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Sample records for innate immunity cytoplasmic

  1. Accessory Factors of Cytoplasmic Viral RNA Sensors Required for Antiviral Innate Immune Response

    PubMed Central

    Oshiumi, Hiroyuki; Kouwaki, Takahisa; Seya, Tsukasa

    2016-01-01

    Type I interferon (IFN) induces many antiviral factors in host cells. RIG-I-like receptors (RLRs) are cytoplasmic viral RNA sensors that trigger the signal to induce the innate immune response that includes type I IFN production. RIG-I and MDA5 are RLRs that form nucleoprotein filaments along viral double-stranded RNA, resulting in the activation of MAVS adaptor molecule. The MAVS protein forms a prion-like aggregation structure, leading to type I IFN production. RIG-I and MDA5 undergo post-translational modification. TRIM25 and Riplet ubiquitin ligases deliver a K63-linked polyubiquitin moiety to the RIG-I N-terminal caspase activation and recruitment domains (CARDs) and C-terminal region; the polyubiquitin chain then stabilizes the two-CARD tetramer structure required for MAVS assembly. MDA5 activation is regulated by phosphorylation. RIOK3 is a protein kinase that phosphorylates the MDA5 protein in a steady state, and PP1α/γ dephosphorylate this protein, resulting in its activation. RIG-I and MDA5 require cytoplasmic RNA helicases for their efficient activation. LGP2, another RLR, is an RNA helicase involved in RLR signaling. This protein does not possess N-terminal CARDs and, thus, cannot trigger downstream signaling by itself. Recent studies have revealed that this protein modulates MDA5 filament formation, resulting in enhanced type I IFN production. Several other cytoplasmic RNA helicases are involved in RLR signaling. DDX3, DHX29, DHX36, and DDX60 RNA helicases have been reported to be involved in RLR-mediated type I IFN production after viral infection. However, the underlying mechanism is largely unknown. Future studies are required to reveal the role of RNA helicases in the RLR signaling pathway. PMID:27252702

  2. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

    PubMed Central

    Kimura, Tomonori; Jain, Ashish; Choi, Seong Won; Mandell, Michael A.; Schroder, Kate; Johansen, Terje

    2015-01-01

    The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans. PMID:26347139

  3. SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition.

    PubMed

    Nguyen, Tan A; Smith, Blake R C; Tate, Michelle D; Belz, Gabrielle T; Barrios, Marilou H; Elgass, Kirstin D; Weisman, Alexandra S; Baker, Paul J; Preston, Simon P; Whitehead, Lachlan; Garnham, Alexandra; Lundie, Rachel J; Smyth, Gordon K; Pellegrini, Marc; O'Keeffe, Meredith; Wicks, Ian P; Masters, Seth L; Hunter, Craig P; Pang, Ken C

    2017-09-19

    Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and-in the case of EMCV and HSV-1-reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

    PubMed Central

    Zhang, Guigen; Chan, Baca; Samarina, Naira; Abere, Bizunesh; Weidner-Glunde, Magdalena; Buch, Anna; Pich, Andreas; Brinkmann, Melanie M.; Schulz, Thomas F.

    2016-01-01

    The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING–dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle. PMID:26811480

  5. Innate immunity.

    PubMed

    Revillard, Jean-Pierre

    2002-01-01

    For more than half a century immunological research has been almost exclusively orientated towards the acquired immune response and the mechanisms of immune tolerance. Major discoveries have enabled us to better understand the functioning of the specific immune system: the structure of antibody molecules, the genetic mechanisms leading to the molecular diversity of B (BCR) and T (TCR) lymphocyte antigen receptors, the biological function of major histocompatibility complex (MHC) molecules in the presentation of peptides to alpha/beta receptor bearing T lymphocytes, the processes of positive and negative selection of lymphocytes during the course of their differentiation. The major role of specific or acquired immunity has been shown by the rapidly lethal character of severe combined immune deficiency diseases and various alterations in the mechanisms of tolerance have been proposed to explain the chronic inflammatory illnesses which are considered to be auto-immune. Natural or innate immunity has been known since the first description of an inflammatory reaction attributed to Cornelius Celsus. It entered into the scientific era at the end of the 19th century with the discovery of phagocytes by Metchnikoff and of the properties of the complement system by Bordet [1] but due to the vastness of the field and its lack of clear definition, it failed to excite the interest of researchers. The discovery of cytokines and progress in knowledge of the mechanisms of the inflammatory reaction have certainly helped to banish preconceived ideas about natural immunity, which was wrongly labelled as non-specific. This has led to the proposition of a wider role for immune functions beyond the level of the cell or the organism [2] and to a better understanding of the importance of the immediate defence mechanisms and their role in the later orientation of the acquired response.

  6. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  7. Innate immunity and adjuvants.

    PubMed

    Akira, Shizuo

    2011-10-12

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.

  8. A receptor-like cytoplasmic kinase, BIK1, associates with a flagellin receptor complex to initiate plant innate immunity

    PubMed Central

    Lu, Dongping; Wu, Shujing; Gao, Xiquan; Zhang, Yulan; Shan, Libo; He, Ping

    2010-01-01

    Plants and animals rely on innate immunity to prevent infections by detection of microbe-associated molecular patterns (MAMPs) through pattern-recognition receptors (PRRs). The plant PRR FLS2, a leucine-rich repeat-receptor kinase, recognizes bacterial flagellin and initiates immune signaling by association with another leucine-rich repeat-receptor-like kinase, BAK1. It remains unknown how the FLS2/BAK1 receptor complex activates intracellular signaling cascades. Here we identified the receptor-like cytoplasmic kinase BIK1 that is rapidly phosphorylated upon flagellin perception, depending on both FLS2 and BAK1. BIK1 associates with FLS2 and BAK1 in vivo and in vitro. BIK1 is phosphorylated by BAK1, and BIK1 also directly phosphorylates BAK1 and FLS2 in vitro. The flagellin phosphorylation site Thr237 of BIK1 is required for its phosphorylation on BAK1 and FLS2, suggesting that BIK1 is likely first phosphorylated upon flagellin perception and subsequently transphosphorylates FLS2/BAK1 to propagate flagellin signaling. Importantly, bik1 mutants are compromised in diverse flagellin-mediated responses and immunity to the nonpathogenic bacterial infection. Thus, BIK1 is an essential component in MAMP signal transduction, which links the MAMP receptor complex to downstream intracellular signaling. PMID:20018686

  9. Chapter 2: Innate Immunity

    PubMed Central

    Turvey, Stuart E.; Broide, David H.

