to depend on the influx of Ca2+ and the activity of a protein kinase. Reversible protein phosphorylation was also shown to be involved in the induction of wound response genes. The plasma membrane H+-ATPase as a possible target of a Ca2+-activated protein kinase and its role in defense signaling are discussed. PMID:9927643

  14. Brain activation of the defensive and appetitive survival systems in obsessive compulsive disorder.

    PubMed

    Gonçalves, Óscar F; Soares, José Miguel; Carvalho, Sandra; Leite, Jorge; Ganho, Ana; Fernandes-Gonçalves, Ana; Frank, Brandon; Pocinho, Fernando; Relvas, João; Carracedo, Angel; Sampaio, Adriana

    2015-06-01

    Several studies have shown that basic emotions are responsible for a significant enhancement of early visual processes and increased activation in visual processing brain regions. It may be possible that the cognitive uncertainty and repeated behavioral checking evident in Obsessive Compulsive Disorder (OCD) is due to the existence of abnormalities in basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional-laden stimuli. The objective of the present study was to test if patients with OCD show evidence of altered basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional stimuli. Fifteen patients with OCD and 12 healthy controls underwent functional magnetic resonance imaging acquisition while being exposed to emotional pictures, with different levels of arousal, intended to trigger the defensive and appetitive basic survival circuits. Overall, the present results seem to indicate dissociation in the activity of the defense and appetitive survival systems in OCD. Results suggest that the clinical group reacts to basic threat with a strong activation of the defensive system mobilizing widespread brain networks (i.e., frontal, temporal, occipital-parietal, and subcortical nucleus) and blocking the activation of the appetitive system when facing positive emotional triggers from the initial stages of visual processing (i.e., superior occipital gyrus). PMID:24760279

  15. The human host as active agent in malaria epidemiology.

    PubMed

    MacCormack, C P

    1987-09-01

    The literature on malaria epidemiology tends to view the human host as a passive or constant factor. However, for at least 2000 years people have been an active factor, causing vast changes in epidemiological patterns. They have cut forest and increased the breeding area of An. gambiae, or changed salinity in rice swamps causing a different change in the dominant vector. Human activity not only increases risk, but influences control by killing mosquito larvae, killing adult mosquitos or preventing mosquitos from feeding. For example, people prefer chloroquine or other anti-malarials to traditional herbal remedies that do not kill parasites, and in some areas introduce larvivorous fish into swamp rice fields and cattle ponds. Bed nets impregnated with residual insecticide simultaneously prevent mosquitos from feeding on people and kill adult mosquitos. Preferences and practices in bed net use in the Gambia are described. PMID:3432961

  16. Activation of defense response pathways by OGs and Flg22 elicitors in Arabidopsis seedlings

    PubMed Central

    Denoux, Carine; Galletti, Roberta; Mammarella, Nicole; Gopalan, Suresh; Werck, Danièle; De Lorenzo, Giulia; Ferrari, Simone; Ausubel, Frederick M.; Dewdney, Julia

    2010-01-01

    We carried out transcriptional profiling analysis in 10 day-old Arabidopsis thaliana seedlings treated with oligogalacturonides (OGs), oligosaccharides derived from the plant cell wall, or the bacterial flagellin peptide Flg22, general elicitors of the basal defense response in plants. Although detected by different receptors, both OGs and Flg22 trigger a fast and transient response that is both similar and comprehensive, and characterized by activation of early stages of multiple defense signaling pathways, particularly JA-associated processes. However, the response to Flg22 is stronger in both the number of genes differentially expressed and the amplitude of change. The magnitude of induction of individual genes is in both cases dose dependent, but even at very high concentrations, OGs do not induce a response that is as comprehensive as that seen with Flg22. While high doses of either microbe-associated molecular pattern (MAMP) elicit a late response that includes activation of senescence processes, SA-dependent secretory pathway genes and PR1 expression are substantially induced only by Flg22. These results suggest a lower threshold for activation of early responses than for sustained or SA-mediated late defenses. Expression patterns of aminocyclopropane-carboxylate synthase genes also implicate ethylene biosynthesis in regulation of the late innate immune response. PMID:19825551

  17. Cosmic bombardment V: Threat object-dispersing approaches to active planetary defense

    SciTech Connect

    Teller, E.; Wood, L. |; Ishikawa, M. |; Hyde, R.

    1995-05-24

    Earth-impacting comets and asteroids with diameters {approx}0.03 - 10 km pose the greatest threats to the terrestrial biosphere in terms of impact frequency-weighted impact consequences, and thus are of most concern to designers of active planetary defenses. Specific gravitational binding energies of such objects range from 10{sup -7} to 10{sup -2} J/gm, and are small compared with the specific energies of 1x10{sup 3} to 3x10{sup 3} J/gm required to vaporize objects of typical composition or the specific energies required to pulverize them, which are 10{sup -1} to 10 J/gm. All of these are small compared to the specific kinetic energy of these objects in the Earth- centered frame, which is 2x10{sup 5} to 2x10{sup 6} J/gm. The prospect naturally arises of negating all such threats by deflecting, pulverizing or vaporizing the objects. Pulverization-with-dispersal is an attractive option of reasonable defensive robustness. Examples of such equipments - which employ no explosives of any type - are given. Vaporization is the maximally robust defensive option, and may be invoked to negate threat objects not observed until little time is left until Earth-strike, and pulverization-with-dispersal has proven inadequate. Physically larger threats may be vaporized with nuclear explosives. No contemporary technical means of any kind appear capable of directly dispersing the -100 km diameter scale Charon- class cometary objects recently observed in the outer solar system, although such objects may be deflected to defensively useful extents. Means of implementing defenses of each of these types are proposed for specificity, and areas for optimization noted. Biospheric impacts of threat object debris are briefly considered, for bounding purposes. Experiments are suggested on cometary and asteroidal objects.

  18. Fire blight disease reactome: RNA-seq transcriptional profile of apple host plant defense responses to Erwinia amylovora pathogen infection

    PubMed Central

    Kamber, Tim; Buchmann, Jan P.; Pothier, Joël F.; Smits, Theo H. M.; Wicker, Thomas; Duffy, Brion

    2016-01-01

    The molecular basis of resistance and susceptibility of host plants to fire blight, a major disease threat to pome fruit production globally, is largely unknown. RNA-sequencing data from challenged and mock-inoculated flowers were analyzed to assess the susceptible response of apple to the fire blight pathogen Erwinia amylovora. In presence of the pathogen 1,080 transcripts were differentially expressed at 48 h post inoculation. These included putative disease resistance, stress, pathogen related, general metabolic, and phytohormone related genes. Reads, mapped to regions on the apple genome where no genes were assigned, were used to identify potential novel genes and open reading frames. To identify transcripts specifically expressed in response to E. amylovora, RT-PCRs were conducted and compared to the expression patterns of the fire blight biocontrol agent Pantoea vagans strain C9-1, another apple pathogen Pseudomonas syringae pv. papulans, and mock inoculated apple flowers. This led to the identification of a peroxidase superfamily gene that was lower expressed in response to E. amylovora suggesting a potential role in the susceptibility response. Overall, this study provides the first transcriptional profile by RNA-seq of the host plant during fire blight disease and insights into the response of susceptible apple plants to E. amylovora. PMID:26883568

  19. Fire blight disease reactome: RNA-seq transcriptional profile of apple host plant defense responses to Erwinia amylovora pathogen infection.

    PubMed

    Kamber, Tim; Buchmann, Jan P; Pothier, Joël F; Smits, Theo H M; Wicker, Thomas; Duffy, Brion

    2016-01-01

    The molecular basis of resistance and susceptibility of host plants to fire blight, a major disease threat to pome fruit production globally, is largely unknown. RNA-sequencing data from challenged and mock-inoculated flowers were analyzed to assess the susceptible response of apple to the fire blight pathogen Erwinia amylovora. In presence of the pathogen 1,080 transcripts were differentially expressed at 48 h post inoculation. These included putative disease resistance, stress, pathogen related, general metabolic, and phytohormone related genes. Reads, mapped to regions on the apple genome where no genes were assigned, were used to identify potential novel genes and open reading frames. To identify transcripts specifically expressed in response to E. amylovora, RT-PCRs were conducted and compared to the expression patterns of the fire blight biocontrol agent Pantoea vagans strain C9-1, another apple pathogen Pseudomonas syringae pv. papulans, and mock inoculated apple flowers. This led to the identification of a peroxidase superfamily gene that was lower expressed in response to E. amylovora suggesting a potential role in the susceptibility response. Overall, this study provides the first transcriptional profile by RNA-seq of the host plant during fire blight disease and insights into the response of susceptible apple plants to E. amylovora. PMID:26883568

  20. MAGNETIC ACTIVITY CYCLES IN THE EXOPLANET HOST STAR {epsilon} ERIDANI

    SciTech Connect

    Metcalfe, T. S.; Mathur, S.; Buccino, A. P.; Mauas, P. J. D.; Petrucci, R.; Brown, B. P.; Soderblom, D. R.; Henry, T. J.; Hall, J. C.; Basu, S.

    2013-02-01

    The active K2 dwarf {epsilon} Eri has been extensively characterized both as a young solar analog and more recently as an exoplanet host star. As one of the nearest and brightest stars in the sky, it provides an unparalleled opportunity to constrain stellar dynamo theory beyond the Sun. We confirm and document the 3-year magnetic activity cycle in {epsilon} Eri originally reported by Hatzes and coworkers, and we examine the archival data from previous observations spanning 45 years. The data show coexisting 3-year and 13-year periods leading into a broad activity minimum that resembles a Maunder minimum-like state, followed by the resurgence of a coherent 3-year cycle. The nearly continuous activity record suggests the simultaneous operation of two stellar dynamos with cycle periods of 2.95 {+-} 0.03 years and 12.7 {+-} 0.3 years, which, by analogy with the solar case, suggests a revised identification of the dynamo mechanisms that are responsible for the so-called 'active' and 'inactive' sequences as proposed by Boehm-Vitense. Finally, based on the observed properties of {epsilon} Eri, we argue that the rotational history of the Sun is what makes it an outlier in the context of magnetic cycles observed in other stars (as also suggested by its Li depletion), and that a Jovian-mass companion cannot be the universal explanation for the solar peculiarities.

  1. The star formation rates of active galactic nuclei host galaxies

    NASA Astrophysics Data System (ADS)

    Ellison, Sara L.; Teimoorinia, Hossen; Rosario, David J.; Mendel, J. Trevor

    2016-05-01

    Using artificial neural network predictions of total infrared luminosities (LIR), we compare the host galaxy star formation rates (SFRs) of ˜21 000 optically selected active galactic nuclei (AGN), 466 low-excitation radio galaxies (LERGs) and 721 mid-IR-selected AGN. SFR offsets (ΔSFR) relative to a sample of star-forming `main-sequence' galaxies (matched in M⋆, z and local environment) are computed for the AGN hosts. Optically selected AGN exhibit a wide range of ΔSFR, with a distribution skewed to low SFRs and a median ΔSFR = -0.06 dex. The LERGs have SFRs that are shifted to even lower values with a median ΔSFR = -0.5 dex. In contrast, mid-IR-selected AGN have, on average, SFRs enhanced by a factor of ˜1.5. We interpret the different distributions of ΔSFR amongst the different AGN classes in the context of the relative contribution of triggering by galaxy mergers. Whereas the LERGs are predominantly fuelled through low accretion rate secular processes which are not accompanied by enhancements in SFR, mergers, which can simultaneously boost SFRs, most frequently lead to powerful, obscured AGN.

  2. Assessment of the fiscal year 1997 Department of Defense budget and program activities for domestic defense against weapons of mass destruction. Master`s thesis

    SciTech Connect

    Guenther, G.R.

    1997-12-01

    This thesis examines Department of Defense involvement in U.S. preparedness to manage the consequences of a nuclear, radiological, biological, or chemical terrorist attack against its cities. It analyzes the establishment and implementation of the Defense Against Weapons of Mass Destruction Act of 1996 which directed the Department of Defense to assist in the training of state and local emergency response agencies involved in consequence management activities. The historical analysis focuses on the proliferation of weapons of mass destruction since the dissolution of the Soviet Union, major terrorist incidents since 1993, international standards, and legislative and executive efforts undertaken to combat terrorism up to 1996. The $150 million Nunn Lugar Domenici amendment to the FY-97 National Defense Authorization Bill is examined in detail from introduction on the Senate floor to eventual passage and enactment. Problems and policy issues associated with resourcing and implementing the resulting Domestic Preparedness Program are treated. Although the DoD was given responsibility for implementing city training, an interagency effort ensued involving the Public Health Service, Environmental Protection Agency, Federal Bureau of Investigation, Federal Emergency Management Agency, Department of Energy, and others. Potential weaknesses may materialize due to several characteristics of the Domestic Preparedness Program, including its novelty and uniqueness, the unorthodox legislative process by which it was established, and its complex organizational structure and temporary nature.

  3. Matrix metalloproteinase-9 deficiency impairs host defense mechanisms against Streptococcus pneumoniae in a mouse model of bacterial meningitis.

    PubMed

    Böttcher, Tobias; Spreer, Annette; Azeh, Ivo; Nau, Roland; Gerber, Joachim

    2003-03-01

    Matrix metalloproteinase-9 (MMP-9) appears to contribute to blood-brain barrier damage and neuronal injury in bacterial meningitis. To further explore the function of MMP-9 in meningeal inflammation, we injected 10(4) colony forming units (CFU) of a Streptoccocus pneumoniae type 3 strain into the right forebrain of MMP-9 deficient mice (MMP-9(-/-), n=16) and wild-type controls (129 x B6, n=15). The clinical course of the disease, leukocyte recruitment into the subarachnoid space and bacterial titers in the brain did not differ. Yet, clearance of the bacteria from blood (log CFU/ml 4.7 [3.8/5.4] vs. 3.6 [3.0/4.0]; P=0.005) and spleen homogenates (log CFU/ml 5.3 [4.8/5.5] vs. 4.0 [2.8/4.7]; P=0.01) was reduced in MMP-9 deficient mice. A reduced systemic bacterial clearance of MMP-9(-/-) mice was confirmed in experimental S. pneumoniae peritonitis/sepsis. This implies a compromised systemic, but not intracerebral host response against S. pneumoniae in MMP-9 deficiency. PMID:12581831

  4. Fungal colonization and host defense reactions in Ulmus americana callus cultures inoculated with Ophiostoma novo-ulmi.

    PubMed

    Aoun, Mirella; Rioux, Danny; Simard, Marie; Bernier, Louis

    2009-06-01

    The host-pathogen interaction leading to Dutch elm disease was analyzed using histo- and cyto-chemical tests in an in vitro system. Friable and hard susceptible Ulmus americana callus cultures were inoculated with the highly aggressive pathogen Ophiostoma novo-ulmi. Inoculated callus tissues were compared with water-treated callus tissues and studied with light microscopy (LM), transmission-electron microscopy (TEM), and scanning-electron microscopy (SEM). New aspects of this interaction are described. These include the histological observation, for the first time in plant callus cultures, of suberin with its typical lamellar structure in TEM and the intracellular presence of O. novo-ulmi. Expression of the phenylalanine ammonia lyase gene, monitored by real-time quantitative polymerase chain reaction, was correlated with the accumulation of suberin, phenols, and lignin in infected callus cultures. This study validates the potential use of the in vitro system for genomic analyses aimed at identifying genes expressed during the interaction in the Dutch elm disease pathosystem. PMID:19453222

  5. CD103+ Conventional Dendritic Cells Are Critical for TLR7/9-Dependent Host Defense against Histoplasma capsulatum, an Endemic Fungal Pathogen of Humans

    PubMed Central

    Van Prooyen, Nancy; Henderson, C. Allen; Hocking Murray, Davina; Sil, Anita

    2016-01-01

    Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNγ from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNγ, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi. PMID:27459510

  6. CELLULAR TRANSCRIPTIONAL PROFILING IN INFLUENZA A VIRUS INFECTED LUNG EPITHELIAL CELLS: THE ROLE OF THE NONSTRUCTURAL NS1 PROTEIN IN THE EVASION OF THE HOST INNATE DEFENSE AND ITS POTENTIAL CONTRIBUTION TO PANDEMIC INFLUENZA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The NS1 protein of influenza A virus contributes to viral pathogenesis, primarily by enabling the virus to disarm the host cell type interferon defense system. We examined the downstream effects of NS1 protein expression during influenza A virus infection on global cellular mRNA levels by measuring ...

  7. Host active defense responses occur within 24 hours after pathogen inoculation in the rice blast system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotypic, cytological and molecular responses of rice to the fungus M. grisea were studied using rice cultivars and lesion mimic plants. Cultivar Katy was susceptible to several virulent Magnaporthe grisea isolates. A Sekiguchi-like lesion mimic mutant of Katy (LmmKaty) has shown enhanced resista...