    2009-01-01

    Recent years have witnessed an explosion of interest in the innate immune system. Questions about how the innate immune system senses infection and empowers a protective immune response are being answered at the molecular level. These basic science discoveries are being translated into a more complete understanding of the central role innate immunity plays in the pathogenesis of many human infectious and inflammatory diseases. It is particularly exciting that we are already seeing a return on these scientific investments with the emergence of novel therapies to harness the power of the innate immune system. In this review we explore the defining characteristics of the innate immune system, and through more detailed examples, we highlight recent breakthroughs that have advanced our understanding of the role of innate immunity in human health and disease. PMID:19932920

  10. Kidney and innate immunity.

    PubMed

    Wang, Ying-Hui; Zhang, Yu-Gen

    2017-03-01

    Innate immune system is an important modulator of the inflammatory response during infection and tissue injury/repair. The kidney as a vital organ with high energy demand plays a key role in regulating the disease related metabolic process. Increasing research interest has focused on the immune pathogenesis of many kidney diseases. However, innate immune cells such as dendritic cells, macrophages, NK cells and a few innate lymphocytes, as well as the complement system are essential for renal immune homeostasis and ensure a coordinated balance between tissue injury and regeneration. The innate immune response provides the first line of host defense initiated by several classes of pattern recognition receptors (PRRs), such as membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), together with inflammasomes responsible for early innate immune response. Although the innate immune system is well studied, the research on the detailed relationship between innate immunity and kidney is still very limited. In this review, we will focus on the innate immune sensing system in renal immune homeostasis, as well as the corresponding pathogenesis of many kidney diseases. The pivotal roles of innate immunity in renal injury and regeneration with special emphasis on kidney disease related immunoregulatory mechanism are also discussed.

  11. Innate Immunity in Disease

    PubMed Central

    Elliott, David E.; Siddique, Sana S.; Weinstock, Joel V.

    2014-01-01

    Cells can innately recognize generic products of viruses, bacteria, fungi, or injured tissue by engagement of pattern recognition receptors. Innate immune cells rapidly respond to this engagement in order to control commensals, thwart pathogens and/or prompt repair. Insufficient or excessive activation of the innate immune response results in disease. This review focuses on pattern recognition receptors and cells of the innate immune system important for intestinal function. Our improving knowledge pertaining to this important aspect of our immune response is opening potential important new therapeutic opportunities for the treatment of disease. PMID:24632348

  12. Innate immunity interactome dynamics.

    PubMed

    Elzawahry, Asmaa; Patil, Ashwini; Kumagai, Yutaro; Suzuki, Yutaka; Nakai, Kenta

    2014-01-06

    Innate immune response involves protein-protein interactions, deoxyribonucleic acid (DNA)-protein interactions and signaling cascades. So far, thousands of protein-protein interactions have been curated as a static interaction map. However, protein-protein interactions involved in innate immune response are dynamic. We recorded the dynamics in the interactome during innate immune response by combining gene expression data of lipopolysaccharide (LPS)-stimulated dendritic cells with protein-protein interactions data. We identified the differences in interactome during innate immune response by constructing differential networks and identifying protein modules, which were up-/down-regulated at each stage during the innate immune response. For each protein complex, we identified enriched biological processes and pathways. In addition, we identified core interactions that are conserved throughout the innate immune response and their enriched gene ontology terms and pathways. We defined two novel measures to assess the differences between network maps at different time points. We found that the protein interaction network at 1 hour after LPS stimulation has the highest interactions protein ratio, which indicates a role for proteins with large number of interactions in innate immune response. A pairwise differential matrix allows for the global visualization of the differences between different networks. We investigated the toll-like receptor subnetwork and found that S100A8 is down-regulated in dendritic cells after LPS stimulation. Identified protein complexes have a crucial role not only in innate immunity, but also in circadian rhythms, pathways involved in cancer, and p53 pathways. The study confirmed previous work that reported a strong correlation between cancer and immunity.

  13. Innate immunity in rice

    PubMed Central

    Chen, Xuewei; Ronald, Pamela C.

    2011-01-01

    Advances in studies of rice innate immunity have led to the identification and characterization of host sensors encoding receptor kinases that perceive conserved microbial signatures. The non-RD domain, a newly recognized hallmark of these receptor kinases is highly expanded in rice (Oryza sativa) compared with Arabidopsis (Arabidopsis thaliana). Researchers have also identified a diverse array of microbial effectors from bacterial and fungal pathogens that triggers immune responses upon perception. These include both, effectors that indirectly target host Nucleotide binding site/Leucine rice repeat (NBS-LRR) proteins and transcription activator-like (TAL) effectors that directly bind promoters of host genes. Here we review the recognition and signaling events that govern rice innate immunity. PMID:21602092

  14. Innate Immunity to Adenovirus

    PubMed Central

    Hendrickx, Rodinde; Stichling, Nicole; Koelen, Jorien; Kuryk, Lukasz; Lipiec, Agnieszka

    2014-01-01

    Abstract Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immunocompromised people, yet infections are usually mild and self-limiting in immunocompetent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and nonimmune cells. Innate defense protects the host and represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors mounted by the host cell upon viral challenge. These factors exert antiviral effects by directly binding to viruses or viral components, or shield the virus, for example, soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins, or defensins. In addition, Toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins, nucleotide-binding oligomerization domain-like inflammatory receptors, and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 and cyclic guanosine monophosphate–adenosine monophosphate synthase. Adenovirus tunes the function of antiviral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3, and E4 and two virus-associated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features. PMID:24512150

  15. Innate immunity to adenovirus.

    PubMed

    Hendrickx, Rodinde; Stichling, Nicole; Koelen, Jorien; Kuryk, Lukasz; Lipiec, Agnieszka; Greber, Urs F

    2014-04-01

    Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immunocompromised people, yet infections are usually mild and self-limiting in immunocompetent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and nonimmune cells. Innate defense protects the host and represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors mounted by the host cell upon viral challenge. These factors exert antiviral effects by directly binding to viruses or viral components, or shield the virus, for example, soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins, or defensins. In addition, Toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins, nucleotide-binding oligomerization domain-like inflammatory receptors, and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 and cyclic guanosine monophosphate-adenosine monophosphate synthase. Adenovirus tunes the function of antiviral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3, and E4 and two virus-associated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features.

  16. Adaptive Control of Innate Immunity

    PubMed Central

    Shanker, Anil

    2010-01-01

    1. Summary The mechanisms by which the immune system responds to an infection or disease depend on a complex interplay between the elements of innate and adaptive immunity. While most of the focus so far has been on the innate instruction of the adaptive immune responses, considerable evidence now suggests an equally important adaptive control of the innate immunity. Several studies yield new insights into how the adaptive immunity by initiating an antigen–specific response can compensate, suppress and activate innate responses at the site of tissue antigen. Here we discuss recent advances in our understanding of the adaptive control of immune effector functions in various pathological and physiological conditions. PMID:20394777

  17. Adaptation in the innate immune system and heterologous innate immunity.

    PubMed

    Martin, Stefan F

    2014-11-01

    The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This "design feature" of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.

  18. Curating the innate immunity interactome

    PubMed Central

    2010-01-01

    Background The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity. Results Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response. Conclusions In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity. PMID:20727158

  19. Innate immune memory in mammals.

    PubMed

    Hamon, Melanie A; Quintin, Jessica

    2016-08-01

    Innate and adaptive immunity have evolved as sophisticated mechanisms of host defence against invading pathogens. Classically the properties attributed to innate immunity are its rapid pleiotropic response, and to adaptive immunity its specificity and ability to retain a long-term memory of past infections. It is now clear that innate immunity also contributes to raising a memory response upon pathogenic assault. In this review we will discuss the interaction between bacterial, viral, fungal and parasitic molecular patterns and innate immune cells in which a memory response is imposed, or has the potential to be imposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Sleep and innate immunity.

    PubMed

    Zielinski, Mark R; Krueger, James M

    2011-01-01

    Many pro-inflammatory molecules, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are somnogenic, while many anti-inflammatory molecules inhibit sleep. Sleep loss increases the production/release of these sleep regulatory pro-inflammatory molecules. Further, sleep changes occurring during various pathologies are mediated by these inflammatory substances in response to pathogen recognition and subsequent inflammatory cellular pathways. This review summarizes information and concepts regarding inflammatory mechanisms of the innate immune system that mediate sleep. Further, we discuss sleep-immune interactions in regards to sleep in general, pathologies, and sleep as a local phenomenon including the central role that extracellular ATP plays in the initiation of sleep.

  1. Bridging innate and adaptive immunity.

    PubMed

    Paul, William E

    2011-12-09

    The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.

  2. Innate immune memory in plants.

    PubMed

    Reimer-Michalski, Eva-Maria; Conrath, Uwe

    2016-08-01

    The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Innate cellular immunity and xenotransplantation

    PubMed Central

    Wang, Hui; Yang, Yong-Guang

    2012-01-01

    Purpose of review This review assesses the recent progress in xenograft rejection by innate immune responses, with a focus on innate cellular xenoreactivity. Recent findings Current literature was reviewed for new insights into the role of innate cellular immunity in xenograft rejection. Increasing evidence confirms that vigorous innate immune cell activation is accounted for by a combination of xenoantigen recognition by activating receptors, and incompatibility in inhibitory receptor-ligand interactions. Although both innate humoral and cellular xenoimmune responses are predominantly elicited by preformed and induced xenoreactive antibodies in nonhuman primates following porcine xenotransplantation, innate immune cells can also be activated by xenografts in the absence of antibodies. The latter antibody-independent response will likely persist in recipients even when adaptive xenoimmune responses are suppressed. In addition to xenograft rejection by recipient innate immune cells, phagocytic cells within liver xenografts are also deleterious to recipients by causing thrombocytopenia. Summary Strategies of overcoming innate immune responses are required for successful clinical xenotransplantation. In addition to developing better immunosuppressive and tolerance induction protocols, endeavors towards further genetic modifications of porcine source animals are ultimately important for successful clinical xenotransplantation. PMID:22262106

  4. Innate Immune Evasion by Filoviruses

    PubMed Central

    Basler, Christopher F.

    2015-01-01

    Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms inclue suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replication in the face of such responses. A greater understanding these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens. PMID:25843618

  5. Innate immunity in allergic disease.

    PubMed

    Minnicozzi, Michael; Sawyer, Richard T; Fenton, Matthew J

    2011-07-01

    The innate immune system consists of multiple cell types that express germline-encoded pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Allergens are frequently found in forms and mixtures that contain PAMPs and DAMPs. The innate immune system is interposed between the external environment and the internal acquired immune system. It is also an integral part of the airways, gut, and skin. These tissues face continuous exposure to allergens, PAMPs, and DAMPs. Interaction of allergens with the innate immune system normally results in immune tolerance but, in the case of allergic disease, this interaction induces recurring and/or chronic inflammation as well as the loss of immunologic tolerance. Upon activation by allergens, the innate immune response commits the acquired immune response to a variety of outcomes mediated by distinct T-cell subsets, such as T-helper 2, regulatory T, or T-helper 17 cells. New studies highlighted in this review underscore the close relationship between allergens, the innate immune system, and the acquired immune system that promotes homeostasis versus allergic disease.

  6. Innate immune recognition of cancer.

    PubMed

    Woo, Seng-Ryong; Corrales, Leticia; Gajewski, Thomas F

    2015-01-01

    The observation that a subset of cancer patients show evidence for spontaneous CD8+ T cell priming against tumor-associated antigens has generated renewed interest in the innate immune pathways that might serve as a bridge to an adaptive immune response to tumors. Manipulation of this endogenous T cell response with therapeutic intent-for example, using blocking antibodies inhibiting PD-1/PD-L1 (programmed death-1/programmed death ligand 1) interactions-is showing impressive clinical results. As such, understanding the innate immune mechanisms that enable this T cell response has important clinical relevance. Defined innate immune interactions in the cancer context include recognition by innate cell populations (NK cells, NKT cells, and γδ T cells) and also by dendritic cells and macrophages in response to damage-associated molecular patterns (DAMPs). Recent evidence has indicated that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the stimulator of interferon gene (STING) pathway and driving type I IFN production. A deeper knowledge of the clinically relevant innate immune pathways involved in the recognition of tumors is leading toward new therapeutic strategies for cancer treatment.

  7. Innate Immune Activation in Obesity

    PubMed Central

    Lumeng, Carey N.

    2014-01-01

    The innate immune system is a prewired set of cellular and humoral components that has developed to sense perturbations in normal physiology and trigger responses to restore the system back to baseline. It is now understood that many of these components can also sense the physiologic changes that occur with obesity and be activated. While the exact reasons for this chronic immune response to obesity are unclear, there is strong evidence to suggest that innate inflammatory systems link obesity and disease. Based on this, anti-inflammatory therapies for diseases like type 2 diabetes and metabolic syndrome may form the core of future treatment plans. This review will highlight the components involved in the innate immune response and discuss the evidence that they contribute to the pathogenesis of obesity-associated diseases. PMID:23068074

  8. GPCRs in invertebrate innate immunity.

    PubMed

    Reboul, Jerome; Ewbank, Jonathan J

    2016-08-15

    G-protein coupled receptors (GPCRs) represent a privileged point of contact between cells and their surrounding environment. They have been widely adopted in vertebrates as mediators of signals involved in both innate and adaptive immunity. Invertebrates rely on innate immune defences to resist infection. We review here evidence from a number of different species, principally the genetically tractable Caenorhabditis elegans and Drosophila melanogaster that points to an important role for GPCRs in modulating innate immunity in invertebrates too. In addition to examples of GPCRs involved in regulating the expression of defence genes, we discuss studies in C. elegans addressing the role of GPCR signalling in pathogen aversive behaviour. Despite the many lacunae in our current knowledge, it is clear that GPCR signalling contributes to host defence across the animal kingdom.