  8. IFN-induced Guanylate Binding Proteins in Inflammasome Activation and Host Defense

    PubMed Central

    Kim, Bae-Hoon; Chee, Jonathan D.; Bradfield, Clinton J.; Park, Eui-Soon; Kumar, Pradeep; MacMicking, John D.

    2016-01-01

    Traditional views of the inflammasome highlight pre-existing core components being assembled under basal conditions shortly after infection or tissue damage. Recent work, however, suggests the inflammasome machinery is also subject to tunable or inducible signals that may accelerate its autocatalytic properties and dictate where inflammasome assembly takes place in the cell. Many of these immune signals operate downstream of interferon (IFN) receptors to elicit inflammasome regulators, including a new family of IFN-induced GTPases termed guanylate binding proteins (GBPs). Here, we examine the critical roles for IFN-induced GBPs in directing inflammasome subtype-specific responses and their consequences for cell-autonomous immunity against a wide variety of microbial pathogens. We discuss emerging mechanisms of action and the potential impact of these GBPs on predisposition to sepsis and other infectious or inflammatory diseases. PMID:27092805

  9. NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth.

    PubMed

    Satoh, Hironori; Moriguchi, Takashi; Saigusa, Daisuke; Baird, Liam; Yu, Lei; Rokutan, Hirofumi; Igarashi, Keiko; Ebina, Masahito; Shibata, Tatsuhiro; Yamamoto, Masayuki

    2016-05-15

    Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088-96. ©2016 AACR. PMID:27020858

  10. Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection

    PubMed Central

    Karki, Rajendra; Man, Si Ming; Malireddi, R.K. Subbarao; Gurung, Prajwal; Vogel, Peter; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi

    2015-01-01

    SUMMARY Invasive pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Aspergillus fumigatus infection produces ligands that could activate inflammasomes but the contribution of these host defenses remains unclear. We show that two inflammasome receptors, AIM2 and NLRP3, recognize intracellular A. fumigatus and collectively induce protective immune responses. Mice lacking both AIM2 and NLRP3 fail to confine Aspergillus hyphae to inflammatory foci, leading to widespread hyphal dissemination to lung blood vessels. These mice succumb to infection more rapidly than WT mice or mice lacking a single inflammasome receptor. AIM2 and NLRP3 activation initiates assembly of a single cytoplasmic inflammasome platform, composed of the adaptor protein ASC along with caspase-1 and caspase-8. Combined actions of caspase-1 and caspase-8 lead to processing of proinflammatory cytokines IL-1β and IL-18 that critically control the infection. Thus, AIM2 and NLRP3 form a dual cytoplasmic surveillance system that orchestrates responses against A. fumigatus infection. PMID:25704009

  11. Intrinsic cellular defenses against human immunodeficiency viruses.

    PubMed

    Blanco-Melo, Daniel; Venkatesh, Siddarth; Bieniasz, Paul D

    2012-09-21

    Viral infections are often detrimental to host survival and reproduction. Consequently, hosts have evolved a variety of mechanisms to defend themselves against viruses. A component of this arsenal is a set of proteins, termed restriction factors, which exhibit direct antiviral activity. Among these are several classes of proteins (APOBEC3, TRIM5, Tetherin, and SAMHD1) that inhibit the replication of human and simian immunodeficiency viruses. Here, we outline the features, mechanisms, and evolution of these defense mechanisms. We also speculate on how restriction factors arose, how they might interact with the conventional innate and adaptive immune systems, and how an understanding of these intrinsic cellular defenses might be usefully exploited. PMID:22999946

  12. Activation of Molecular Signatures for Antimicrobial and Innate Defense Responses in Skin with Transglutaminase 1 Deficiency

    PubMed Central

    Uchiyama, Ryosuke; Jitsukawa, Orie; Yamanishi, Kiyofumi

    2016-01-01

    Mutations of the transglutaminase 1 gene (TGM1) are a major cause of autosomal recessive congenital ichthyoses (ARCIs) that are associated with defects in skin barrier structure and function. However, the molecular processes induced by the transglutaminase 1 deficiency are not fully understood. The aim of the present study was to uncover those processes by analysis of cutaneous molecular signatures. Gene expression profiles of wild-type and Tgm1–/–epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in Tgm1–/–epidermis. Based on that result, the induction of Il1b and antimicrobial peptide genes, S100a8, S100a9, Defb14, Camp, Slpi, Lcn2, Ccl20 and Wfdc12, was confirmed by quantitative real-time PCR. A protein array revealed that levels of IL-1β, G-CSF, GM-CSF, CXCL1, CXCL2, CXCL9 and CCL2 were increased in Tgm1–/–skin. Epidermal growth factor receptor (EGFR) ligand genes, Hbegf, Areg and Ereg, were activated in Tgm1–/–epidermis. Furthermore, the antimicrobial activity of an epidermal extract from Tgm1–/–mice was significantly increased against both Escherichia coli and Staphylococcus aureus. In the epidermis of ichthyosiform skins from patients with TGM1 mutations, S100A8/9 was strongly positive. The expression of those antimicrobial and defense response genes was also increased in the lesional skin of an ARCI patient with TGM1 mutations. These results suggest that the up-regulation of molecular signatures for antimicrobial and innate defense responses is characteristic of skin with a transglutaminase 1 deficiency, and this autonomous process might be induced to reinforce the defective barrier function of the skin. PMID:27442430

  13. Progestin-Containing Contraceptives Alter Expression of Host Defense-Related Genes of the Endometrium and Cervix

    PubMed Central

    Goldfien, Gabriel A.; Barragan, Fatima; Chen, Joseph; Takeda, Margaret; Irwin, Juan C.; Perry, Jean; Greenblatt, Ruth M.; Smith-McCune, Karen K.

    2015-01-01

    Epidemiological studies indicate that progestin-containing contraceptives increase susceptibility to HIV, although the underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA and LNG-IUS users, and individual genes included pattern recognition receptors, complement components, and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability but not immune function genes. Together, these results indicate that progestins influence expression of immune-related genes in endometrium relevant to local recruitment of HIV target cells with potential to increase susceptibility and underscore the importance of the upper reproductive tract when assessing the safety of contraceptive products. PMID:25634912

  14. LPS inmobilization on porous and non-porous supports as an approach for the isolation of anti-LPS host-defense peptides

    PubMed Central

    López-Abarrategui, Carlos; del Monte-Martínez, Alberto; Reyes-Acosta, Osvaldo; Franco, Octavio L.; Otero-González, Anselmo J.

    2013-01-01

    Lipopolysaccharides (LPSs) are the major molecular component of the outer membrane of Gram-negative bacteria. This molecule is recognized as a sign of bacterial infection, responsible for the development of local inflammatory response and, in extreme cases, septic shock. Unfortunately, despite substantial advances in the pathophysiology of sepsis, there is no efficacious therapy against this syndrome yet. As a consequence, septic shock syndrome continues to increase, reaching mortality rates over 50% in some cases. Even though many preclinical studies and clinical trials have been conducted, there is no Food and Drug Administration-approved drug yet that interacts directly against LPS. Cationic host-defense peptides (HDPs) could be an alternative solution since they possess both antimicrobial and antiseptic properties. HDPs are small, positively charged peptides which are evolutionarily conserved components of the innate immune response. In fact, binding to diverse chemotypes of LPS and inhibition of LPS-induced pro-inflammatory cytokines from macrophages have been demonstrated for different HDPs. Curiously, none of them have been isolated by their affinity to LPS. A diversity of supports could be useful for such biological interaction and suitable for isolating HDPs that recognize LPS. This approach could expand the rational search for anti-LPS HDPs. PMID:24409171

  15. Host-defense peptides from skin secretions of Fraser's clawed frog Xenopus fraseri (Pipidae): Further insight into the evolutionary history of the Xenopodinae.

    PubMed

    Conlon, J Michael; Mechkarska, Milena; Kolodziejek, Jolanta; Nowotny, Norbert; Coquet, Laurent; Leprince, Jérôme; Jouenne, Thierry; Vaudry, Hubert

    2014-12-01

    Peptidomic analysis of norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus fraseri Boulenger, 1905 (Pipidae) led to identification of 13 host-defense peptides. The primary structures of the peptides demonstrate that they belong to the magainin (3 peptides), peptide glycine-leucine-amide, PGLa (4 peptides), and xenopsin-precursor fragment, XPF (2 peptides) families, first identified in Xenopus laevis, together with caerulein precursor fragment-related peptides, CPF-RP (4 peptides), first identified in Silurana tropicalis. In addition, the secretions contain a molecular variant of xenopsin displaying the substitution Arg(4)→Lys compared with X. laevis xenopsin and peptide glycine-tyrosine-amide (PGYa) (GRIIPIYPEFERVFA KKVYPLY.NH2) whose function is unknown. The most potent antimicrobial peptide identified is CPF-RP-F1 (GFGSVLGKALKFGANLL.NH2) with MIC=12.5μM against Staphylococcus aureus and 50μM against Escherichia coli. On the basis of similarities in morphology and advertisement calls, X. fraseri has been placed in a species group that includes the octoploids Xenopus amieti and Xenopus andrei, and the tetraploid Xenopus pygmaeus. Cladistic analyses based upon the primary structures of magainin, PGLa, and CPF-RP peptides support a close evolutionary relationship between X. fraseri, X. amieti and X. andrei but suggest a more distant relationship with X. pygmaeus. PMID:25463057

  16. LPS inmobilization on porous and non-porous supports as an approach for the isolation of anti-LPS host-defense peptides.

    PubMed

    López-Abarrategui, Carlos; Del Monte-Martínez, Alberto; Reyes-Acosta, Osvaldo; Franco, Octavio L; Otero-González, Anselmo J

    2013-01-01

    Lipopolysaccharides (LPSs) are the major molecular component of the outer membrane of Gram-negative bacteria. This molecule is recognized as a sign of bacterial infection, responsible for the development of local inflammatory response and, in extreme cases, septic shock. Unfortunately, despite substantial advances in the pathophysiology of sepsis, there is no efficacious therapy against this syndrome yet. As a consequence, septic shock syndrome continues to increase, reaching mortality rates over 50% in some cases. Even though many preclinical studies and clinical trials have been conducted, there is no Food and Drug Administration-approved drug yet that interacts directly against LPS. Cationic host-defense peptides (HDPs) could be an alternative solution since they possess both antimicrobial and antiseptic properties. HDPs are small, positively charged peptides which are evolutionarily conserved components of the innate immune response. In fact, binding to diverse chemotypes of LPS and inhibition of LPS-induced pro-inflammatory cytokines from macrophages have been demonstrated for different HDPs. Curiously, none of them have been isolated by their affinity to LPS. A diversity of supports could be useful for such biological interaction and suitable for isolating HDPs that recognize LPS. This approach could expand the rational search for anti-LPS HDPs. PMID:24409171

  17. Expression of Allene Oxide Synthase Determines Defense Gene Activation in Tomato1

    PubMed Central

    Sivasankar, Sobhana; Sheldrick, Bay; Rothstein, Steven J.

    2000-01-01

    Allene oxide synthase (AOS; hydroperoxide dehydratase; EC 4.2.1.92) catalyzes the first step in the biosynthesis of jasmonic acid from lipoxygenase-derived hydroperoxides of free fatty acids. Using the AOS cDNA from tomato (Lycopersicon esculentum), in which the role of jasmonic acid in wound-induced defense gene activation has been best described, we examined the kinetics of AOS induction in response to wounding and elicitors, in parallel with that of the wound-inducible PIN II (proteinase inhibitor II) gene. AOS was induced in leaves by wounding, systemin, 12-oxophytodienoic acid, and methyl jasmonate. The levels of AOS mRNA started declining by 4 h after induction, whereas the levels of PIN II mRNA continued to increase up to 20 h after induction. Salicylic acid inhibited AOS and PIN II expression, and the addition of 12-oxophytodienoic acid or methyl jasmonate did not prevent the inhibition of PIN II expression in the presence of salicylic acid. Ethylene induced the expression of AOS, but the presence of ethylene alone did not produce an optimal induction of PIN II. The addition of silver thiosulfate, an ethylene action inhibitor, prevented the wound-induced expression of both AOS and PIN II. Products of hydroperoxide lyase affected neither AOS nor PIN II, but induced expression of prosystemin. Based on these results, we propose an updated model for defense gene activation in tomato. PMID:10759530

  18. A background traffic activity analysis in a canonical NATO (North Atlantic Treaty Organization) defense

    SciTech Connect

    Rogers, J.N.; Tooman, T.P.

    1989-04-01

    A canonical defense study in a NATO brigade sector on the northern flank of the US V Corps sector in the Federal Republic of Germany is wargamed to depict the expected vehicular movements during a 24 hour time period. All NATO and Warsaw Pact situations and forces played intentionally portray a ''normal'' battlefield situation, that is one in which events occur according to the established tactics and doctrines for both NATO and WP forces. Activity details which are almost always ignored in broader studies are included. The periodic displacement of high value units (e.g., artillery, air defense, headquarters and target acquisition) to preclude enemy fixing and targeting; the resupply down to company and occasionally platoon level of ammunition, petroleum, rations, etc.; the movement of commanders and staffs; the activity of combat engineers to include site preparation, construction and minefield emplacement; the action of reconnaissance and patrol units; the security of the rear area and POW processing; and the evacuation of casualties are analyzed. The resulting database records the position for every vehicle in both forces at each minute during the period of analysis and is thus an ideal framework for a variety of further studies, such as analyses of intelligence collection devices and modern ordinances. 9 refs., 30 figs., 9 tabs.

  19. [Features of brain oscillatory activity and cardiac defense in treatment arterial hypertensives].

    PubMed

    Aftanas, L I; Brak, I V; Gilinskaia, O M; Pavlov, S V; Reva, N V

    2014-01-01

    Stress reactivity of the motivational system of defense can be assessed with the aid the cardiac defense response (CDR) - the reaction of the cardiovascular system to unexpected aversive unconditioned stimulus. The main objective of the study was revealing putative contribution of oscillatory systems of the brain into central pathogenic mechanisms of enhanced blood pressure (BP) stress-reactivity in naive patients with arterial hypertension (AH) of the 1st-2nd degrees (n = 17) and healthy control (n = 19) subjects. Using dynamic registration "beat-by-beat" arterial pressure, and oscillatory activity related EEG (64 channels) is estimated using the event-related synchronization/desynchronization (ERD/ERS). Along with abnormally high blood pressure in patients with hypertension background set significantly lower concentrations of serotonin blood platelets and increased tonic activation of the left hemisphere, reflected in the asymmetric reduction of delta- (2-4 Hz) and theta-1 (4-6 Hz) power in the central and parietal cortex in the hemisphere CDR of the patients are characterized by hyperactivity both short- and long-latency components of blood pressure. According to the dynamic analysis of the concomitant EEG, long-latency BP components may be accounted by, among other mechanisms, weakening of the descending ("top-down") inhibitory control, hypothetically implemented with the high-frequency EEG alpha (10-12 Hz) oscillations from the medial central-parietal cortex of both hemispheres of the brain. PMID:25464727

  20. Functional Analysis of the Host Defense Peptide Human Beta Defensin-1: New Insight into Its Potential Role in Cancer

    PubMed Central

    Bullard, Rebecca S.; Gibson, Willietta; Bose, Sudeep; Belgrave, Jamila K.; Eaddy, Andre C.; Wright, Corey J.; Hazen-Martin, Debra J.; Lage, Janice M.; Keane, Thomas E.; Ganz, Tomas A.; Donald, Carlton D.

    2007-01-01

    Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involoved may include cMYC and/or PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death. PMID:17868871

  1. Cumberlandian Mollusk Conservation Program. Activity 2: potential fish hosts

    SciTech Connect

    Koch, L.M.; Hickman, G.D.; Swor, C.T.

    1986-02-01

    Fish species from sand/gravel substrates and from rubble substrates which are the most likely hosts for Cumberlandian mussel fauna, C. caelata and Q. intermedia, from the Clinch, Duck, Elk, and Powell Rivers are reported. Infection with mollusk glochidia was used with overlap and occurrences to develop a ranking of each species potential as a suitable host for Cumberlandian mollusks. 12 ref., 4 figs., 9 tabs.