  9. Ambient ozone and pulmonary innate immunity

    PubMed Central

    Al-Hegelan, Mashael; Tighe, Robert M.; Castillo, Christian; Hollingsworth, John W.

    2013-01-01

    Ambient ozone is a criteria air pollutant that impacts both human morbidity and mortality. The effect of ozone inhalation includes both toxicity to lung tissue and alteration of the host immunologic response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage. Emerging evidence supports that ozone can modify the host innate immune response and that this response to inhaled ozone is dependent on genes of innate immunity. Improved understanding of the complex interaction between environmental ozone and host innate immunity will provide fundamental insight into the pathogenesis of inflammatory airways disease. We review the current evidence supporting that environmental ozone inhalation: (1) modifies cell types required for intact innate immunity, (2) is partially dependent on genes of innate immunity, (3) primes pulmonary innate immune responses to LPS, and (4) contributes to innate-adaptive immune system cross-talk. PMID:21132467

  10. Taste Receptors in Innate Immunity

    PubMed Central

    Lee, Robert J.

    2014-01-01

    Taste receptors were first identified on the tongue, where they initiate a signaling pathway that communicates information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has shown that taste receptors are also expressed in a myriad of other tissues, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these extraoral taste receptors remain unknown, but emerging evidence suggests that bitter and sweet taste receptors in the airway are important sentinels of innate immunity. This review discusses taste receptor signaling, focusing on the G-protein coupled–receptors that detect bitter, sweet, and savory tastes, followed by an overview of extraoral taste receptors and in-depth discussion of studies demonstrating the roles of taste receptors in airway innate immunity. Future research on extraoral taste receptors has significant potential for identification of novel immune mechanisms and insights into host-pathogen interactions. PMID:25323130

  11. Innate Immunity and Breast Milk

    PubMed Central

    Cacho, Nicole Theresa; Lawrence, Robert M.

    2017-01-01

    Human milk is a dynamic source of nutrients and bioactive factors; unique in providing for the human infant’s optimal growth and development. The growing infant’s immune system has a number of developmental immune deficiencies placing the infant at increased risk of infection. This review focuses on how human milk directly contributes to the infant’s innate immunity. Remarkable new findings clarify the multifunctional nature of human milk bioactive components. New research techniques have expanded our understanding of the potential for human milk’s effect on the infant that will never be possible with milk formulas. Human milk microbiome directly shapes the infant’s intestinal microbiome, while the human milk oligosaccharides drive the growth of these microbes within the gut. New techniques such as genomics, metabolomics, proteomics, and glycomics are being used to describe this symbiotic relationship. An expanded role for antimicrobial proteins/peptides within human milk in innate immune protection is described. The unique milieu of enhanced immune protection with diminished inflammation results from a complex interaction of anti-inflammatory and antioxidative factors provided by human milk to the intestine. New data support the concept of mucosal-associated lymphoid tissue and its contribution to the cellular content of human milk. Human milk stem cells (hMSCs) have recently been discovered. Their direct role in the infant for repair and regeneration is being investigated. The existence of these hMSCs could prove to be an easily harvested source of multilineage stem cells for the study of cancer and tissue regeneration. As the infant’s gastrointestinal tract and immune system develop, there is a comparable transition in human milk over time to provide fewer immune factors and more calories and nutrients for growth. Each of these new findings opens the door to future studies of human milk and its effect on the innate immune system and the developing

  12. TLRs and innate immunity

    PubMed Central

    2009-01-01

    One of the most fundamental questions in immunology pertains to the recognition of non-self, which for the most part means microbes. How do we initially realize that we have been inoculated with microbes, and how is the immune response ignited? Genetic studies have made important inroads into this question during the past decade, and we now know that in mammals, a relatively small number of receptors operate to detect signature molecules that herald infection. One or more of these signature molecules are displayed by almost all microbes. These receptors and the signals they initiate have been studied in depth by random germline mutagenesis and positional cloning (forward genetics). Herein is a concise description of what has been learned about the Toll-like receptors, which play an essential part in the perception of microbes and shape the complex host responses that occur during infection. PMID:18757776

  13. Tuning innate immunity by translation.

    PubMed

    Rauscher, Robert; Ignatova, Zoya

    2015-12-01

    In multicellular organisms, the epithelia is a contact surface with the surrounding environment and is exposed to a variety of adverse biotic (pathogenic) and abiotic (chemical) factors. Multi-layered pathways that operate on different time scales have evolved to preserve cellular integrity and elicit stress-specific response. Several stress-response programs are activated until a complete elimination of the stress is achieved. The innate immune response, which is triggered by pathogenic invasion, is rather harmful when active over a prolonged time, thus the response follows characteristic oscillatory trajectories. Here, we review different translation programs that function to precisely fine-tune the time at which various components of the innate immune response dwell between active and inactive. We discuss how different pro-inflammatory pathways are co-ordinated to temporally offset single reactions and to achieve an optimal balance between fighting pathogens and being less harmful for healthy cells.

  14. Systems biology of innate immunity

    PubMed Central

    Zak, Daniel E.; Aderem, Alan

    2009-01-01

    Summary Systems biology is the comprehensive and quantitative analysis of the interactions between all of the components of biological systems over time. Systems biology involves an iterative cycle, in which emerging biological problems drive the development of new technologies and computational tools. These technologies and tools then open new frontiers that revolutionize biology. Innate immunity is well suited for systems analysis, because the relevant cells can be isolated in various functional states and their interactions can be reconstituted in a biologically meaningful manner. Application of the tools of systems biology to the innate immune system will enable comprehensive analysis of the complex interactions that maintain the difficult balance between host defense and inflammatory disease. In this review, we discuss innate immunity in the context of the systems biology concepts, emergence, robustness, and modularity, and we describe emerging technologies we are applying in our systems-level analyses. These technologies include genomics, proteomics, computational analysis, forward genetics screens, and analyses that link human genetic polymorphisms to disease resistance. PMID:19120490

  15. The birth of innate immunity.

    PubMed

    Gallo, Richard L

    2013-08-01

    Modern immunology has seen an apparent revolution with the recognition that human immune defense is not only the responsibility of bone marrow-derived leucocytes, but also dependent on a coordinated network of many cell types including epithelial cells, fibroblasts and neural elements. This classic paper by Alexander Fleming and V.D. Allison (British J of Exp Path, 111, 1922, 252) was largely forgotten for 75 years and describes the discovery that epithelia produce a protein with direct antimicrobial activity. Thus, this paper represents the birth of the field now referred to as innate immunity and first describes an antimicrobial protein (AMP).