  2. Francisella tularensis subsp. tularensis Induces a Unique Pulmonary Inflammatory Response: Role of Bacterial Gene Expression in Temporal Regulation of Host Defense Responses

    PubMed Central

    Walters, Kathie-Anne; Olsufka, Rachael; Kuestner, Rolf E.; Cho, Ji Hoon; Li, Hong; Zornetzer, Gregory A.; Wang, Kai; Skerrett, Shawn J.; Ozinsky, Adrian

    2013-01-01

    Pulmonary exposure to Francisella tularensis is associated with severe lung pathology and a high mortality rate. The lack of induction of classical inflammatory mediators, including IL1-β and TNF-α, during early infection has led to the suggestion that F. tularensis evades detection by host innate immune surveillance and/or actively suppresses inflammation. To gain more insight into the host response to Francisella infection during the acute stage, transcriptomic analysis was performed on lung tissue from mice exposed to virulent (Francisella tularensis ssp tularensis SchuS4). Despite an extensive transcriptional response in the lungs of animals as early as 4 hrs post-exposure, Francisella tularensis was associated with an almost complete lack of induction of immune-related genes during the initial 24 hrs post-exposure. This broad subversion of innate immune responses was particularly evident when compared to the pulmonary inflammatory response induced by other lethal (Yersinia pestis) and non-lethal (Legionella pneumophila, Pseudomonas aeruginosa) pulmonary infections. However, the unique induction of a subset of inflammation-related genes suggests a role for dysregulation of lymphocyte function and anti-inflammatory pathways in the extreme virulence of Francisella. Subsequent activation of a classical inflammatory response 48 hrs post-exposure was associated with altered abundance of Francisella-specific transcripts, including those associated with bacterial surface components. In summary, virulent Francisella induces a unique pulmonary inflammatory response characterized by temporal regulation of innate immune pathways correlating with altered bacterial gene expression patterns. This study represents the first simultaneous measurement of both host and Francisella transcriptome changes that occur during in vivo infection and identifies potential bacterial virulence factors responsible for regulation of host inflammatory pathways. PMID:23690939

  3. Host suitability and diet mixing influence activities of detoxification enzymes in adult Japanese beetles.

    PubMed

    Adesanya, Adekunle; Liu, Nannan; Held, David W

    2016-05-01

    Induction of cytochrome P450, glutathione S transferase (GST), and carboxylesterase (CoE) activity was measured in guts of the scarab Popillia japonica Newman, after consumption of single or mixed plant diets of previously ranked preferred (rose, Virginia creeper, crape myrtle and sassafras) or non-preferred hosts (boxelder, riverbirch and red oak). The goal of this study was to quantify activities of P450, GST and CoE enzymes in the midgut of adult P. japonica using multiple substrates in response to host plant suitability (preferred host vs non-preferred hosts), and single and mixed diets. Non-preferred hosts were only sparingly fed upon, and as a group induced higher activities of P450, GST and CoE than did preferred hosts. However, enzyme activities for some individual plant species were similar across categories of host suitability. Similarly, beetles tended to have greater enzyme activities after feeding on a mixture of plants compared to a single plant type, but mixing per se does not seem as important as the species represented in the mix. Induction of detoxification enzymes on non-preferred hosts, or when switching between hosts, may explain, in part, the perceived feeding preferences of this polyphagous insect. The potential consequences of induced enzyme activities on the ecology of adult Japanese beetles are discussed. PMID:26964493

  4. Heterogeneity of mprF sequences in methicillin-resistant Staphylococcus aureus clinical isolates: role in cross-resistance between daptomycin and host defense antimicrobial peptides.

    PubMed

    Bayer, Arnold S; Mishra, Nagendra N; Sakoulas, George; Nonejuie, Poochit; Nast, Cynthia C; Pogliano, Joseph; Chen, Kuan-Tsen; Ellison, Steven N; Yeaman, Michael R; Yang, Soo-Jin

    2014-12-01

    Over the past several years, single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been proposed to be associated with a gain-of-function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) in Staphylococcus aureus. We investigated the frequencies of SNPs within the mprF ORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistant S. aureus (MRSA) isolates of the clonal complex 5 genotype were used. In addition to mprF SNPs and DAP-HDP cross-resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i) mprF expression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of ≤ 1 μg/ml) exhibited mprF SNPs, occasionally with high-level mprF sequence variation from the genotype reference strain. However, none of these SNPs were localized to well-chronicled mprF hot spot locations associated with DAP-R in S. aureus. In contrast, all 8 DAP-R isolates demonstrated SNPs within such known mprF hot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhanced mprF expression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array of mprF SNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrent mprF dysregulation, were associated with the DAP-R phenotype. PMID:25288091

  5. Synergistic interaction among begomoviruses leads to the suppression of host defense-related gene expression and breakdown of resistance in chilli.

    PubMed

    Singh, Ashish Kumar; Kushwaha, Nirbhay; Chakraborty, Supriya

    2016-05-01

    Chilli (Capsicum sp.) is one of the economically important spice and vegetable crops grown in India and suffers great losses due to the infection of begomoviruses. Conventional breeding approaches have resulted in development of a few cultivars of chilli resistant to begomoviruses. A severe leaf curl disease was observed on one such resistant chilli cultivar (Capsicum annuum cv. Kalyanpur Chanchal) grown in the experimental field of the Jawaharlal Nehru University, New Delhi. Four different viral genomic components namely, Chilli leaf curl virus (DNA A), Tomato leaf curl Bangladesh betasatellite (DNA β), Tomato leaf curl New Delhi virus (DNA A), and Tomato leaf curl Gujarat virus (DNA B) were associated with the severe leaf curl disease. Further, frequent association of these four genomic components was also observed in symptomatic plants of other chilli cultivars (Capsicum annuum cv. Kashi Anmol and Capsicum chinense cv. Bhut Jolokia) grown in the experimental field. Interaction studies among the isolated viral components revealed that Nicotiana benthamiana and chilli plants inoculated with four genomic components of begomoviruses exhibited severe leaf curl disease symptoms. In addition, this synergistic interaction resulted in increased viral DNA accumulation in infected plants. Resistant chilli plants co-inoculated with four genomic components of begomoviruses showed drastic reduction of host basal (ascorbate peroxidase, thionin, polyphenol oxidase) and specific defense-related gene (NBS-LRR) expression. Our results suggested that synergistic interaction among begomoviruses created permissive cellular environment in the resistant chilli plants which leads to breakdown of natural resistance, a phenomenon observed for the first time in chilli. PMID:26780359

  6. Disease Interactions in a Shared Host Plant: Effects of Pre-Existing Viral Infection on Cucurbit Plant Defense Responses and Resistance to Bacterial Wilt Disease

    PubMed Central

    Mauck, Kerry E.; Pulido, Hannier; De Moraes, Consuelo M.; Stephenson, Andrew G.; Mescher, Mark C.

    2013-01-01

    Both biotic and abiotic stressors can elicit broad-spectrum plant resistance against subsequent pathogen challenges. However, we currently have little understanding of how such effects influence broader aspects of disease ecology and epidemiology in natural environments where plants interact with multiple antagonists simultaneously. In previous work, we have shown that healthy wild gourd plants (Cucurbita pepo ssp. texana) contract a fatal bacterial wilt infection (caused by Erwinia tracheiphila) at significantly higher rates than plants infected with Zucchini yellow mosaic virus (ZYMV). We recently reported evidence that this pattern is explained, at least in part, by reduced visitation of ZYMV-infected plants by the cucumber beetle vectors of E. tracheiphila. Here we examine whether ZYMV-infection may also directly elicit plant resistance to subsequent E. tracheiphila infection. In laboratory studies, we assayed the induction of key phytohormones (SA and JA) in single and mixed infections of these pathogens, as well as in response to the feeding of A. vittatum cucumber beetles on healthy and infected plants. We also tracked the incidence and progression of wilt disease symptoms in plants with prior ZYMV infections. Our results indicate that ZYMV-infection slightly delays the progression of wilt symptoms, but does not significantly reduce E. tracheiphila infection success. This observation supports the hypothesis that reduced rates of wilt disease in ZYMV-infected plants reflect reduced visitation by beetle vectors. We also documented consistently strong SA responses to ZYMV infection, but limited responses to E. tracheiphila in the absence of ZYMV, suggesting that the latter pathogen may effectively evade or suppress plant defenses, although we observed no evidence of antagonistic cross-talk between SA and JA signaling pathways. We did, however, document effects of E. tracheiphila on induced responses to herbivory that may influence host-plant quality for (and

  7. Tetraploidization of diploid Dioscorea results in activation of the antioxidant defense system and increased heat tolerance.

    PubMed

    Zhang, Xiao-Yi; Hu, Chun-Gen; Yao, Jia-Ling

    2010-01-15

    Polyploidy is reported to show increased tolerance to environmental stress. In this work, tetraploid plants of Dioscorea zingiberensis were obtained by colchicine treatment of shoots propagated in vitro. The highest tetraploid induction rate was achieved by treatment with 0.15% colchicine for 24h. Diploid and tetraploid plants were exposed to normal (28 degrees C) and high temperature (42 degrees C) for 5d during which physiological indices were measured. Compared with diploid plants, relative electrolyte leakage and contents of malondialdehyde, superoxide anions and hydrogen peroxide were lower in tetraploids, while activities of antioxidant enzymes, such as superoxide dismutase, peroxidase, catalase, ascorbate peroxidase and glutathione reductase, were stimulated and antioxidants (ascorbic acid and glutathione) were maintained at high concentrations. These results indicate that tetraploid plants possess a stronger antioxidant defense system and increased heat tolerance. PMID:19692145

  8. Defensive activation during the rubber hand illusion: Ownership versus proprioceptive drift.

    PubMed

    Riemer, Martin; Bublatzky, Florian; Trojan, Jörg; Alpers, Georg W

    2015-07-01

    A strong link between body perception and emotional experience has been proposed. To examine the interaction between body perception and anticipatory anxiety, two well-established paradigms were combined: The rubber hand illusion (RHI) and the threat-of-shock paradigm. An artificial hand and the participants' own hand (hidden from sight) were touched synchronously or asynchronously, while either threat-of-shock or safety was cued. Potentiated startle reflexes and enhanced skin conductance responses were observed during threat as compared to safety conditions, but threat conditions did not interact with illusory body perceptions. Thus, defense system activation was not modulated by altered body representations. Physiological responses increased with the sense of ownership for the artificial limb, but not with proprioceptive drift towards its location. The results indicate that ownership ratings and proprioceptive drift capture different aspects of the RHI. The study presents a new approach to investigate the relationship between body representations and emotional states. PMID:25960069

  9. Defensive sesquiterpenes from Senecio candidans and S. magellanicus, and their structure-activity relationships.

    PubMed

    Reina, Matías; Santana, Omar; Domínguez, Dulce M; Villarroel, Luis; Fajardo, Víctor; Rodríguez, Matías L; González-Coloma, Azucena

    2012-03-01

    Eleven eremophilanolides, 1-3 and 6-13, and two eremophilanes, 24 and 25, were isolated from Senecio candidans and S. magellanicus from the Magallanes Region (Chile). Compounds 2, 3, 9, and 10 have not been previously reported as natural products. Their structures were established by NMR spectroscopic analysis and chemical transformations. The X-ray analysis of compounds 11, 13, and 17 were also performed. Different semisynthetic analogs from eremophilanolide 11 were generated to carry out a structure-activity relationship study. Their possible plant defensive role was tested against herbivorous insects (Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae) and plants (Lactuca sativa). Additionally, their effects on insect (Sf9) and mammalian (CHO) cell lines were tested. PMID:22422530

  10. Enhanced antioxidant defense due to extracellular catalase activity in Syrian hamster during arousal from hibernation.

    PubMed

    Ohta, Hitomi; Okamoto, Iwao; Hanaya, Toshiharu; Arai, Shigeyuki; Ohta, Tsunetaka; Fukuda, Shigeharu

    2006-08-01

    Mammalian hibernators are considered a natural model for resistance to ischemia-reperfusion injuries, and protective mechanisms against oxidative stress evoked by repeated hibernation-arousal cycles in these animals are increasingly the focus of experimental investigation. Here we show that extracellular catalase activity provides protection against oxidative stress during arousal from hibernation in Syrian hamster. To examine the serum antioxidant defense system, we first assessed the hibernation-arousal state-dependent change in serum attenuation of cytotoxicity induced by hydrogen peroxide. Serum obtained from hamsters during arousal from hibernation at a rectal temperature of 32 degrees C, concomitant with the period of increased oxidative stress, attenuated the cytotoxicity four-fold more effectively than serum from cenothermic control hamsters. Serum catalase activity significantly increased during arousal, whereas glutathione peroxidase activity decreased by 50%, compared with cenothermic controls. The cytoprotective effect of purified catalase at the concentration found in serum was also confirmed in a hydrogen peroxide-induced cytotoxicity model. Moreover, inhibition of catalase by aminotriazole led to an 80% loss of serum hydrogen peroxide scavenging activity. These results suggest that extracellular catalase is effective for protecting hibernators from oxidative stress evoked by arousal from hibernation. PMID:16807122

  11. Surveillance-Activated Defenses Block the ROS–Induced Mitochondrial Unfolded Protein Response

    PubMed Central

    Runkel, Eva D.; Liu, Shu; Baumeister, Ralf; Schulze, Ekkehard

    2013-01-01

    Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal transduction of the mitochondrial unfolded protein response (UPRmt) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPRmt, and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS–induced UPRmt. Activation of the UPRmt, but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS–induced UPRmt, suggesting that surveillance-activated defenses specifically inhibit the UPRmt but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism. PMID:23516373

  12. The Bark-Beetle-Associated Fungus, Endoconidiophora polonica, Utilizes the Phenolic Defense Compounds of Its Host as a Carbon Source1[OPEN

    PubMed Central

    Wadke, Namita; Kandasamy, Dineshkumar; Vogel, Heiko; Wingfield, Brenda D.; Paetz, Christian

    2016-01-01

    Norway spruce (Picea abies) is periodically attacked by the bark beetle Ips typographus and its fungal associate, Endoconidiophora polonica, whose infection is thought to be required for successful beetle attack. Norway spruce produces terpenoid resins and phenolics in response to fungal and bark beetle invasion. However, how the fungal associate copes with these chemical defenses is still unclear. In this study, we investigated changes in the phenolic content of Norway spruce bark upon E. polonica infection and the biochemical factors mediating these changes. Although genes encoding the rate-limiting enzymes in Norway spruce stilbene and flavonoid biosynthesis were actively transcribed during fungal infection, there was a significant time-dependent decline of the corresponding metabolites in fungal lesions. In vitro feeding experiments with pure phenolics revealed that E. polonica transforms both stilbenes and flavonoids to muconoid-type ring-cleavage products, which are likely the first steps in the degradation of spruce defenses to substrates that can enter the tricarboxylic acid cycle. Four genes were identified in E. polonica that encode catechol dioxygenases carrying out these reactions. These enzymes catalyze the cleavage of phenolic rings with a vicinal dihydroxyl group to muconoid products accepting a wide range of Norway spruce-produced phenolics as substrates. The expression of these genes and E. polonica utilization of the most abundant spruce phenolics as carbon sources both correlated positively with fungal virulence in several strains. Thus, the pathways for the degradation of phenolic compounds in E. polonica, initiated by catechol dioxygenase action, are important to the infection, growth, and survival of this bark beetle-vectored fungus and may play a major role in the ability of I. typographus to colonize spruce trees. PMID:27208235

  13. Cell death-inducing stresses are required for defense activation in DS1-phosphatidic acid phosphatase-silenced Nicotiana benthamiana.

    PubMed

    Nakano, Masahito; Yoshioka, Hirofumi; Ohnishi, Kouhei; Hikichi, Yasufumi; Kiba, Akinori

    2015-07-20

    We previously identified DS1 plants that showed resistance to compatible Ralstonia solanacearum with accelerated defense responses. Here, we describe activation mechanisms of defense responses in DS1 plants. After inoculation with incompatible R. solanacearum 8107, DS1 plants showed hyperinduction of hypersensitive response (HR) and reactive oxygen species (ROS) generation. Transient expression of PopP1 and AvrA induced hyperinduction of HR and ROS generation. Furthermore, Pseudomonas cichorii (Pc) and a type III secretion system (TTSS)-deficient mutant of P. cichorii showed accelerated induction of HR and ROS generation. Chitin and flg22 did not induce either HR or ROS hyperaccumulation; however, INF1 accelerated HR and ROS in DS1 plants. Activation of these defense responses was closely associated with increased phosphatidic acid (PA) content. Our results show that DS1 plants exhibit PA-mediated sensitization of plant defenses and that cell death-inducing stress is required to achieve full activation of defense responses. PMID:26188395

  14. The staphylococcal surface-glycopolymer wall teichoic acid (WTA) is crucial for complement activation and immunological defense against Staphylococcus aureus infection.

    PubMed

    Kurokawa, Kenji; Takahashi, Kazue; Lee, Bok Luel

    2016-10-01

    Staphylococcus aureus is a Gram-positive bacterial pathogen that is decorated by glycopolymers, including wall teichoic acid (WTA), peptidoglycan, lipoteichoic acid, and capsular polysaccharides. These bacterial surface glycopolymers are recognized by serum antibodies and a variety of pattern recognition molecules, including mannose-binding lectin (MBL). Recently, we demonstrated that human serum MBL senses staphylococcal WTA. Whereas MBL in infants who have not yet fully developed adaptive immunity binds to S. aureus WTA and activates complement serum, MBL in adults who have fully developed adaptive immunity cannot bind to WTA because of an inhibitory effect of serum anti-WTA IgG. Furthermore, we showed that human anti-WTA IgGs purified from pooled adult serum IgGs triggered activation of classical complement-dependent opsonophagocytosis against S. aureus. Because the epitopes of WTA that are recognized by anti-WTA IgG and MBL have not been determined, we constructed several S. aureus mutants with altered WTA glycosylation. Our intensive biochemical studies provide evidence that the β-GlcNAc residues of WTA are required for the induction of anti-WTA IgG-mediated opsonophagocytosis and that both β- and α-GlcNAc residues are required for MBL-mediated complement activation. The molecular interactions of other S. aureus cell wall components and host recognition proteins are also discussed. In summary, in this review, we discuss the biological importance of S. aureus cell surface glycopolymers in complement activation and host defense responses. PMID:27424796

  15. Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response

    SciTech Connect

    Zheng, Yi; Tao, Shasha; Lian, Fangru; Chau, Binh T.; Chen, Jie; Sun, Guifan; Fang, Deyu; Lantz, R. Clark; Zhang, Donna D.

    2012-12-15

    Exposure to arsenic is associated with an increased risk of lung disease. Novel strategies are needed to reduce the adverse health effects associated with arsenic exposure in the lung. Nrf2, a transcription factor that mediates an adaptive cellular defense response, is effective in detoxifying environmental insults and prevents a broad spectrum of diseases induced by environmental exposure to harmful substances. In this report, we tested whether Nrf2 activation protects mice from arsenic-induced toxicity. We used an in vivo arsenic inhalation model that is highly relevant to low environmental human exposure to arsenic-containing dusts. Two-week exposure to arsenic-containing dust resulted in pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung; all of which were blocked by sulforaphane (SF) in an Nrf2-dependent manner. Mechanistically, SF-mediated activation of Nrf2 alleviated inflammatory responses by modulating cytokine production. This study provides strong evidence that dietary intervention targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with arsenic exposure. -- Highlights: ► Exposed to arsenic particles and/or SF have elevated Nrf2 and its target genes. ► Sulforaphane prevents pathological alterations, oxidative damage and cell death. ► Sulforaphane alleviates infiltration of inflammatory cells into the lungs. ► Sulforaphane suppresses arsenic-induced proinflammatory cytokine production.

  16. Proteome of Soybean Seed Exudates Contains Plant Defense-Related Proteins Active against the Root-Knot Nematode Meloidogyne incognita.

    PubMed

    Rocha, Raquel O; Morais, Janne K S; Oliveira, Jose T A; Oliveira, Hermogenes D; Sousa, Daniele O B; Souza, Carlos Eduardo A; Moreno, Frederico B; Monteiro-Moreira, Ana Cristina O; de Souza Júnior, José Dijair Antonino; de Sá, Maria F Grossi; Vasconcelos, Ilka M

    2015-06-10

    Several studies have described the effects of seed exudates against microorganisms, but only few of them have investigated the proteins that have defensive activity particularly against nematode parasites. This study focused on the proteins released in the exudates of soybean seeds and evaluated their nematicidal properties against Meloidogyne incognita. A proteomic approach indicated the existence of 63 exuded proteins, including β-1,3-glucanase, chitinase, lectin, trypsin inhibitor, and lipoxygenase, all of which are related to plant defense. The presence of some of these proteins was confirmed by their in vitro activity. The soybean exudates were able to reduce the hatching of nematode eggs and to cause 100% mortality of second-stage juveniles (J2). The pretreatment of J2 with these exudates resulted in a 90% reduction of the gall number in tobacco plants. These findings suggest that the exuded proteins are directly involved in plant defense against soil pathogens, including nematodes, during seed germination. PMID:26034922

  17. Subchronic atrazine exposure changes defensive behaviour profile and disrupts brain acetylcholinesterase activity of zebrafish.

    PubMed

    Schmidel, Ademir J; Assmann, Karla L; Werlang, Chariane C; Bertoncello, Kanandra T; Francescon, Francini; Rambo, Cassiano L; Beltrame, Gabriela M; Calegari, Daiane; Batista, Cibele B; Blaser, Rachel E; Roman Júnior, Walter A; Conterato, Greicy M M; Piato, Angelo L; Zanatta, Leila; Magro, Jacir Dal; Rosemberg, Denis B

    2014-01-01

    Animal behaviour is the interaction between environment and an individual organism, which also can be influenced by its neighbours. Variations in environmental conditions, as those caused by contaminants, may lead to neurochemical impairments altering the pattern of the behavioural repertoire of the species. Atrazine (ATZ) is an herbicide widely used in agriculture that is frequently detected in surface water, affecting non-target species. The zebrafish is a valuable model organism to assess behavioural and neurochemical effects of different contaminants since it presents a robust behavioural repertoire and also all major neurotransmitter systems described for mammalian species. The goal of this study was to evaluate the effects of subchronic ATZ exposure in defensive behaviours of zebrafish (shoaling, thigmotaxis, and depth preference) using the split depth tank. Furthermore, to investigate a putative role of cholinergic signalling on ATZ-mediated effects, we tested whether this herbicide alters acetylcholinesterase (AChE) activity in brain and muscle preparations. Fish were exposed to ATZ for 14days and the following groups were tested: control (0.2% acetone) and ATZ (10 and 1000μg/L). The behaviour of four animals in the same tank was recorded for 6min and biological samples were prepared. Our results showed that 1000μg/L ATZ significantly increased the inter-fish distance, as well as the nearest and farthest neighbour distances. This group also presented an increase in the shoal area with decreased social interaction. No significant differences were detected for the number of animals in the shallow area, latency to enter the shallow and time spent in shallow and deep areas of the apparatus, but the ATZ 1000 group spent significantly more time near the walls. Although ATZ did not affect muscular AChE, it significantly reduced AChE activity in brain. Exposure to 10μg/L ATZ did not affect behaviour or AChE activity. These data suggest that ATZ impairs defensive

  18. Intracellular Oxidant Activity, Antioxidant Enzyme Defense System, and Cell Senescence in Fibroblasts with Trisomy 21

    PubMed Central

    Rodríguez-Sureda, Víctor; Vilches, Ángel; Sánchez, Olga; Audí, Laura; Domínguez, Carmen

    2015-01-01

    Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS. PMID:25852816

  19. Intracellular oxidant activity, antioxidant enzyme defense system, and cell senescence in fibroblasts with trisomy 21.

    PubMed

    Rodríguez-Sureda, Víctor; Vilches, Ángel; Sánchez, Olga; Audí, Laura; Domínguez, Carmen

    2015-01-01

    Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS. PMID:25852816

  20. Defensive behaviour and biological activities of the abdominal secretion in the ant Crematogaster scutellaris (Hymenoptera: Myrmicinae).

    PubMed

    Marlier, J F; Quinet, Y; de Biseau, J C

    2004-11-30

    Using bioassays, the defensive behaviour of Crematogaster scutellaris and the biological activities of its abdominal secretion were investigated. Beside classical aggressive behaviours such as grips, C. scutellaris workers performed frequent characteristic gaster flexions during interspecific encounters, sometimes tempting to apply their abdominal secretion topically on the enemy. The toxicity of the venom of C. scutellaris to other ants greatly differed among the species tested, some being killed after the topical application of only three droplets, while others were quite resistant to a dose of 90 droplets. All ant species tested were strongly and immediately repelled by a contact between their antennae or mouthparts with the venom of C. scutellaris. Abdominal secretion was never used during intraspecific interference and workers were resistant to a topical application of the venom of their own species. Intraspecific repellency was significant but moderate compared to interspecific one. Workers of C. scutellaris were never seen using their venom during prey capture. In conclusion, the main biological activity of the abdominal secretion of C. scutellaris seems to be its repellency to other ant species. This is supported by field experiments showing that Pheidole pallidula foragers were efficiently repelled at coexploited baits, allowing the monopolization of most prey by C. scutellaris. PMID:15518992

  1. Increased activity correlates with reduced ability to mount immune defenses to endotoxin in zebra finches.

    PubMed

    Lopes, Patricia C; Springthorpe, Dwight; Bentley, George E

    2014-10-01

    When suffering from infection, animals experience behavioral and physiological alterations that potentiate the immune system's ability to fight pathogens. The behavioral component of this response, termed "sickness behavior," is characterized by an overall reduction in physical activity. A growing number of reports demonstrate substantial flexibility in these sickness behaviors, which can be partially overcome in response to mates, intruders and parental duties. Since it is hypothesized that adopting sickness behaviors frees energetic resources for mounting an immune response, we tested whether diminished immune responses coincided with reduced sickness behaviors by housing male zebra finches (Taeniopygia guttata) in social conditions that alter their behavioral response to an endotoxin. To facilitate our data collection, we developed and built a miniaturized sensor capable of detecting changes in dorsoventral acceleration and categorizing them as different behaviors when attached to the finches. We found that the immune defenses (quantified as haptoglobin-like activity, ability to change body temperature and bacterial killing capacity) increased as a function of increased time spent resting. The findings indicate that when animals are sick attenuation of sickness behaviors may exact costs, such as reduced immune function. The extent of these costs depends on how relevant the affected components of immunity are for fighting a specific infection. PMID:24888267

  2. 10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility...

  3. 10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility...

  4. 10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility...

  5. 10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility...

  6. 10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility...

  7. 18 CFR 2.60 - Facilities and activities during an emergency-accounting treatment of defense-related expenditures.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Facilities and activities during an emergency-accounting treatment of defense-related expenditures. 2.60 Section 2.60 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY...

  8. Regulation of Plant Defense Response to Fungal Pathogens: Two Types of Protein Kinases in the Reversible Phosphorylation of the Host Plasma Membrane H+-ATPase.

    PubMed Central

    Xing, T; Higgins, VJ; Blumwald, E

    1996-01-01

    The role of reversible phosphorylation of the host plasma membrane H+-ATPase in signal transduction during the incompatible interaction between tomato cells and the fungal pathogen Cladosporium fulvum was investigated. Tomato cells (with the Cf-5 resistance gene) or isolated plasma membranes from Cf-5 cells treated with elicitor preparations from race 2.3 or 4 of C. fulvum (containing the avr5 gene product) showed a marked dephosphorylation of plasma membrane H+-ATPase. Similar treatment with elicitor preparations from races 5 and 2.4.5.9.11 (lacking the avr5 gene product) showed no change in dephosphorylation. Elicitor (race 4) treatment of cells, but not of isolated plasma membranes, for 2 hr resulted in rephosphorylation of the ATPase via Ca2+-dependent protein kinases. The initial (first hour) rephosphorylation was enhanced by protein kinase C (PKC) activators and was prevented by PKC inhibitors. Activity of a second kinase appeared after 1 hr and was responsible for the continuing phosphorylation of the H+-ATPase. This latter Ca2+-dependent kinase was inhibited by a calmodulin (CaM) antagonist and by an inhibitor of Ca2+/CaM-dependent protein kinase II. The activation of the Ca2+/CaM-dependent protein kinase depended on the prior activation of the PKC-like kinase. PMID:12239392

  9. Host natural suppressor activity regulates hemopoietic engraftment kinetics in antibody-conditioned recipient mice

    SciTech Connect

    Sadelain, M.W.; Green, D.R.; Wegmann, T.G. )

    1990-03-01

    Resistance to semi-allogeneic or syngeneic hemopoietic stem cell engraftment can be reduced by treating the unirradiated host with anti-class I MHC antibody. In our previous studies we showed a direct correlation between such resistance and the level of natural suppressor (NS) activity in the host. Thus newborn mice that have high NS activity are very resistant to marrow engraftment, as are adults pretreated with CFA that increases NS activity in the bone marrow. We have now devised a method that allows us to follow hemopoietic engraftment kinetics within the marrow cavity itself by assaying individual CFU-granulocyte/macrophage progenitor cells for their host or donor origin over the immediate post-transplant period. By using this method, we find a close correlation between the rate of marrow engraftment and reduction in host NS activity. Marrow engraftment does not correlate with the reduction of either total host bone marrow cellular content or CFU-granulocyte/macrophage progenitor cell levels. NS activity is mediated by Thy-1-, partially radiosensitive, nylon wool nonadherent cells without NK activity. Adoptively transferred Thy-1-, irradiated spleen cells containing NS activity induced by pretreatment with CFA delayed engraftment kinetics in the marrow cavity. Thus hemopoietic engraftment in the marrow cavity appears to be controlled by an inhibitory regulatory activity that is reflected in the in vitro NS assay. These studies suggest new regulatory targets for selective host conditioning to eliminate resistance to marrow transplantation.

  10. Detection of neural activity in the brains of Japanese honeybee workers during the formation of a "hot defensive bee ball".

    PubMed

    Ugajin, Atsushi; Kiya, Taketoshi; Kunieda, Takekazu; Ono, Masato; Yoshida, Tadaharu; Kubo, Takeo

    2012-01-01

    Anti-predator behaviors are essential to survival for most animals. The neural bases of such behaviors, however, remain largely unknown. Although honeybees commonly use their stingers to counterattack predators, the Japanese honeybee (Apis cerana japonica) uses a different strategy to fight against the giant hornet (Vespa mandarinia japonica). Instead of stinging the hornet, Japanese honeybees form a "hot defensive bee ball" by surrounding the hornet en masse, killing it with heat. The European honeybee (A. mellifera ligustica), on the other hand, does not exhibit this behavior, and their colonies are often destroyed by a hornet attack. In the present study, we attempted to analyze the neural basis of this behavior by mapping the active brain regions of Japanese honeybee workers during the formation of a hot defensive bee ball. First, we identified an A. cerana homolog (Acks = Apis cerana kakusei) of kakusei, an immediate early gene that we previously identified from A. mellifera, and showed that Acks has characteristics similar to kakusei and can be used to visualize active brain regions in A. cerana. Using Acks as a neural activity marker, we demonstrated that neural activity in the mushroom bodies, especially in Class II Kenyon cells, one subtype of mushroom body intrinsic neurons, and a restricted area between the dorsal lobes and the optic lobes was increased in the brains of Japanese honeybee workers involved in the formation of a hot defensive bee ball. In addition, workers exposed to 46°C heat also exhibited Acks expression patterns similar to those observed in the brains of workers involved in the formation of a hot defensive bee ball, suggesting that the neural activity observed in the brains of workers involved in the hot defensive bee ball mainly reflects thermal stimuli processing. PMID:22431987

  11. Chitosan controls postharvest anthracnose in bell pepper by activating defense-related enzymes.

    PubMed

    Edirisinghe, Madushani; Ali, Asgar; Maqbool, Mehdi; Alderson, Peter G

    2014-12-01

    Anthracnose, a postharvest disease caused by the fungus Colletotrichum capsici is the most devastating disease of bell pepper that causes great economic losses especially in tropical climates. Therefore, the objective of this study was to evaluate the antifungal properties of chitosan (low molecular weight from crab shell, Mw: 50 kDa and 75-85 % deacetylated) against anthracnose by inducing defense-related enzymes. The concentrations of 0, 0.5, 1.0, 1.5 and 2.0 % chitosan were used to control the fungus in vitro and postharvest. There was a reduction in C. capsici mycelial growth and the highest chitosan concentration (2.0 %) reduced the growth by 70 % after 7 days incubation. In germination test, the concentration of 1.5 and 2.0 % chitosan reduced spore germination in C. capsici between 80 % and 84 %, respectively. In postharvest trial the concentration of 1.5 % decreased the anthracnose severity in pepper fruit by approximately 76 % after 28 days of storage (10 ± 1 °C; 80 % RH). For enzymatic activities, the concentration of 1.5 and 2.0 % chitosan increased the polyphenol oxidase (PPO), peroxidase (POD) and total phenolics in inoculated bell pepper during storage. Based on these results, the chitosan presents antifungal properties against C. capsici, as well as potential to induce resistance on bell pepper. PMID:25477684

  12. Sulforaphane protects Microcystin-LR-induced toxicity through activation of the Nrf2-mediated defensive response

    SciTech Connect

    Gan Nanqin; Mi Lixin; Sun Xiaoyun; Dai Guofei; Chung Funglung; Song Lirong

    2010-09-01

    Microcystins (MCs), a cyclic heptapeptide hepatotoxins, are mainly produced by the bloom-forming cyanobacerium Microcystis, which has become an environmental hazard worldwide. Long term consumption of MC-contaminated water may induce liver damage, liver cancer, and even human death. Therefore, in addition to removal of MCs in drinking water, novel strategies that prevent health damages are urgently needed. Sulforaphane (SFN), a natural-occurring isothiocyanate from cruciferous vegetables, has been reported to reduce and eliminate toxicities from xenobiotics and carcinogens. The purpose of the present study was to provide mechanistic insights into the SFN-induced antioxidative defense system against MC-LR-induced cytotoxicity. We performed cell viability assays, including MTS assay, colony formation assay and apoptotic cell sorting, to study MC-LR-induced cellular damage and the protective effects by SFN. The results showed that SFN protected MC-LR-induced damages at a nontoxic and physiological relevant dose in HepG2, BRL-3A and NIH 3 T3 cells. The protection was Nrf2-mediated as evident by transactivation of Nrf2 and activation of its downstream genes, including NQO1 and HO-1, and elevated intracellular GSH level. Results of our studies indicate that pretreatment of cells with 10 {mu}M SFN for 12 h significantly protected cells from MC-LR-induced damage. SFN-induced protective response was mediated through Nrf2 pathway.