  16. Innate Immunity against Leishmania Infections

    PubMed Central

    Gurung, Prajwal; Kanneganti, Thirumala-Devi

    2015-01-01

    Leishmaniasis is a major health problem that affects more than 300 million people throughout the world. The morbidity associated with the disease causes serious economic burden in Leishmania endemic regions. Despite the morbidity and economic burden associated with Leishmaniasis, this disease rarely gets noticed and is still categorized under neglected tropical diseases. The lack of research combined with the ability of Leishmania to evade immune recognition has rendered our efforts to design therapeutic treatments or vaccines challenging. Herein, we review the literature on Leishmania from innate immune perspective and discuss potential problems as well as solutions and future directions that could aid in identifying novel therapeutic targets to eliminate this parasite. PMID:26249747

  17. Mast cells in innate immunity.

    PubMed

    Marshall, Jean S; Jawdat, Dunia M

    2004-07-01

    Mast cells have been most extensively studied in their traditional role as an early effector cell of allergic disease. However, in the majority of individuals, it might be the role of this cell as a sentinel in host defense that is most important. Mast cells have been repeatedly demonstrated to play a critical role in defense against bacterial infections, and evidence for their involvement in early responses to viral and fungal pathogens is growing. Mast cells are activated during innate immune responses by multiple mechanisms, including well-established responses to complement components. In addition, novel mechanisms have emerged as a result of the explosion of knowledge in our understanding of pattern-recognition receptors. The mast cell shares many features with other innate immune effector cells, such as neutrophils and macrophages. However, a unique role for mast cells is defined not only by their extensive mediator profile but also by their ability to interact with the vasculature, to expedite selective cell recruitment, and to set the stage for an appropriate acquired response. Copyright 2004 American Academy of Allergy, Asthma and Immunology

  18. Blurring Borders: Innate Immunity with Adaptive Features

    PubMed Central

    Kvell, K.; Cooper, EL.; Engelmann, P.; Bovari, J.; Nemeth, P.

    2007-01-01

    Adaptive immunity has often been considered the penultimate of immune capacities. That system is now being deconstructed to encompass less stringent rules that govern its initiation, actual effector activity, and ambivalent results. Expanding the repertoire of innate immunity found in all invertebrates has greatly facilitated the relaxation of convictions concerning what actually constitutes innate and adaptive immunity. Two animal models, incidentally not on the line of chordate evolution (C. elegans and Drosophila), have contributed enormously to defining homology. The characteristics of specificity and memory and whether the antigen is pathogenic or nonpathogenic reveal considerable information on homology, thus deconstructing the more fundamentalist view. Senescence, cancer, and immunosuppression often associated with mammals that possess both innate and adaptive immunity also exist in invertebrates that only possess innate immunity. Strict definitions become blurred casting skepticism on the utility of creating rigid definitions of what innate and adaptive immunity are without considering overlaps. PMID:18317532

  19. Innate immunity in vertebrates: an overview.

    PubMed

    Riera Romo, Mario; Pérez-Martínez, Dayana; Castillo Ferrer, Camila

    2016-06-01

    Innate immunity is a semi-specific and widely distributed form of immunity, which represents the first line of defence against pathogens. This type of immunity is critical to maintain homeostasis and prevent microbe invasion, eliminating a great variety of pathogens and contributing with the activation of the adaptive immune response. The components of innate immunity include physical and chemical barriers, humoral and cell-mediated components, which are present in all jawed vertebrates. The understanding of innate defence mechanisms in non-mammalian vertebrates is the key to comprehend the general picture of vertebrate innate immunity and its evolutionary history. This is also essential for the identification of new molecules with applications in immunopharmacology and immunotherapy. In this review, we describe and discuss the main elements of vertebrate innate immunity, presenting core findings in this field and identifying areas that need further investigation. © 2016 John Wiley & Sons Ltd.

  20. [Innate immunity, Toll receptor and sepsis].

    PubMed

    Carrillo-Esper, Raúl

    2003-01-01

    The innate immune response is the first line of defense against infection. Toll-like receptors (TLRs) recognize bacterial lipopolysaccharide and other pathogen-associated molecular patterns (PAMPs). Intracellular signals initiated by interaction between Toll receptors and specific PAMPs results in inflammatory response. Sepsis and septic shock are the result of an exaggerated inflammatory systemic response induced by innate immune dysregulation.

  1. Innate immune responses to Pseudomonas aeruginosa infection

    PubMed Central

    Lavoie, Elise G.; Wangdi, Tamding; Kazmierczak, Barbara I.

    2011-01-01

    Innate immune responses play a critical role in controlling acute infections due to Pseudomonas aeruginosa in both mice and in humans. In this review we focus on innate immune recognition and clearance mechanisms that are important for controlling P. aeruginosa in the mammalian lung, with particular attention to those that influence the outcome of in vivo infection in murine models. PMID:21839853

  2. Testicular defense systems: immune privilege and innate immunity.

    PubMed

    Zhao, Shutao; Zhu, Weiwei; Xue, Shepu; Han, Daishu

    2014-09-01

    The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.

  3. Evolutionary responses of innate Immunity to adaptive immunity

    USDA-ARS?s Scientific Manuscript database

    Innate immunity is present in all metazoans, whereas the evolutionarily more novel adaptive immunity is limited to jawed fishes and their descendants (gnathostomes). We observe that the organisms that possess adaptive immunity lack diversity in their innate pattern recognition receptors (PRRs), rais...

  4. Immunological memory within the innate immune system

    PubMed Central

    Sun, Joseph C; Ugolini, Sophie; Vivier, Eric

    2014-01-01

    Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen-specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings. PMID:24674969

  5. Tweaking Innate Immunity: the Promise of Innate Immunologicals As Anti-infectives

    PubMed Central

    Rosenthal, Kenneth L

    2006-01-01

    New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as ‘innate immunologicals’) can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines. PMID:18382644

  6. Bone and the Innate Immune System

    PubMed Central

    Charles, Julia F.; Nakamura, Mary C.