  13. Ozone Sensitivity in Hybrid Poplar Is Correlated with a Lack of Defense-Gene Activation1

    PubMed Central

    Riehl Koch, Jennifer; Scherzer, Amy J.; Eshita, Steven M.; Davis, Keith R.

    1998-01-01

    Ozone is a major gaseous pollutant thought to contribute to forest decline. Although the physiological and morphological responses of forest trees to ozone have been well characterized, little is known about the molecular basis for these responses. Our studies compared the response to ozone of ozone-sensitive and ozone-tolerant clones of hybrid poplar (Populus maximowizii × Populus trichocarpa) at the physiological and molecular levels. Gas-exchange analyses demonstrated clear differences between the ozone-sensitive clone 388 and the ozone-tolerant clone 245. Although ozone induced a decrease in photosynthetic rate and stomatal conductance in both clones, the magnitude of the decrease in stomatal conductance was significantly greater in the ozone-tolerant clone. RNA-blot analysis established that ozone-induced mRNA levels for phenylalanine ammonia-lyase, O-methyltransferase, a pathogenesis-related protein, and a wound-inducible gene were significantly higher in the ozone-tolerant than in the ozone-sensitive plants. Wound- and pathogen-induced levels of these mRNAs were also higher in the ozone-tolerant compared with the ozone-sensitive plants. The different physiological and molecular responses to ozone exposure exhibited by clones 245 and 388 suggest that ozone tolerance involves the activation of salicylic-acid- and jasmonic-acid-mediated signaling pathways, which may be important in triggering defense responses against oxidative stress. PMID:9847098

  14. A Novel Strategy for Exploitation of Host RNase E Activity by a Marine Cyanophage.

    PubMed

    Stazic, Damir; Pekarski, Irena; Kopf, Matthias; Lindell, Debbie; Steglich, Claudia

    2016-07-01

    Previous studies have shown that infection of Prochlorococcus MED4 by the cyanophage P-SSP7 leads to increased transcript levels of host endoribonuclease (RNase) E. However, it has remained enigmatic whether this is part of a host defense mechanism to degrade phage messenger RNA (mRNA) or whether this single-strand RNA-specific RNase is utilized by the phage. Here we describe a hitherto unknown means through which this cyanophage increases expression of RNase E during phage infection and concomitantly protects its own RNA from degradation. We identified two functionally different RNase E mRNA variants, one of which is significantly induced during phage infection. This transcript lacks the 5' UTR, is considerably more stable than the other transcript, and is likely responsible for increased RNase E protein levels during infection. Furthermore, selective enrichment and in vivo analysis of double-stranded RNA (dsRNA) during infection revealed that phage antisense RNAs (asRNAs) sequester complementary mRNAs to form dsRNAs, such that the phage protein-coding transcriptome is nearly completely covered by asRNAs. In contrast, the host protein-coding transcriptome is only partially covered by asRNAs. These data suggest that P-SSP7 orchestrates degradation of host RNA by increasing RNase E expression while masking its own transcriptome from RNase E degradation in dsRNA complexes. We propose that this combination of strategies contributes significantly to phage progeny production. PMID:27182944

  15. Annual Report To Congress. Department of Energy Activities Relating to the Defense Nuclear Facilities Safety Board, Calendar Year 2003

    SciTech Connect

    None, None

    2004-02-28

    The Department of Energy (Department) submits an Annual Report to Congress each year detailing the Department’s activities relating to the Defense Nuclear Facilities Safety Board (Board), which provides advice and recommendations to the Secretary of Energy (Secretary) regarding public health and safety issues at the Department’s defense nuclear facilities. In 2003, the Department continued ongoing activities to resolve issues identified by the Board in formal recommendations and correspondence, staff issue reports pertaining to Department facilities, and public meetings and briefings. Additionally, the Department is implementing several key safety initiatives to address and prevent safety issues: safety culture and review of the Columbia accident investigation; risk reduction through stabilization of excess nuclear materials; the Facility Representative Program; independent oversight and performance assurance; the Federal Technical Capability Program (FTCP); executive safety initiatives; and quality assurance activities. The following summarizes the key activities addressed in this Annual Report.

  16. On the Host Galaxy of GRB 150101B and the Associated Active Galactic Nucleus

    NASA Astrophysics Data System (ADS)

    Xie, Chen; Fang, Taotao; Wang, Junfeng; Liu, Tong; Jiang, Xiaochuan

    2016-06-01

    We present a multi-wavelength analysis of the host galaxy of short-duration gamma-ray burst (GRB) 150101B. Follow-up optical and X-ray observations suggested that the host galaxy, 2MASX J12320498-1056010, likely harbors low-luminosity active galactic nuclei (AGNs). Our modeling of the spectral energy distribution has confirmed the nature of the AGN, making it the first reported GRB host that contains an AGN. We have also found the host galaxy is a massive elliptical galaxy with stellar population of ∼5.7 Gyr, one of the oldest among the short-duration GRB hosts. Our analysis suggests that the host galaxy can be classified as an X-ray bright, optically normal galaxy, and the central AGN is likely dominated by a radiatively inefficient accretion flow. Our work explores an interesting connection that may exist between GRB and AGN activities of the host galaxy, which can help in understanding the host environment of the GRB events and the roles of AGN feedback.

  17. Passive and active defense in toads: the parotoid macroglands in Rhinella marina and Rhaebo guttatus.

    PubMed

    Mailho-Fontana, Pedro L; Antoniazzi, Marta M; Toledo, Luís F; Verdade, Vanessa K; Sciani, Juliana M; Barbaro, Katia C; Pimenta, Daniel C; Rodrigues, Miguel T; Jared, Carlos

    2014-02-01

    Amphibians have many skin poison glands used in passive defense, in which the aggressor causes its own poisoning when biting prey. In some amphibians the skin glands accumulate in certain regions forming macroglands, such as the parotoids of toads. We have discovered that the toad Rhaebo guttatus is able to squirt jets of poison towards the aggressor, contradicting the typical amphibian defense. We studied the R. guttatus chemical defense, comparing it with Rhinella marina, a sympatric species showing typical toad passive defense. We found that only in R. guttatus the parotoid is adhered to the scapula and do not have a calcified dermal layer. In addition, in this species, the plugs obstructing the glandular ducts are more fragile when compared to R. marina. As a consequence, the manual pressure necessary to extract the poison from the parotoid is twice as high in R. marina when compared to that used in R. guttatus. Compared to R. marina, the poison of R. guttatus is less lethal, induces edema and provokes nociception four times more intense. We concluded that the ability of R. guttatus to voluntary squirt poison is directly related to its stereotyped defensive behavior, together with the peculiar morphological characteristics of its parotoids. Since R. guttatus poison is practically not lethal, it is possibly directed to predators' learning, causing disturbing effects such as pain and edema. The unique mechanism of defense of R. guttatus may mistakenly justify the popular myth that toads, in general, squirt poison into people's eyes. PMID:24130001

  18. THE PROPERTIES OF QUASAR HOSTS AT THE PEAK OF THE QUASAR ACTIVITY

    SciTech Connect

    Kotilainen, Jari K.; Falomo, Renato; Decarli, Roberto; Treves, Aldo; Uslenghi, Michela; Scarpa, Riccardo E-mail: renato.falomo@oapd.inaf.i E-mail: aldo.treves@uninsubria.i E-mail: riccardo.scarpa@gtc.iac.e

    2009-10-01

    We present near-infrared imaging obtained with ESO VLT/ISAAC of a sample of 16 low luminosity radio-quiet quasars (RQQs) at the epoch around the peak of the quasar activity (2 < z < 3), aimed at investigating their host galaxies. For 11 quasars, we are able to detect the host galaxies and derive their properties, while for the other 5 quasars, upper limits to the host luminosity are estimated. The luminosities of the host galaxies of RQQs at high redshift are in the range of those of massive inactive elliptical galaxies. This work complements our previous systematic study of quasar hosts aimed to trace the cosmological luminosity evolution of the host galaxies up to z approx 2 and extends our pilot study of a few luminous quasars at z > 2. The luminosity trend with a cosmic epoch resembles that observed for massive inactive galaxies, suggesting a similar star formation history. In particular, both quasar host galaxies and massive inactive galaxies appear mostly assembled already at the peak age of the quasar activity. This result is of key importance for testing the models of joint formation and evolution of galaxies and their active nuclei.

  19. Cyclic lipopeptide iturin A structure-dependently induces defense response in Arabidopsis plants by activating SA and JA signaling pathways.

    PubMed

    Kawagoe, Yumi; Shiraishi, Soma; Kondo, Hiroko; Yamamoto, Shoko; Aoki, Yoshinao; Suzuki, Shunji

    2015-05-15

    Iturin A is the most well studied antifungal cyclic lipopeptide produced by Bacillus species that are frequently utilized as biological control agents. Iturin A not only shows strong antifungal activity against phytopathogens but also induces defense response in plants, thereby reducing plant disease severity. Here we report the defense signaling pathways triggered by iturin A in Arabidopsis salicylic acid (SA) or jasmonic acid (JA)-insensitive mutants. Iturin A activated the transcription of defense genes PR1 and PDF1.2 through the SA and JA signaling pathways, respectively. The role of iturin A as an elicitor was dependent on the cyclization of the seven amino acids and/or the β-hydroxy fatty acid chain. The iturin A derivative peptide, NH2-(L-Asn)-(D-Tyr)-(D-Asn)-(L-Gln)-(L-Pro)-(D-Asn)-(L-Ser)-COOH, completely suppressed PR1 and PDF1.2 gene expression in wild Arabidopsis plants. The identification of target molecules binding to iturin A and its derivative peptide is expected to shed new light on defense response in plants through the SA and JA signaling pathways. PMID:25842204

  20. The nuclear immune receptor RPS4 is required for RRS1SLH1-dependent constitutive defense activation in Arabidopsis thaliana.

    PubMed

    Sohn, Kee Hoon; Segonzac, Cécile; Rallapalli, Ghanasyam; Sarris, Panagiotis F; Woo, Joo Yong; Williams, Simon J; Newman, Toby E; Paek, Kyung Hee; Kobe, Bostjan; Jones, Jonathan D G

    2014-10-01

    Plant nucleotide-binding leucine-rich repeat (NB-LRR) disease resistance (R) proteins recognize specific "avirulent" pathogen effectors and activate immune responses. NB-LRR proteins structurally and functionally resemble mammalian Nod-like receptors (NLRs). How NB-LRR and NLR proteins activate defense is poorly understood. The divergently transcribed Arabidopsis R genes, RPS4 (resistance to Pseudomonas syringae 4) and RRS1 (resistance to Ralstonia solanacearum 1), function together to confer recognition of Pseudomonas AvrRps4 and Ralstonia PopP2. RRS1 is the only known recessive NB-LRR R gene and encodes a WRKY DNA binding domain, prompting suggestions that it acts downstream of RPS4 for transcriptional activation of defense genes. We define here the early RRS1-dependent transcriptional changes upon delivery of PopP2 via Pseudomonas type III secretion. The Arabidopsis slh1 (sensitive to low humidity 1) mutant encodes an RRS1 allele (RRS1SLH1) with a single amino acid (leucine) insertion in the WRKY DNA-binding domain. Its poor growth due to constitutive defense activation is rescued at higher temperature. Transcription profiling data indicate that RRS1SLH1-mediated defense activation overlaps substantially with AvrRps4- and PopP2-regulated responses. To better understand the genetic basis of RPS4/RRS1-dependent immunity, we performed a genetic screen to identify suppressor of slh1 immunity (sushi) mutants. We show that many sushi mutants carry mutations in RPS4, suggesting that RPS4 acts downstream or in a complex with RRS1. Interestingly, several mutations were identified in a domain C-terminal to the RPS4 LRR domain. Using an Agrobacterium-mediated transient assay system, we demonstrate that the P-loop motif of RPS4 but not of RRS1SLH1 is required for RRS1SLH1 function. We also recapitulate the dominant suppression of RRS1SLH1 defense activation by wild type RRS1 and show this suppression requires an intact RRS1 P-loop. These analyses of RRS1SLH1 shed new light

  1. Phenotypic analysis of apoplastic effectors from the phytopathogenic nematode, Globodera rostochiensis demonstrates that an expansin can induce and suppress host defenses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The potato cyst nematode Globodera rostochiensis (Woll.) is an important pest of potato. Like other biotrophic pathogens, plant parasitic nematodes are presumed to employ effector proteins, secreted into the apoplast as well as the host cytoplasm to successfully infect their hosts. We have identifie...

  2. No Effect of Host Species on Phenoloxidase Activity in a Mycophagous Beetle

    PubMed Central

    Formica, Vincent; Chan, Amanda Kar-Men

    2015-01-01

    Ecological immunology is an interdisciplinary field that helps elucidate interactions between the environment and immune response. The host species individuals experience have profound effects on immune response in many species of insects. However, this conclusion comes from studies of herbivorous insects even though species of mycophagous insects also inhabit many different host species. The goal of this study was to determine if fungal host species as well as individual, sex, body size, and host patch predict one aspect of immune function, phenoloxidase activity (PO). We sampled a metapopulation of Bolitotherus cornutus, a mycophagous beetle in southwestern Virginia. B. cornutus live on three species of fungus that differ in nutritional quality, social environment, and density. A filter paper phenoloxidase assay was used to quantify phenoloxidase activity. Overall, PO activity was significantly repeatable among individuals (0.57) in adult B. cornutus. While there was significant variance among individuals in PO activity, there were surprisingly no significant differences in PO activity among subpopulations, beetles living on different host species, or between the sexes; there was also no effect of body size. Our results suggest that other factors such as age, genotype, disease prevalence, or natal environment may be generating variance among individuals in PO activity. PMID:26513243

  3. The Importance of the KR-Rich Region of the Coat Protein of Ourmia melon virus for Host Specificity, Tissue Tropism, and Interference With Antiviral Defense.

    PubMed

    Rossi, Marika; Vallino, Marta; Abbà, Simona; Ciuffo, Marina; Balestrini, Raffaella; Genre, Andrea; Turina, Massimo

    2015-01-01

    The N-terminal region of the Ourmia melon virus (OuMV) coat protein (CP) contains a short lysine/arginine-rich (KR) region. By alanine scanning mutagenesis, we showed that the KR region influences pathogenicity and virulence of OuMV without altering viral particle assembly. A mutant, called OuMV6710, with three basic residue substitutions in the KR region, was impaired in the ability to maintain the initial systemic infection in Nicotiana benthamiana and to infect both cucumber and melon plants systemically. The integrity of this protein region was also crucial for encapsidation of viral genomic RNA; in fact, certain mutations within the KR region partially compromised the RNA encapsidation efficiency of the CP. In Arabidopsis thaliana Col-0, OuMV6710 was impaired in particle accumulation; however, this phenotype was abolished in dcl2/dcl4 and dcl2/dcl3/dcl4 Arabidopsis mutants defective for antiviral silencing. Moreover, in contrast to CPwt, in situ immunolocalization experiments indicated that CP6710 accumulates efficiently in the spongy mesophyll tissue of infected N. benthamiana and A. thaliana leaves but only occasionally infects palisade tissues. These results provided strong evidence of a crucial role for OuMV CP during viral infection and highlighted the relevance of the KR region in determining tissue tropism, host range, pathogenicity, and RNA affinity, which may be all correlated with a possible CP silencing-suppression activity. PMID:25494356

  4. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?

    PubMed

    Rösler, Barbara; Herold, Susanne

    2016-12-01

    Influenza viruses (IVs) circulate seasonally and are a common cause of respiratory infections in pediatric and adult patients. Additionally, recurrent pandemics cause massive morbidity and mortality worldwide. Infection may result in rapid progressive viral pneumonia with fatal outcome. Since accurate treatment strategies are still missing, research refocuses attention to lung pathology and cellular crosstalk to develop new therapeutic options.Alveolar epithelial cells (AECs) play an important role in orchestrating the pulmonary antiviral host response. After IV infection they release a cascade of immune mediators, one of which is granulocyte and macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to promote differentiation, activation and mobilization of myeloid cells. In the lung, GM-CSF drives immune functions of alveolar macrophages and dendritic cells (DCs) and also improves epithelial repair processes through direct interaction with AECs. During IV infection, AEC-derived GM-CSF shows a lung-protective effect that is also present after local GM-CSF application. This mini-review provides an overview on GM-CSF-modulated immune responses to IV pneumonia and its therapeutic potential in severe IV pneumonia. PMID:27480877

  5. The (Phased?) Activity of Stars Hosting Hot Jupiters

    NASA Astrophysics Data System (ADS)

    Pillitteri, Ignazio; Wolk, Scott J.; Lopez-Santiago, J.; Sciortino, Salvatore

    2015-01-01

    The activity of stars harboring hot Jupiters could be influenced by their close-in planets. Cases of enhanced chromospheric activity are reported in literature, suggesting magnetic interaction at well determined planetary phases. In X-rays and FUV, we have studied star-planet interaction (SPI) occurring in the system of HD 189733. In X-rays, HD 189733 shows features of high activity that can be ascribed to the influence of the magnetic field of its planetary companion. Through a wavelet analysis of a flare, we inferred a long magnetic loop of 2 R_* to 4 R_*, and a local magnetic field of strength in 40-100 G. The size of the flaring loop suggests a role of the hot Jupiter in triggering this kind of X-ray variability. In FUV, HST-COS spectra of HD 189733 shows temporal variations in intensity and Doppler shifts of Si III and Si IV lines that can be ascribed to plasma flowing from the planetary atmosphere and accreting onto the star under the action of the combined magnetic field of star and planet. The material from the planetary atmosphere can flow onto the parent star as predicted by MHD models. The foot point of the accretion on the stellar surface results in phased variability observed in X-rays and FUV, when the point, comoving with the planet, emerges at the limb of the star.

  6. Blueberry Supplementation Attenuates Microglial Activation in Hippocampal Intraocular Grafts to aged hosts

    PubMed Central

    Willis, Lauren M.; Freeman, Linnea; Bickford, Paula C.; Quintero, E. Matthew; Umphlet, Claudia D.; Moore, Alfred B.; Goetzl, Laura; Granholm, Ann-Charlotte

    2010-01-01

    Transplantation of central nervous tissue has been proposed as a therapeutic intervention for age-related neurodegenerative diseases and stroke. However, survival of embryonic neuronal cells is hampered by detrimental factors in the aged host brain such as circulating inflammatory cytokines and oxidative stress. We have previously found that supplementation with 2% blueberry in the diet increases graft growth and neuronal survival in intraocular hippocampal grafts to aged hosts. In the present study we explored possible biochemical mechanisms for this increased survival, and we here report decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged hosts fed a 2% blueberry diet. Markers for astrocytes and for activated microglial cells were both decreased long-term after grafting to blueberry-treated hosts compared to age-matched rats on a control diet. Similar findings were obtained in the host brain, with a reduction in OX-6 immunoreactive microglial cells in the hippocampus of those recipients treated with blueberry. In addition, immunoreactivity for the pro-inflammatory cytokine IL-6 was found to be significantly attenuated in intraocular grafts by the 2% blueberry diet. These studies demonstrate direct effects of blueberry upon microglial activation both during isolated conditions and in the aged host brain and suggest that this nutraceutical can attenuate age-induced inflammation. PMID:20014277

  7. Department of Defense Education Activity: School, District, Area, and System. Accountability Profiles, 1996-1997.

    ERIC Educational Resources Information Center

    Dependents Schools (DOD), Washington, DC.

    This document contains accountability profiles with detailed information for the overseas schools of the Department of Defense Dependents Schools (DoDDS). Each profile contains a description of the school, district, or area characteristics and highlights identified by the principal or superintendent. Profiles also contain the 1996-1997 benchmark…

  8. Projected near-future CO2 levels increase activity and alter defensive behaviours in the tropical squid Idiosepius pygmaeus

    PubMed Central

    Spady, Blake L.; Watson, Sue-Ann; Chase, Tory J.; Munday, Philip L.

    2014-01-01

    ABSTRACT Carbon dioxide (CO2) levels projected to occur in the oceans by the end of this century cause a range of behavioural effects in fish, but whether other highly active marine organisms, such as cephalopods, are similarly affected is unknown. We tested the effects of projected future CO2 levels (626 and 956 µatm) on the behaviour of male two-toned pygmy squid, Idiosepius pygmaeus. Exposure to elevated CO2 increased the number of active individuals by 19–25% and increased movement (number of line-crosses) by nearly 3 times compared to squid at present-day CO2. Squid vigilance and defensive behaviours were also altered by elevated CO2 with >80% of individuals choosing jet escape responses over defensive arm postures in response to a visual startle stimulus, compared with 50% choosing jet escape responses at control CO2. In addition, more escape responses were chosen over threat behaviours in body pattern displays at elevated CO2 and individuals were more than twice as likely to use ink as a defence strategy at 956 µatm CO2, compared with controls. Increased activity could lead to adverse effects on energy budgets as well as increasing visibility to predators. A tendency to respond to a stimulus with escape behaviours could increase survival, but may also be energetically costly and could potentially lead to more chases by predators compared with individuals that use defensive postures. These results demonstrate that projected future ocean acidification affects the behaviours of a tropical squid species. PMID:25326517

  9. Projected near-future CO2 levels increase activity and alter defensive behaviours in the tropical squid Idiosepius pygmaeus.

    PubMed

    Spady, Blake L; Watson, Sue-Ann; Chase, Tory J; Munday, Philip L

    2014-01-01

    Carbon dioxide (CO2) levels projected to occur in the oceans by the end of this century cause a range of behavioural effects in fish, but whether other highly active marine organisms, such as cephalopods, are similarly affected is unknown. We tested the effects of projected future CO2 levels (626 and 956 µatm) on the behaviour of male two-toned pygmy squid, Idiosepius pygmaeus. Exposure to elevated CO2 increased the number of active individuals by 19-25% and increased movement (number of line-crosses) by nearly 3 times compared to squid at present-day CO2. Squid vigilance and defensive behaviours were also altered by elevated CO2 with >80% of individuals choosing jet escape responses over defensive arm postures in response to a visual startle stimulus, compared with 50% choosing jet escape responses at control CO2. In addition, more escape responses were chosen over threat behaviours in body pattern displays at elevated CO2 and individuals were more than twice as likely to use ink as a defence strategy at 956 µatm CO2, compared with controls. Increased activity could lead to adverse effects on energy budgets as well as increasing visibility to predators. A tendency to respond to a stimulus with escape behaviours could increase survival, but may also be energetically costly and could potentially lead to more chases by predators compared with individuals that use defensive postures. These results demonstrate that projected future ocean acidification affects the behaviours of a tropical squid species. PMID:25326517

  10. Nitric oxide is involved in methyl jasmonate-induced defense responses and secondary metabolism activities of Taxus cells.

    PubMed

    Wang, Jian Wen; Wu, Jian Yong

    2005-06-01

    Methyl jasmonate (MeJA), a methyl ester of jasmonic acid (JA), is a well-established signal molecule in plant defense responses and an effective inducer of secondary metabolite accumulation in plant cell cultures such as the valuable anticancer diterpenoid taxol (paclitaxel) in Taxus spp. This work examines the involvement of nitric oxide (NO) in MeJA-induced plant defense responses and secondary metabolism in Taxus chinensis cell cultures. Exogenously supplied MeJA at 100 microM induced rapid production of NO in the Taxus cell cultures, reaching a maximum within 6 h of MeJA supply. Several other responses occurred concomitantly, including the production of hydrogen peroxide (H2O2), and the increases in intracellular malondialdehyde (MDA) content, lipoxygenase (LOX) and phenylalanine ammonium-lyase (PAL) activities. The MeJA-induced H2O2 production was suppressed by an NO donor, sodium nitroprusside (SNP), but enhanced by NO inhibitors, N (omega)-nitro-L-arginine (L-NNA) and 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO). In contrast, the MeJA-induced MDA, LOX and PAL were all enhanced by the NO donor but suppressed by the NO inhibitors. The NO inhibitors also suppressed MeJA-induced taxol accumulation. These results are suggestive of a role for NO as a signal element for activating the MeJA-induced defense responses and secondary metabolism activities of plant cells. PMID:15829512

  11. Receptor-mediated activation of a plant Ca2+-permeable ion channel involved in pathogen defense

    PubMed Central

    Zimmermann, Sabine; Nürnberger, Thorsten; Frachisse, Jean-Marie; Wirtz, Wolfgang; Guern, Jean; Hedrich, Rainer; Scheel, Dierk

    1997-01-01

    Pathogen recognition at the plant cell surface typically results in the initiation of a multicomponent defense response. Transient influx of Ca2+ across the plasma membrane is postulated to be part of the signaling chain leading to pathogen resistance. Patch-clamp analysis of parsley protoplasts revealed a novel Ca2+-permeable, La3+-sensitive plasma membrane ion channel of large conductance (309 pS in 240 mM CaCl2). At an extracellular Ca2+ concentration of 1 mM, which is representative of the plant cell apoplast, unitary channel conductance was determined to be 80 pS. This ion channel (LEAC, for large conductance elicitor-activated ion channel) is reversibly activated upon treatment of parsley protoplasts with an oligopeptide elicitor derived from a cell wall protein of Phytophthora sojae. Structural features of the elicitor found previously to be essential for receptor binding, induction of defense-related gene expression, and phytoalexin formation are identical to those required for activation of LEAC. Thus, receptor-mediated stimulation of this channel appears to be causally involved in the signaling cascade triggering pathogen defense in parsley. PMID:11038609

  12. HtrA chaperone activity contributes to host cell binding in Campylobacter jejuni

    PubMed Central

    2011-01-01

    Background Acute gastroenteritis caused by the food-borne pathogen Campylobacter jejuni is associated with attachment of bacteria to the intestinal epithelium and subsequent invasion of epithelial cells. In C. jejuni, the periplasmic protein HtrA is required for efficient binding to epithelial cells. HtrA has both protease and chaperone activity, and is important for virulence of several bacterial pathogens. Results The aim of this study was to determine the role of the dual activities of HtrA in host cell interaction of C. jejuni by comparing an htrA mutant lacking protease activity, but retaining chaperone activity, with a ΔhtrA mutant and the wild type strain. Binding of C. jejuni to both epithelial cells and macrophages was facilitated mainly by HtrA chaperone activity that may be involved in folding of outer membrane adhesins. In contrast, HtrA protease activity played only a minor role in interaction with host cells. Conclusion We show that HtrA protease and chaperone activities contribute differently to C. jejuni's interaction with mammalian host cells, with the chaperone activity playing the major role in host cell binding. PMID:21939552

  13. Physcomitrella patens activates reinforcement of the cell wall, programmed cell death and accumulation of evolutionary conserved defense signals...upon Botrytis cinerea infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The moss Physcomitrella patens is an evolutionarily basal model system suitable to analyze plant defense responses activated after pathogen assault. Upon infection with the necrotroph Botrytis cinerea (B. cinerea), several defense mechanisms are induced in P. patens, including the fortification of t...

  14. Herschel Observed Stripe 82 Quasars and Their Host Galaxies: Connections between AGN Activity and host Galaxy Star Formation

    NASA Astrophysics Data System (ADS)

    Dong, X. Y.; Wu, Xue-Bing

    2016-06-01

    In this work, we present a study of 207 quasars selected from the Sloan Digital Sky Survey quasar catalogs and the Herschel Stripe 82 survey. Quasars within this sample are high-luminosity quasars with a mean bolometric luminosity of 1046.4 erg s‑1. The redshift range of this sample is within z < 4, with a mean value of 1.5 ± 0.78. Because we only selected quasars that have been detected in all three Herschel-SPIRE bands, the quasar sample is complete yet highly biased. Based on the multi-wavelength photometric observation data, we conducted a spectral energy distribution (SED) fitting through UV to FIR. Parameters such as active galactic nucleus (AGN) luminosity, far-IR (FIR) luminosity, stellar mass, as well as many other AGN and galaxy properties are deduced from the SED fitting results. The mean star formation rate (SFR) of the sample is 419 M ⊙ yr‑1 and the mean gas mass is ∼1011.3 M ⊙. All of these results point to an IR luminous quasar system. Compared with star formation main sequence (MS) galaxies, at least 80 out of 207 quasars are hosted by starburst galaxies. This supports the statement that luminous AGNs are more likely to be associated with major mergers. The SFR increases with the redshift up to z = 2. It is correlated with the AGN bolometric luminosity, where {L}{{FIR}}\\propto {L}{{Bol}}0.46+/- 0.03. The AGN bolometric luminosity is also correlated with the host galaxy mass and gas mass. Yet the correlation between L FIR and L Bol has higher significant level, implies that the link between AGN accretion and the SFR is more primal. The M BH/M * ratio of our sample is 0.02, higher than the value 0.005 in the local universe. It might indicate an evolutionary trend of the M BH–M * scaling relation.

  15. Activation and interruption of the reproduction of Varroa destructor is triggered by host signals (Apis mellifera).

    PubMed

    Frey, Eva; Odemer, Richard; Blum, Thomas; Rosenkranz, Peter

    2013-05-01

    The reproductive cycle of the parasitic mite Varroa destructor is closely linked to the development of the honey bee host larvae. Using a within colony approach we introduced phoretic Varroa females into brood cells of different age in order to analyze the capacity of certain stages of the honey bee larva to either activate or interrupt the reproduction of Varroa females. Only larvae within 18 h (worker) and 36 h (drones), respectively, after cell capping were able to stimulate the mite's oogenesis. Therewith we could specify for the first time the short time window where honey bee larvae provide the signals for the activation of the Varroa reproduction. Stage specific volatiles of the larval cuticle are at least part of these activation signals. This is confirmed by the successful stimulation of presumably non-reproducing mites to oviposition by the application of a larval extract into the sealed brood cells. According to preliminary quantitative GC-MS analysis we suggest certain fatty acid ethyl esters as candidate compounds. If Varroa females that have just started with egg formation are transferred to brood cells containing host larvae of an elder stage two-thirds of these mites stopped their oogenesis. This confirms the presence of an additional signal in the host larvae allowing the reproducing mites to adjust their own reproductive cycle to the ontogenetic development of the host. From an adaptive point of view that sort of a stop signal enables the female mite to save resources for a next reproductive cycle if the own egg development is not sufficiently synchronized with the development of the host. The results presented here offer the opportunity to analyze exactly those host stages that have the capacity to activate or interrupt the Varroa reproduction in order to identify the crucial host signals. PMID:23376006

  16. The Human Host Defense Ribonucleases 1, 3 and 7 Are Elevated in Patients with Sepsis after Major Surgery—A Pilot Study

    PubMed Central

    Martin, Lukas; Koczera, Patrick; Simons, Nadine; Zechendorf, Elisabeth; Hoeger, Janine; Marx, Gernot; Schuerholz, Tobias

    2016-01-01

    Sepsis is the most common cause of death in intensive care units and associated with widespread activation of host innate immunity responses. Ribonucleases (RNases) are important components of the innate immune system, however the role of RNases in sepsis has not been investigated. We evaluated serum levels of RNase 1, 3 and 7 in 20 surgical sepsis patients (Sepsis), nine surgical patients (Surgery) and 10 healthy controls (Healthy). RNase 1 and 3 were elevated in Sepsis compared to Surgery (2.2- and 3.1-fold, respectively; both p < 0.0001) or compared to Healthy (3.0- and 15.5-fold, respectively; both p < 0.0001). RNase 1 showed a high predictive value for the development of more than two organ failures (AUC 0.82, p = 0.01). Patients with renal dysfunction revealed higher RNase 1 levels than without renal dysfunction (p = 0.03). RNase 1 and 3 were higher in respiratory failure than without respiratory failure (p < 0.0001 and p = 0.02, respectively). RNase 7 was not detected in Healthy patients and only in two patients of Surgery, however RNase 7 was detected in 10 of 20 Sepsis patients. RNase 7 was higher in renal or metabolic failure than without failure (p = 0.04 and p = 0.02, respectively). In conclusion, RNase 1, 3 and 7 are secreted into serum under conditions with tissue injury, such as major surgery or sepsis. Thus, RNases might serve as laboratory parameters to diagnose and monitor organ failure in sepsis. PMID:26927088

  17. Pathogen-mediated proteolysis of the cell death regulator RIPK1 and the host defense modulator RIPK2 in human aortic endothelial cells.