    2014-01-01

    The immune system and bone are intimately linked with significant physical and functionally related interactions. The innate immune system functions as an immediate response system to initiate protections against local challenges such as pathogens and cellular damage. Bone is a very specific microenvironment in which infectious attack is less common but repair and regeneration are ongoing and important functions. Thus in the bone the primary goal of innate immune and bone interactions is to maintain tissue integrity. Innate immune signals are critical for removal of damaged and apoptotic cells and to stimulate normal tissue repair and regeneration. In this review we focus on these innate immune mechanisms that function to regulate bone homeostasis. PMID:24500569

  7. [Innate immunity primary immunodeficiencies and infections].

    PubMed

    Duchamp, M; Miot, C; Bustamante, J C; Picard, C

    2016-07-01

    The diagnosis of primary immunodeficiency diseases (PIDs) is important for the early and adaptive care of patients and their families. Among the various known PIDs, a number of them concern the innate immune system, which involve a set of cells and mechanisms involved in the host defense by a nonspecific and fast response. The majority of patients with innate immunity defects have a predisposition to one isolated type of infection (bacterial, viral, or fungal), dependent on the genetic defect involved. This article describes the different PIDs involving innate immunity and the immunological investigations allowing for their diagnosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Innate Immunity and BK Virus: Prospective Strategies.

    PubMed

    Kariminik, Ashraf; Yaghobi, Ramin; Dabiri, Shahriar

    2016-03-01

    Recent information demonstrated that BK virus reactivation is a dominant complication after kidney transplantation, which occurs because of immunosuppression. BK virus reactivation is the main reason of transplanted kidney losing. Immune response against BK virus is the major inhibitor of the virus reactivation. Therefore, improving our knowledge regarding the main parameters that fight against BK viruses can shed light on to direct new treatment strategies to suppress BK infection. Innate immunity consists of numerous cell systems and also soluble molecules, which not only suppress virus replication, but also activate adaptive immunity to eradicate the infection. Additionally, it appears that immune responses against reactivated BK virus are the main reasons for induction of BK virus-associated nephropathy (BKAN). Thus, improving our knowledge regarding the parameters and detailed mechanisms of innate immunity and also the status of innate immunity of the patients with BK virus reactivation and its complications can introduce new prospective strategies to either prevent or as therapy of the complication. Therefore, this review was aimed to collate the most recent data regarding the roles played by innate immunity against BK virus and also the status of innate immunity in the patients with reactivation BK virus and BKAN.

  9. [Regulation of allergy by innate immune system].

    PubMed

    Kumagai, Yutaro; Akira, Shizuo

    2009-11-01

    Allergy is an immune disease including asthma. Activation of Th2 response, such as production of IL-4, IL-5 and IL-13 from CD4+ T cells and IgG1 or IgE from B cells is responsible for allergy. Activation of acquired immune system requires preceding activation of innate immunity, therefore innate immunity may control Th2 response and allergy. Recent studies revealed that dendritic cells, epithelial cells, and basophils play central roles in the initiation of Th2 response. In this review, we will summarize the current understanding on the control of Th2 and allergic responses by innate immune system, and discuss recent findings on house dust mite-induced allergic response based on these understandings.

  10. Innate immunity in lophotrochozoans: the annelids.

    PubMed

    Salzet, Michel; Tasiemski, Aurélie; Cooper, Edwin

    2006-01-01

    Innate immunity plays a major role as a first defense against microbes. Effectors of the innate response include pattern recognition receptors (PRR), phagocytic cells, proteolytic cascades and peptides/proteins with antimicrobial properties. Each element of these events has been well studied in vertebrates and in some invertebrates such as annelids. From these different researches, it appears that mammalian innate immunity could be considered as a mosaic of invertebrate immune responses. Annelids belonging to the lophotrochozoans' group are primitive coelomates that possess specially developed cellular immunity against pathogens including phagocytosis, encapsulation and spontaneous cytotoxicity of coelomocytes against allogenic or xenogenic cells. They have also developed an important humoral immunity that is based on antimicrobial, hemolytic and clotting properties of their body fluid. In the present review, we will emphasize the different immunodefense strategies that adaptation has taken during the course of evolution of two classes of annelids i.e. oligochaetes and achaetes.

  11. Vaccine adjuvants: putting innate immunity to work.

    PubMed

    Coffman, Robert L; Sher, Alan; Seder, Robert A

    2010-10-29

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

  12. Vaccine Adjuvants: Putting Innate Immunity to Work

    PubMed Central

    Coffman, Robert L.; Sher, Alan; Seder, Robert A.

    2012-01-01

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens. PMID:21029960

  13. Ion Channels in Innate and Adaptive Immunity

    PubMed Central

    Feske, Stefan; Wulff, Heike; Skolnik, Edward Y.

    2016-01-01

    Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy. PMID:25861976

  14. Innate Immune Activity in Glomerular Podocytes

    PubMed Central

    Xia, Hong; Bao, Wenduona; Shi, Shaolin

    2017-01-01

    Glomerular podocytes are specialized in structure and play an essential role in glomerular filtration. In addition, podocyte stress can initiate glomerular damage by inducing the injury of other glomerular cell types. Studies have shown that podocytes possess the property of immune cells and may be involved in adaptive immunity. Emerging studies have also shown that podocytes possess signaling pathways of innate immune responses and that innate immune responses often result in podocyte injury. More recently, mitochondrial-derived damage-associated molecular patterns (mtDAMPs) have been shown to play a critical role in a variety of pathological processes in cells. In the present mini-review, we summarize the recent advances in the studies of innate immunity and its pathogenic role in podocytes, particularly, from the perspective of mtDAMPs. PMID:28228761

  15. Innate Immune Sensing and Response to Influenza

    PubMed Central

    Pulendran, Bali; Maddur, Mohan S.

    2015-01-01

    Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocom-promised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza. PMID:25078919

  16. Cytoplasmic nucleic acid sensors in antiviral immunity.

    PubMed

    Ranjan, Priya; Bowzard, J Bradford; Schwerzmann, Joy W; Jeisy-Scott, Victoria; Fujita, Takashi; Sambhara, Suryaprakash

    2009-08-01

    The innate immune system uses pattern recognition receptors (PRRs) to sense invading microbes and initiate a rapid protective response. PRRs bind and are activated by structural motifs, such as nucleic acids or bacterial and fungal cell wall components, collectively known as pathogen-associated molecular patterns. PRRs that recognize pathogen-derived nucleic acids are present in vesicular compartments and in the cytosol of most cell types. Here, we review recent studies of these cytosolic sensors, focusing on the nature of the ligands for DNA-dependent activator of interferon (DAI)-regulatory factors, absent in melanoma 2 (AIM2), and the retinoic acid-inducible gene I-like helicase (RLH) family of receptors, the basis of ligand recognition and the signaling pathways triggered by the activation of these receptors. An increased understanding of these molecular aspects of innate immunity will guide the development of novel antiviral therapeutics.