    PubMed

    Madrigal, Andrés G; Barth, Kenneth; Papadopoulos, George; Genco, Caroline Attardo

    2012-01-01

    Porphyromonas gingivalis is the primary etiologic agent of periodontal disease that is associated with other human chronic inflammatory diseases, including atherosclerosis. The ability of P. gingivalis to invade and persist within human aortic endothelial cells (HAEC) has been postulated to contribute to a low to moderate chronic state of inflammation, although how this is specifically achieved has not been well defined. In this study, we demonstrate that P. gingivalis infection of HAEC resulted in the rapid cleavage of receptor interacting protein 1 (RIPK1), a mediator of tumor necrosis factor (TNF) receptor-1 (TNF-R1)-induced cell activation or death, and RIPK2, a key mediator of both innate immune signaling and adaptive immunity. The cleavage of RIPK1 or RIPK2 was not observed in cells treated with apoptotic stimuli, or cells stimulated with agonists to TNF-R1, nucleotide oligomerization domain receptor 1(NOD1), NOD2, Toll-like receptor 2 (TLR2) or TLR4. P. gingivalis-induced cleavage of RIPK1 and RIPK2 was inhibited in the presence of a lysine-specific gingipain (Kgp) inhibitor. RIPK1 and RIPK2 cleavage was not observed in HAEC treated with an isogenic mutant deficient in the lysine-specific gingipain, confirming a role for Kgp in the cleavage of RIPK1 and RIPK2. Similar proteolysis of poly (ADP-ribose) polymerase (PARP) was observed. We also demonstrated direct proteolysis of RIPK2 by P. gingivalis in a cell-free system which was abrogated in the presence of a Kgp-specific protease inhibitor. Our studies thus reveal an important role for pathogen-mediated modification of cellular kinases as a potential strategy for bacterial persistence within target host cells, which is associated with low-grade chronic inflammation, a hallmark of pathogen-mediated chronic inflammatory disorders. PMID:22685397

  18. Fighting a losing battle: vigorous immune response countered by pathogen suppression of host defenses in the chytridiomycosis-susceptible frog Atelopus zeteki.

    PubMed

    Ellison, Amy R; Savage, Anna E; DiRenzo, Grace V; Langhammer, Penny; Lips, Karen R; Zamudio, Kelly R

    2014-07-01

    The emergence of the disease chytridiomycosis caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in dramatic global amphibian declines. Although many species have undergone catastrophic declines and/or extinctions, others appear to be unaffected or persist at reduced frequencies after Bd outbreaks. The reasons behind this variance in disease outcomes are poorly understood: differences in host immune responses have been proposed, yet previous studies suggest a lack of robust immune responses to Bd in susceptible species. Here, we sequenced transcriptomes from clutch-mates of a highly susceptible amphibian, Atelopus zeteki, with different infection histories. We found significant changes in expression of numerous genes involved in innate and inflammatory responses in infected frogs despite high susceptibility to chytridiomycosis. We show evidence of acquired immune responses generated against Bd, including increased expression of immunoglobulins and major histocompatibility complex genes. In addition, fungal-killing genes had significantly greater expression in frogs previously exposed to Bd compared with Bd-naïve frogs, including chitinase and serine-type proteases. However, our results appear to confirm recent in vitro evidence of immune suppression by Bd, demonstrated by decreased expression of lymphocyte genes in the spleen of infected compared with control frogs. We propose susceptibility to chytridiomycosis is not due to lack of Bd-specific immune responses but instead is caused by failure of those responses to be effective. Ineffective immune pathway activation and timing of antibody production are discussed as potential mechanisms. However, in light of our findings, suppression of key immune responses by Bd is likely an important factor in the lethality of this fungus. PMID:24841130

  19. Fighting a Losing Battle: Vigorous Immune Response Countered by Pathogen Suppression of Host Defenses in the Chytridiomycosis-Susceptible Frog Atelopus zeteki

    PubMed Central

    Ellison, Amy R.; Savage, Anna E.; DiRenzo, Grace V.; Langhammer, Penny; Lips, Karen R.; Zamudio, Kelly R.

    2014-01-01

    The emergence of the disease chytridiomycosis caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in dramatic global amphibian declines. Although many species have undergone catastrophic declines and/or extinctions, others appear to be unaffected or persist at reduced frequencies after Bd outbreaks. The reasons behind this variance in disease outcomes are poorly understood: differences in host immune responses have been proposed, yet previous studies suggest a lack of robust immune responses to Bd in susceptible species. Here, we sequenced transcriptomes from clutch-mates of a highly susceptible amphibian, Atelopus zeteki, with different infection histories. We found significant changes in expression of numerous genes involved in innate and inflammatory responses in infected frogs despite high susceptibility to chytridiomycosis. We show evidence of acquired immune responses generated against Bd, including increased expression of immunoglobulins and major histocompatibility complex genes. In addition, fungal-killing genes had significantly greater expression in frogs previously exposed to Bd compared with Bd-naïve frogs, including chitinase and serine-type proteases. However, our results appear to confirm recent in vitro evidence of immune suppression by Bd, demonstrated by decreased expression of lymphocyte genes in the spleen of infected compared with control frogs. We propose susceptibility to chytridiomycosis is not due to lack of Bd-specific immune responses but instead is caused by failure of those responses to be effective. Ineffective immune pathway activation and timing of antibody production are discussed as potential mechanisms. However, in light of our findings, suppression of key immune responses by Bd is likely an important factor in the lethality of this fungus. PMID:24841130

  20. Annual report to Congress: Department of Energy activities relating to the Defense Nuclear Facilities Safety Board, calendar year 1998

    SciTech Connect

    1999-02-01

    This is the ninth Annual Report to the Congress describing Department of Energy (Department) activities in response to formal recommendations and other interactions with the Defense Nuclear Facilities Safety Board (Board). The Board, an independent executive-branch agency established in 1988, provides advice and recommendations to the Secretary of energy regarding public health and safety issues at the Department`s defense nuclear facilities. The Board also reviews and evaluates the content and implementation of health and safety standards, as well as other requirements, relating to the design, construction, operation, and decommissioning of the Department`s defense nuclear facilities. The locations of the major Department facilities are provided. During 1998, Departmental activities resulted in the proposed closure of one Board recommendation. In addition, the Department has completed all implementation plan milestones associated with four other Board recommendations. Two new Board recommendations were received and accepted by the Department in 1998, and two new implementation plans are being developed to address these recommendations. The Department has also made significant progress with a number of broad-based initiatives to improve safety. These include expanded implementation of integrated safety management at field sites, a renewed effort to increase the technical capabilities of the federal workforce, and a revised plan for stabilizing excess nuclear materials to achieve significant risk reduction.

  1. Annual report to Congress: Department of Energy activities relating to the Defense Nuclear Facilities Safety Board, Calendar Year 1999

    SciTech Connect

    2000-02-01

    This is the tenth Annual Report to the Congress describing Department of Energy activities in response to formal recommendations and other interactions with the Defense Nuclear Facilities Safety Board (Board). The Board, an independent executive-branch agency established in 1988, provides advice and recommendations to the Secretary of Energy regarding public health and safety issues at the Department's defense nuclear facilities. The Board also reviews and evaluates the content and implementation of health and safety standards, as well as other requirements, relating to the design, construction, operation, and decommissioning of the Department's defense nuclear facilities. During 1999, Departmental activities resulted in the closure of nine Board recommendations. In addition, the Department has completed all implementation plan milestones associated with three Board recommendations. One new Board recommendation was received and accepted by the Department in 1999, and a new implementation plan is being developed to address this recommendation. The Department has also made significant progress with a number of broad-based initiatives to improve safety. These include expanded implementation of integrated safety management at field sites, opening of a repository for long-term storage of transuranic wastes, and continued progress on stabilizing excess nuclear materials to achieve significant risk reduction.

  2. ABA Is an Essential Signal for Plant Resistance to Pathogens Affecting JA Biosynthesis and the Activation of Defenses in Arabidopsis[W

    PubMed Central

    Adie, Bruce A.T.; Pérez-Pérez, Julián; Pérez-Pérez, Manuel M.; Godoy, Marta; Sánchez-Serrano, José-J.; Schmelz, Eric A.; Solano, Roberto

    2007-01-01

    Analyses of Arabidopsis thaliana defense response to the damping-off oomycete pathogen Pythium irregulare show that resistance to P. irregulare requires a multicomponent defense strategy. Penetration represents a first layer, as indicated by the susceptibility of pen2 mutants, followed by recognition, likely mediated by ERECTA receptor-like kinases. Subsequent signaling of inducible defenses is predominantly mediated by jasmonic acid (JA), with insensitive coi1 mutants showing extreme susceptibility. In contrast with the generally accepted roles of ethylene and salicylic acid cooperating with or antagonizing, respectively, JA in the activation of defenses against necrotrophs, both are required to prevent disease progression, although much less so than JA. Meta-analysis of transcriptome profiles confirmed the predominant role of JA in activation of P. irregulare–induced defenses and uncovered abscisic acid (ABA) as an important regulator of defense gene expression. Analysis of cis-regulatory sequences also revealed an unexpected overrepresentation of ABA response elements in promoters of P. irregulare–responsive genes. Subsequent infections of ABA-related and callose-deficient mutants confirmed the importance of ABA in defense, acting partly through an undescribed mechanism. The results support a model for ABA affecting JA biosynthesis in the activation of defenses against this oomycete. PMID:17513501

  3. The mtDNA NARP mutation activates the actin-Nrf2 signaling of antioxidant defenses

    SciTech Connect

    Dassa, Emmanuel Philippe; Paupe, Vincent; Goncalves, Sergio; Rustin, Pierre

    2008-04-11

    An efficient handling of superoxides by antioxidant defenses is a crucial issue for cells with respiratory chain deficient mitochondria. We used human cultured skin fibroblasts to delineate the mechanism controlling the expression of antioxidant defenses in the case of a severe ATPase deficiency resulting from an 8993T>G mutation in the mitochondrial ATPase6 gene. We observed the nuclear translocation of the transcription factor Nrf2 associated with thinning of the actin stress fibers. The mobilization of the Nrf2 signaling pathway could be mimicked by a chemical blockade of the ATPase with a specific inhibitor, oligomycin. Interestingly enough, Nrf2 nuclear translocation was not observed in the case of a severe cytochrome oxidase deficiency, indicating that studying the status of this signaling pathway could throw some light on the importance of the oxidative insult associated with different respiratory chain defects.

  4. Seasonal activity and host associations of Ixodes scapularis (Acari: Ixodidae) in southeastern Missouri.

    PubMed

    Kollars, T M; Oliver, J H; Kollars, P G; Durden, L A

    1999-11-01

    Based on tick collections recovered from wild vertebrates and by dragging, the seasonal occurrence of adult blacklegged ticks, Ixodes scapularis Say, extended from October through May in southeastern Missouri. Adult activity was bimodal with the higher peak occurring in November followed by a lower peak in February. The activity of immature I. scapularis had the general pattern of that found in the Northeast where Lyme disease is hyperendemic, with larval activity (July) peaking after that of nymphs (May and June). Vertebrates varied in their importance as hosts of I. scapularis. White-tailed deer, Odocoileus virginanus (Zimmerman), and coyotes, Canis latrans Say, were the primary hosts of adult I. scapularis. Broad-headed skinks, Eumeces laticeps (Schneider), and eastern fence lizards, Sceloporus undulatus (Latreille), were the primary hosts of nymphal I. scapularis. The broad-headed skink, 5-lined skink, Eumeces fasciatus (L.), and Carolina wren, Thryothorus ludovicianus (Latham), were the primary hosts of larval I. scapularis. Homeotherms were important hosts of immature I. scapularis, accounting for 30% of nymphs and 39% of larvae collected. The eastern cottontail rabbit, Sylvilagus floridanus (Allen), may play an important role in the epidemiology of Lyme disease in Missouri. Isolates of Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner were made from ticks recovered from rabbits, making the cottontail rabbit a key species for further study of the epidemiology of Lyme borreliosis in Missouri. PMID:10593072

  5. Study of the modulatory activity of BZ (omega) receptor ligands on defensive behaviors in mice: evaluation of the importance of intrinsic efficacy and receptor subtype selectivity.

    PubMed

    Griebel, G; Perrault, G; Sanger, D J

    1999-01-01

    1. This study examined the hypothesis that the anxiolytic effects of benzodiazepine (BZ (omega)) receptor ligands may be associated with actions at a defined receptor subtype and/or their level of intrinsic activity using the mouse defense test battery. 2. This test has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. 3. The drugs used were the non-selective BZ (omega) receptor full agonist diazepam, the non-selective BZ (omega) receptor partial agonist bretazenil and the beta-carboline abecarnil which acts as a full agonist on GABAA receptors containing the alpha 1- and the alpha 3-subunits and as a partial agonist at receptors containing the alpha 2- and the alpha 5-subunits. The drugs were given alone and diazepam was co-administered with either bretazenil or abecarnil. 4. When administered alone, diazepam attenuated several defensive responses including risk assessment activities, defensive threat/attack reactions upon forced contact with the rat and escape attempts following the removal of the rat from the apparatus. Unlike diazepam, bretazenil was devoid of significant activity on defense and abecarnil displayed depressant activity. 5. Bretazenil blocked all behavioral effects of diazepam on defense behaviors. The co-administration of diazepam and abecarnil produced a behavioral profile similar to that observed when diazepam was administered alone, indicating that abecarnil did not influence the effects of diazepam on defense. By contrast, diazepam completely antagonized the sedative effects of abecarnil. 6. These findings indicate that only BZ (omega) ligands with high intrinsic efficacy at all BZ (omega) receptor subtypes display clear and specific effects on defensive behaviors in mice, and suggest that GABAA receptors

  6. An X-ray survey of ultra-active planet hosts

    NASA Astrophysics Data System (ADS)

    Schmitt, Jurgen

    2013-10-01

    We propose to obtain snapshot observations of a sample of ultra-active planet hosts. The sample is complete in that it comprises all known transiting systems (not observed/proposed) within 250 pc, orbital periods below 10 days and strong activity as photometric variations in excess of 1% and/or Ca II emission; the sample does include all suitable objects detected by Kepler. The sensitivity of the proposed XMM-Newton observations allows the detection of stars with X-ray luminosities in excess of 10^29 erg/sec. Because of the proximity to their hosts these planets are the prime candidates for the process of planetary atmospheric evaporation through hydrodynamic blow-off. With our study we establish the hosts' high-energy properties and pave the way for meaningful follow-up studies.

  7. Ultraviolet and X-ray Activity and Flaring on Low-Mass Exoplanet Host Stars

    NASA Astrophysics Data System (ADS)

    France, Kevin; Parke Loyd, R. O.; Brown, Alexander

    2015-08-01

    The spectral and temporal behavior of exoplanet host stars is a critical input to models of the chemistry and evolution of planetary atmospheres. High-energy photons (X-ray to NUV) from these stars regulate the atmospheric temperature profiles and photochemistry on orbiting planets, influencing the production of potential “biomarker” gases. We present results from the MUSCLES Treasury Survey, an ongoing study of time-resolved UV and X-ray spectroscopy of nearby M and K dwarf exoplanet host stars. This program uses contemporaneous Hubble Space Telescope and Chandra (or XMM) observations to characterize the time variability of the energetic radiation field incident on the habitable zones planetary systems at d < 15 pc. We find that all exoplanet host stars observed to date exhibit significant levels of chromospheric and transition region UV emission. M dwarf exoplanet host stars display 30 - 2000% UV emission line amplitude variations on timescales of minutes-to-hours. The relative flare/quiescent UV flux amplitudes on old (age > 1 Gyr) planet-hosting M dwarfs are comparable to active flare stars (e.g., AD Leo), despite their lack of flare activity at visible wavelengths. We also detect similar UV flare behavior on a subset of our K dwarf exoplanet host stars. We conclude that strong flares and stochastic variability are common, even on “optically inactive” M dwarfs hosting planetary systems. These results argue that the traditional assumption of weak UV fields and low flare rates on older low-mass stars needs to be revised.

  8. Zebra chip-diseased potato tubers are characterized by increased levels of host secondary metabolites, amino acids, and defense-related proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Zebra chip disease, a serious threat to potato production in the United States and elsewhere, is associated with 'Cadidatus Liberibacter solacearum'. Little is known about host chemistry effects on zebra chip disease symptom development in potatoes (Solanum tuberosum). This research compared chemic...

  9. Caspase-8 activity is part of the BeWo trophoblast cell defense mechanisms against Trypanosoma cruzi infection.

    PubMed

    Carrillo, Ileana; Droguett, Daniel; Castillo, Christian; Liempi, Ana; Muñoz, Lorena; Maya, Juan Diego; Galanti, Norbel; Kemmerling, Ulrike

    2016-09-01

    Congenital Chagas disease is caused by the protozoan parasite Trypanosoma cruzi that must cross the placental barrier during transmission. The trophoblast constitutes the first tissue in contact with the maternal-blood circulating parasite. Importantly, the congenital transmission rates are low, suggesting the presence of local placental defense mechanisms. Cellular proliferation and differentiation as well as apoptotic cell death are induced by the parasite and constitute part of the epithelial turnover of the trophoblast, which has been suggested to be part of those placental defenses. On the other hand, caspase-8 is an essential molecule in the modulation of trophoblast turnover by apoptosis and by epithelial differentiation. As an approach to study whether T. cruzi induced trophoblast turnover and infection is mediated by caspase-8, we infected BeWo cells (a trophoblastic cell line) with the parasite and determined in the infected cells the expression and enzymatic activity of caspase-8, DNA synthesis (as proliferation marker), β-human chorionic gonadotropin (β-hCG) (as differentiation marker) and activity of Caspase-3 (as apoptotic death marker). Parasite load in BeWo cells was measured by DNA quantification using qPCR and cell counting. Our results show that T. cruzi induces caspase-8 activity and that its inhibition increases trophoblast cells infection while decreases parasite induced cellular differentiation and apoptotic cell death, but not cellular proliferation. Thus, caspase-8 activity is part of the BeWo trophoblast cell defense mechanisms against T. cruzi infection. Together with our previous results, we suggest that the trophoblast turnover is part of local placental anti-parasite mechanisms. PMID:27328973

  10. A serpin mutant links Toll activation to melanization in the host defence of Drosophila

    PubMed Central

    Ligoxygakis, Petros; Pelte, Nadège; Ji, Chuanyi; Leclerc, Vincent; Duvic, Bernard; Belvin, Marcia; Jiang, Haobo; Hoffmann, Jules A.; Reichhart, Jean-Marc

    2002-01-01

    A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component. PMID:12456640

  11. Active penetration of Trypanosoma cruzi into host cells: historical considerations and current concepts

    PubMed Central

    de Souza, Wanderley; de Carvalho, Tecia M. Ulisses

    2013-01-01

    In the present short review, we analyze past experiments that addressed the interactions of intracellular pathogenic protozoa (Trypanosoma cruzi, Toxoplasma gondii, and Plasmodium) with host cells and the initial use of the term active penetration to indicate that a protozoan “crossed the host cell membrane, penetrating into the cytoplasm.” However, the subsequent use of transmission electron microscopy showed that, for all of the protozoans and cell types examined, endocytosis, classically defined as involving the formation of a membrane-bound vacuole, took place during the interaction process. As a consequence, the recently penetrated parasites are always within a vacuole, designated the parasitophorous vacuole (PV). PMID:23355838

  12. Defensive activation to (un)predictable interoceptive threat: The NPU respiratory threat test (NPUr).

    PubMed

    Schroijen, Mathias; Fantoni, Simona; Rivera, Carmen; Vervliet, Bram; Schruers, Koen; van den Bergh, Omer; van Diest, Ilse

    2016-06-01

    Potentially life-threatening interoceptive sensations easily engage the behavioral defensive system. Resulting fear and anxiety toward interoceptive threat are functionally distinct states that are hypothesized to play a prominent role in the etiology of panic disorder. The present study aimed to investigate whether fear- and anxiety-potentiated startle responses occur to predictable and unpredictable interoceptive threat, respectively. Therefore, we modified the NPU threat test (Schmitz & Grillon, ) and replaced the aversive electrocutaneous stimulus with an aversive interoceptive stimulus (a breathing occlusion, making it briefly impossible to breathe). Healthy participants (N = 48) underwent three instructed conditions. A visual cue signaled the occlusion in the predictable condition (P), whereas another cue was unrelated to the occurrence of the occlusion in the unpredictable condition (U). The safe condition (N) also had a visual cue, but no occlusion. Both fear- and anxiety-potentiated startle blink responses were observed in response to predictable and unpredictable respiratory threat, respectively. The current study presents and validates the NPU respiratory threat test (NPUr) as an ecologically valid paradigm to study both anxiety and fear in response to a panic-relevant interoceptive threat. The paradigm allows future testing of contextual generalization, investigation of different clinical groups, and more explicit comparisons of defensive responding to interoceptive versus exteroceptive threats. PMID:26879710

  13. Seasonal changes in the activity of antioxidative defense in the kidneys of the euthermic ground squirrel (Citellus citellus).

    PubMed

    Buzadzić, B; Blagojević, D; Korać, B; Saicić, Z S; Spasić, M B; Petrović, V M

    1998-01-01

    The aim of this work was to determine the activity of the antioxidant enzymes: superoxide dismutase (EC 1.15.1.1; SOD), catalase (EC 1.11.1.6; CAT), glutathione peroxidase (EC 1.11.1.9; GSH-Px), glutathione-S-transferase (EC 2.5.1.18; GST), glutathione reductase (EC 1.6.4.2; GR) and the low molecular mass antioxidants: ascorbic acid (ASA) and vitamin E (vit E) in the kidney of ground squirrels during circannual changes. Keeping the ground squirrel at the temperature of thermic neutrality (30 degrees C) provides a stable euthermic state during the whole year and thus any change is due to the circannual rhythm. The highest specific activity of all examined antioxidative defense enzymes in the kidney was found in the spring, when ground squirrels are seasonally the most active. In the summer, lower specific activity of GSH-Px as well as of SOD and CAT were noted and, when expressed per g wet mass, only a decrease in GSH-Px activity was recorded. In the kidney of ground squirrels kept at 30 degrees C, the lowest specific activity of all examined enzymes was found during the winter and, when expressed per g wet mass, only the SOD activity was lower than in the spring and summer. Higher amounts of vitamins C and E were found in the ground squirrel kidneys in the summer. The results obtained in this work demonstrate that circannual regulation of metabolic activity, which is inherent to seasonal hibernators, is also expressed at the level of antioxidative defense in the kidneys. PMID:9726801

  14. The host stars of Kepler's habitable exoplanets: superflares, rotation and activity

    NASA Astrophysics Data System (ADS)

    Armstrong, D. J.; Pugh, C. E.; Broomhall, A.-M.; Brown, D. J. A.; Lund, M. N.; Osborn, H. P.; Pollacco, D. L.

    2016-01-01

    We embark on a detailed study of the light curves of Kepler's most Earth-like exoplanet host stars using the full length of Kepler data. We derive rotation periods, photometric activity indices, flaring energies, mass-loss rates, gyrochronological ages, X-ray luminosities and consider implications for the planetary magnetospheres and habitability. Furthermore, we present the detection of superflares in the light curve of Kepler-438, the exoplanet with the highest Earth Similarity Index to date. Kepler-438b orbits at a distance of 0.166 au to its host star, and hence may be susceptible to atmospheric stripping. Our sample is taken from the Habitable Exoplanet Catalogue, and consists of the stars Kepler-22, Kepler-61, Kepler-62, Kepler-174, Kepler-186, Kepler-283, Kepler-296, Kepler-298, Kepler-438, Kepler-440, Kepler-442, Kepler-443 and KOI-4427, between them hosting 15 of the most habitable transiting planets known to date from Kepler.

  15. Herpesvirus orthologues of CD200 bind host CD200R but not related activating receptors.

    PubMed

    Kwong, Lai Shan; Akkaya, Munir; Barclay, A Neil; Hatherley, Deborah

    2016-01-01

    Several herpesviruses have acquired the gene for the CD200 membrane protein from their hosts and can downregulate myeloid activity through interaction of this viral CD200 orthologue with the host receptor for CD200, namely CD200R, which can give inhibitory signals. This receptor is a 'paired receptor', meaning proteins related to the inhibitory CD200R are present but differ in that they can give activating signals and also give a negligible interaction with CD200. We showed that the viral orthologues e127 from rat cytomegalovirus and K14 from human herpesvirus 8 do not bind the activating CD200R-like proteins from their respective species, although they do bind the inhibitory receptors. It is thought that the activating receptors have evolved in response to pathogens targeting the inhibitory receptor. In this case, the CD200 orthologue is not trapped by the activating receptor but has maintained the specificity of the host from which it was acquired, suggesting that the activating members of the CD200R family have evolved to protect against a different pathogen. PMID:26538068

  16. New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection

    PubMed Central

    Wang, Huaqing; Kim, Janice J.; Denou, Emmanuel; Gallagher, Amanda; Thornton, David J.; Shajib, M. Sharif; Xia, Lijun; Schertzer, Jonathan D.; Grencis, Richard K.; Philpott, Dana J.

    2015-01-01

    Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite Trichuris muris. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and Nod2 double-knockout (Nod DKO) mice after T. muris infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and Nod2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or Nod2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and Nod2 agonists upregulated core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS-stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and Nod2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense. PMID:26527214

  17. Plant Defense against Insect Herbivores

    PubMed Central

    Fürstenberg-Hägg, Joel; Zagrobelny, Mika; Bak, Søren

    2013-01-01

    Plants have been interacting with insects for several hundred million years, leading to complex defense approaches against various insect feeding strategies. Some defenses are constitutive while others are induced, although the insecticidal defense compound or protein classes are often similar. Insect herbivory induce several internal signals from the wounded tissues, including calcium ion fluxes, phosphorylation cascades and systemic- and jasmonate signaling. These are perceived in undamaged tissues, which thereafter reinforce their defense by producing different, mostly low molecular weight, defense compounds. These bioactive specialized plant defense compounds may repel or intoxicate insects, while defense proteins often interfere with their digestion. Volatiles are released upon herbivory to repel herbivores, attract predators or for communication between leaves or plants, and to induce defense responses. Plants also apply morphological features like waxes, trichomes and latices to make the feeding more difficult for the insects. Extrafloral nectar, food bodies and nesting or refuge sites are produced to accommodate and feed the predators of the herbivores. Meanwhile, herbivorous insects have adapted to resist plant defenses, and in some cases even sequester the compounds and reuse them in their own defense. Both plant defense and insect adaptation involve metabolic costs, so most plant-insect interactions reach a stand-off, where both host and herbivore survive although their development is suboptimal. PMID:23681010

  18. The Type I NADH Dehydrogenase of Mycobacterium tuberculosis Counters Phagosomal NOX2 Activity to Inhibit TNF-α-Mediated Host Cell Apoptosis

    PubMed Central

    Miller, Jessica L.; Velmurugan, Kamalakannan; Cowan, Mark J.; Briken, Volker

    2010-01-01

    The capacity of infected cells to undergo apoptosis upon insult with a pathogen is an ancient innate immune defense mechanism. Consequently, the ability of persisting, intracellular pathogens such as the human pathogen Mycobacterium tuberculosis (Mtb) to inhibit infection-induced apoptosis of macrophages is important for virulence. The nuoG gene of Mtb, which encodes the NuoG subunit of the type I NADH dehydrogenase, NDH-1, is important in Mtb-mediated inhibition of host macrophage apoptosis, but the molecular mechanism of this host pathogen interaction remains elusive. Here we show that the apoptogenic phenotype of MtbΔnuoG was significantly reduced in human macrophages treated with caspase-3 and -8 inhibitors, TNF-α-neutralizing antibodies, and also after infection of murine TNF−/− macrophages. Interestingly, incubation of macrophages with inhibitors of reactive oxygen species (ROS) reduced not only the apoptosis induced by the nuoG mutant, but also its capacity to increase macrophage TNF-α secretion. The MtbΔnuoG phagosomes showed increased ROS levels compared to Mtb phagosomes in primary murine and human alveolar macrophages. The increase in MtbΔnuoG induced ROS and apoptosis was abolished in NOX-2 deficient (gp91−/−) macrophages. These results suggest that Mtb, via a NuoG-dependent mechanism, can neutralize NOX2-derived ROS in order to inhibit TNF-α-mediated host cell apoptosis. Consistently, an Mtb mutant deficient in secreted catalase induced increases in phagosomal ROS and host cell apoptosis, both of which were dependent upon macrophage NOX-2 activity. In conclusion, these results serendipitously reveal a novel connection between NOX2 activity, phagosomal ROS, and TNF-α signaling during infection-induced apoptosis in macrophages. Furthermore, our study reveals a novel function of NOX2 activity in innate immunity beyond the initial respiratory burst, which is the sensing of persistent intracellular pathogens and subsequent induction of host

  19. Macrophage defense mechanisms against intracellular bacteria

    PubMed Central

    Weiss, Günter; Schaible, Ulrich E

    2015-01-01

    Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics. PMID:25703560

  20. Commercializing Defense Technologies and Helping Defense Firms Succeed in Commercial Markets: A Report on the Objectives, Activities, and Accomplishments of the TAP-IN Program

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Technology Access for Product Innovation (TAP-IN), the largest technology deployment project funded by TRP, was competitively selected through a national solicitation for proposals. TAP-IN was created to help companies access and apply defense technologies and help defense-dependent companies enter new commercial markets. Defense technologies included technologies developed by DoD, DOE, NASA, and their contractors. TAP-IN was structured to provide region-based technology access services that were able to draw on technology resources nationwide. TAP-IN provided expert assistance in all stages of the commercialization process from concept through prototype design to capital sourcing and marketing strategy. TAP-IN helped companies locate new technology, identify business partners, secure financing, develop ideas for new products, identify new markets, license technology, solve technical problems, and develop company-specific applications of federal technology. TAP-IN leveraged NASA's existing commercial technology network to create an integrated national network of organizations that assisted companies in every state. In addition to NASA's six regional technology transfer centers (RTTCs), TAP-IN included business and technology development organizations in every state, the Industrial Designers Society of America, and the Federal Laboratory Consortium (FLC).

  1. Vaccination of koalas (Phascolarctos cinereus) with a recombinant chlamydial major outer membrane protein adjuvanted with poly I:C, a host defense peptide and polyphosphazine, elicits strong and long lasting cellular and humoral immune responses.

    PubMed

    Khan, Shahneaz Ali; Waugh, Courtney; Rawlinson, Galit; Brumm, Jacqui; Nilsson, Karen; Gerdts, Volker; Potter, Andrew; Polkinghorne, Adam; Beagley, Kenneth; Timms, Peter

    2014-10-01

    Chlamydial infections are wide spread in koalas across their range and a solution to this debilitating disease has been sought for over a decade. Antibiotics are the currently accepted therapeutic measure, but are not an effective treatment due to the asymptomatic nature of some infections and a low efficacy rate. Thus, a vaccine would be an ideal way to address this infectious disease threat in the wild. Previous vaccine trials have used a three-dose regimen; however this is very difficult to apply in the field as it would require multiple capture events, which are stressful and invasive processes for the koala. In addition, it requires skilled koala handlers and a significant monetary investment. To overcome these challenges, in this study we utilized a polyphosphazine based poly I:C and a host defense peptide adjuvant combined with recombinant chlamydial major outer membrane protein (rMOMP) antigen to induce long lasting (54 weeks) cellular and humoral immunity in female koalas with a novel single immunizing dose. Immunized koalas produced a strong IgG response in plasma, as well as at mucosal sites. Moreover, they showed high levels of C. pecorum specific neutralizing antibodies in the plasma as well as vaginal and conjunctival secretions. Lastly, Chlamydia-specific lymphocyte proliferation responses were produced against both whole chlamydial elementary bodies and rMOMP protein, over the 12-month period. The results of this study suggest that a single dose rMOMP vaccine incorporating a poly I:C, host defense peptide and polyphosphazine adjuvant is able to stimulate both arms of the immune system in koalas, thereby providing an alternative to antibiotic treatment and/or a three-dose vaccine regime. PMID:25196393

  2. Arabidopsis Sigma Factor Binding Proteins Are Activators of the WRKY33 Transcription Factor in Plant Defense[W

    PubMed Central

    Lai, Zhibing; Li, Ying; Wang, Fei; Cheng, Yuan; Fan, Baofang; Yu, Jing-Quan; Chen, Zhixiang

    2011-01-01

    Necrotrophic pathogens are important plant pathogens that cause many devastating plant diseases. Despite their impact, our understanding of the plant defense response to necrotrophic pathogens is limited. The WRKY33 transcription factor is important for plant resistance to necrotrophic pathogens; therefore, elucidation of its functions will enhance our understanding of plant immunity to necrotrophic pathogens. Here, we report the identification of two WRKY33-interacting proteins, nuclear-encoded SIGMA FACTOR BINDING PROTEIN1 (SIB1) and SIB2, which also interact with plastid-encoded plastid RNA polymerase SIGMA FACTOR1. Both SIB1 and SIB2 contain an N-terminal chloroplast targeting signal and a putative nuclear localization signal, suggesting that they are dual targeted. Bimolecular fluorescence complementation indicates that WRKY33 interacts with SIBs in the nucleus of plant cells. Both SIB1 and SIB2 contain a short VQ motif that is important for interaction with WRKY33. The two VQ motif–containing proteins recognize the C-terminal WRKY domain and stimulate the DNA binding activity of WRKY33. Like WRKY33, both SIB1 and SIB2 are rapidly and strongly induced by the necrotrophic pathogen Botrytis cinerea. Resistance to B. cinerea is compromised in the sib1 and sib2 mutants but enhanced in SIB1-overexpressing transgenic plants. These results suggest that dual-targeted SIB1 and SIB2 function as activators of WRKY33 in plant defense against necrotrophic pathogens. PMID:21990940

  3. Red Dwarf Stars: Ages, Rotation, Magnetic Dynamo Activity and the Habitability of Hosted Planets

    NASA Astrophysics Data System (ADS)

    Engle, S. G.; Guinan, E. F.

    2011-12-01

    We report on our continued efforts to understand and delineate the magnetic dynamo-induced behavior/variability of red dwarf (K5 V - M6 V) stars over their long lifetimes. These properties include: rotation, light variations (from star spots), coronal-chr