  17. Control of adaptive immunity by the innate immune system.

    PubMed

    Iwasaki, Akiko; Medzhitov, Ruslan

    2015-04-01

    Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.

  18. Control of adaptive immunity by the innate immune system

    PubMed Central

    Iwasaki, Akiko; Medzhitov, Ruslan

    2015-01-01

    Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity. PMID:25789684

  19. Inflammatory bowel disease related innate immunity and adaptive immunity.

    PubMed

    Huang, Yuan; Chen, Zhonge

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis remains not yet clear. Current researchers believe that after environmental factors act on individuals with genetic susceptibility, an abnormal intestinal immune response is launched under stimulation of intestinal flora. However, previous studies only focused on adaptive immunity in the pathogenesis of IBD. Currently, roles of innate immune response in the pathogenesis of intestinal inflammation have also drawn much attention. In this study, IBD related innate immunity and adaptive immunity were explained, especially the immune mechanisms in the pathogenesis of IBD.

  20. Adaptive immune cells temper initial innate responses.

    PubMed

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2007-10-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

  1. Adaptive immune cells temper initial innate responses

    PubMed Central

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2008-01-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25−Foxp3− or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses. PMID:17891146

  2. Innate Immune sensing of DNA viruses

    PubMed Central

    Rathinam, Vijay A. K.; Fitzgerald, Katherine A.

    2011-01-01

    DNA viruses are a significant contributor to human morbidity and mortality. The immune system protects against viral infections through coordinated innate and adaptive immune responses. While the antigen-specific adaptive mechanisms have been extensively studied, the critical contributions of innate immunity to anti-viral defenses have only been revealed in the very recent past. Central to these anti-viral defenses is the recognition of viral pathogens by a diverse set of germ-line encoded receptors that survey nearly all cellular compartments for the presence of pathogens. In this review, we discuss the recent advances in the innate immune sensing of DNA viruses and focus on the recognition mechanisms involved. PMID:21334037

  3. The innate immune system in demyelinating disease.

    PubMed

    Mayo, Lior; Quintana, Francisco J; Weiner, Howard L

    2012-07-01

    Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases.

  4. New insights into upper airway innate immunity

    PubMed Central

    Hariri, Benjamin M.

    2016-01-01

    Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these pathogens is paramount for sinonasal epithelial cells to be able to prepare a defensive response. Toll-like receptors and, more recently, bitter taste receptors and sweet taste receptors have been implicated as sensors able to detect the presence of these pathogens and certain compounds that they secrete. Activation of these receptors also triggers innate immune responses to prevent or counteract infection, including mucociliary clearance and the production and secretion of antimicrobial compounds (e.g., defensins). Objective: To provide an overview of the current knowledge of the role of innate immunity in the upper airway, the mechanisms by which it is carried out, and its clinical relevance. Methods: A literature review of the existing knowledge of the role of innate immunity in the human sinonasal cavity was performed. Results: Clinical and basic science studies have shown that the physical epithelial cell barrier, mucociliary clearance, and antimicrobial compound secretion play pivotal innate immune roles in defending the sinonasal cavity from infection. Clinical findings have also linked dysfunction of these defense mechanisms with diseases, such as chronic rhinosinusitis and cystic fibrosis. Recent discoveries have elucidated the significance of bitter and sweet taste receptors in modulating immune responses in the upper airway. Conclusion: Numerous innate immune mechanisms seem to work in a concerted fashion to keep the sinonasal cavity free of infection. Understanding sinonasal innate immune function and dysfunction in health and disease has important implications for patients with respiratory ailments, such as chronic rhinosinusitis and cystic fibrosis. PMID:27657896

  5. Corruption of innate immunity by bacterial proteases.

    PubMed

    Potempa, Jan; Pike, Robert N

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host's innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections.

  6. Corruption of Innate Immunity by Bacterial Proteases

    PubMed Central

    Potempa, Jan; Pike, Robert N.

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host’s innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections. PMID:19756242

  7. Immunological memory within the innate immune system.

    PubMed

    Sun, Joseph C; Ugolini, Sophie; Vivier, Eric

    2014-06-17

    Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen-specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings. © 2014 The Authors.

  8. Innate immune system cells in atherosclerosis.

    PubMed

    Chávez-Sánchez, Luis; Espinosa-Luna, Jose E; Chávez-Rueda, Karina; Legorreta-Haquet, María V; Montoya-Díaz, Eduardo; Blanco-Favela, Francisco

    2014-01-01

    Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune system involvement. A key component of atherosclerotic plaque inflammation is the persistence of different innate immune cell types including mast cells, neutrophils, natural killer cells, monocytes, macrophages and dendritic cells. Several endogenous signals such as oxidized low-density lipoproteins, and exogenous signals such as lipopolysaccharides, trigger the activation of these cells. In particular, these signals orchestrate the early and late inflammatory responses through the secretion of pro-inflammatory cytokines and contribute to plaque evolution through the formation of foam cells, among other events. In this review we discuss how innate immune system cells affect atherosclerosis pathogenesis.

  9. Evolutionary genetics of insect innate immunity

    PubMed Central

    2015-01-01

    Patterns of evolution in immune defense genes help to understand the evolutionary dynamics between hosts and pathogens. Multiple insect genomes have been sequenced, with many of them having annotated immune genes, which paves the way for a comparative genomic analysis of insect immunity. In this review, I summarize the current state of comparative and evolutionary genomics of insect innate immune defense. The focus is on the conserved and divergent components of immunity with an emphasis on gene family evolution and evolution at the sequence level; both population genetics and molecular evolution frameworks are considered. PMID:25750410

  10. Evolutionary genetics of insect innate immunity.

    PubMed

    Viljakainen, Lumi

    2015-11-01

    Patterns of evolution in immune defense genes help to understand the evolutionary dynamics between hosts and pathogens. Multiple insect genomes have been sequenced, with many of them having annotated immune genes, which paves the way for a comparative genomic analysis of insect immunity. In this review, I summarize the current state of comparative and evolutionary genomics of insect innate immune defense. The focus is on the conserved and divergent components of immunity with an emphasis on gene family evolution and evolution at the sequence level; both population genetics and molecular evolution frameworks are considered. © The Author 2015. Published by Oxford University Press.

  11. Innate immune modulation in EBV infection

    PubMed Central

    2011-01-01

    Epstein-Barr Virus (EBV) belongs to the gammaherpesvirus family, members of which are oncogenic. Compared with other closely related herpesviruses, EBV has developed much more elaborate and sophisticated strategies for subverting host immune system, which may account for its high prevalence in immune competent hosts. Thus, study of EBV-specific immune dysregulation is important for understanding EBV latency and oncogenesis, and will identify potential molecular targets for immunotherapeutic interventions. Here I summarize the recent findings of individual EBV products in regulating host immune responses, with emphasis on the innate immune modulation. PMID:21429244

  12. Adrenergic regulation of innate immunity: a review

    PubMed Central

    Scanzano, Angela; Cosentino, Marco

    2015-01-01

    The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential. PMID:26321956

  13. Neutrophils: Cinderella of innate immune system.

    PubMed

    Kumar, V; Sharma, A

    2010-11-01

    Neutrophils are the first line of innate immune defense against infectious diseases. However, since their discovery by Elie Metchnikoff, they have always been considered tissue-destructive cells responsible for inflammatory tissue damage occurring during acute infections. Now, extensive research in the field of neutrophil cell biology and their role skewing the immune response in various infections or inflammatory disorders revealed their importance in the regulation of immune response. Along with releasing various antimicrobial molecules, neutrophils also release neutrophil extracellular traps (NETs) for the containment of infection and inflammation. Activated neutrophils provide signals for the activation and maturation of macrophages as well as dendritic cells. Neutrophils are also involved in the regulation of T-cell immune response against various pathogens and tumor antigens. Thus, the present review is intended to highlight the emerging role of neutrophils in the regulation of both innate and adaptive immunity during acute infectious or inflammatory conditions.

  14. Immune tolerance induction by integrating innate and adaptive immune regulators

    PubMed Central

    Suzuki, Jun; Ricordi, Camillo; Chen, Zhibin

    2009-01-01

    A diversity of immune tolerance mechanisms have evolved to protect normal tissues from immune damage. Immune regulatory cells are critical contributors to peripheral tolerance. These regulatory cells, exemplified by the CD4+Foxp3+ regulatory T (Treg) cells and a recently identified population named myeloid-derived suppressor cells (MDSCs), regulate immune responses and limiting immune-mediated pathology. In a chronic inflammatory setting, such as allograft-directed immunity, there may be a dynamic “crosstalk” between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage. CTLA4-B7-based interaction between the two branches may function as a molecular “bridge” to facilitate such “crosstalk”. Understanding the interplays among Treg cells, innate suppressors and pathogenic effector T (Teff) cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immunosuppressive elements in the innate and adaptive immune system. Successful development of localized strategies of regulatory cell therapies could circumvent the requirement for very high number of cells and decrease the risks associated with systemic immunosuppression. To realize the potential of innate and adaptive immune regulators for the still-elusive goal of immune tolerance induction, adoptive cell therapies may also need to be coupled with agents enhancing endogenous tolerance mechanisms. PMID:19919733

  15. Innate lymphoid cells in inflammation and immunity.

    PubMed

    McKenzie, Andrew N J; Spits, Hergen; Eberl, Gerard

    2014-09-18

    Innate lymphoid cells (ILCs) were first described as playing important roles in the development of lymphoid tissues and more recently in the initiation of inflammation at barrier surfaces in response to infection or tissue damage. It has now become apparent that ILCs play more complex roles throughout the duration of immune responses, participating in the transition from innate to adaptive immunity and contributing to chronic inflammation. The proximity of ILCs to epithelial surfaces and their constitutive strategic positioning in other tissues throughout the body ensures that, in spite of their rarity, ILCs are able to regulate immune homeostasis effectively. Dysregulation of ILC function might result in chronic pathologies such as allergies, autoimmunity, and inflammation. A new role for ILCs in the maintenance of metabolic homeostasis has started to emerge, underlining their importance in fundamental physiological processes beyond infection and immunity.

  16. The innate immune system and transplantation.

    PubMed

    Farrar, Conrad A; Kupiec-Weglinski, Jerzy W; Sacks, Steven H

    2013-10-01

    The sensitive and broadly reactive character of the innate immune system makes it liable to activation by stress factors other than infection. Thermal and metabolic stresses experienced during the transplantation procedure are sufficient to trigger the innate immune response and also augment adaptive immunity in the presence of foreign antigen on the donor organ. The resulting inflammatory and immune reactions combine to form a potent effector response that can lead to graft rejection. Here we examine the evidence that the complement and toll-like receptor systems are central to these pathways of injury and present a formidable barrier to transplantation. We review extensive information about the effector mechanisms that are mediated by these pathways, and bring together what is known about the damage-associated molecular patterns that initiate this sequence of events. Finally, we refer to two ongoing therapeutic trials that are evaluating the validity of these concepts in man.

  17. Humoral innate immune response and disease

    PubMed Central

    Shishido, Stephanie N.; Varahan, Sriram; Yuan, Kai; Li, Xiangdong; Fleming, Sherry D.

    2012-01-01

    The humoral innate immune response consists of multiple components, including the naturally occurring antibodies (NAb), pentraxins and the complement and contact cascades. As soluble, plasma components, these innate proteins provide key elements in the prevention and control of disease. However, pathogens and cells with altered self proteins utilize multiple humoral components to evade destruction and promote pathogy. Many studies have examined the relationship between humoral immunity and autoimmune disorders. This review focuses on the interactions between the humoral components and their role in promoting the pathogenesis of bacterial and viral infections and chronic diseases such as atherosclerosis and cancer. Understanding the beneficial and detrimental aspects of the individual components and the interactions between proteins which regulate the innate and adaptive response will provide therapeutic targets for subsequent studies. PMID:22771788

  18. Trained immunity: A smart way to enhance innate immune defence.

    PubMed

    van der Meer, Jos W M; Joosten, Leo A B; Riksen, Niels; Netea, Mihai G

    2015-11-01

    The innate arm of the immune system is generally viewed as primitive and non-specific and - in contrast to the adaptive immune arm - not to possess memory. However in plants and invertebrate animals that lack adaptive immunity, innate immunity will exhibit a prolonged enhanced functional state after adequate priming. A similar enhancement of function of the innate immunity has occasionally been described in vertebrates, including humans. Over the past few years we have studied this phenomenon in greater detail and we have coined the term 'Trained (innate) immunity' (TI). TI can be induced by a variety of stimuli, of which we have studied BCG and β-glucan in greater detail. The non-specific protective effects of BCG that have been observed in vaccination studies in the literature are probably due to TI. Monocytes and macrophages are among the main cells of the innate immune arm that can be trained. We have discovered that both BCG (via NOD2 signalling) and β-glucan (via dectin-1) induce epigenetic reprogramming, in particular stable changes in histone trimethylation at H3K4. These epigenetic changes lead to cellular activation, enhanced cytokine production and a change in the metabolic state of the cell with a shift from oxidative phosphorylation to aerobic glycolysis. TI is not only important for host defence and vaccine responses, but most probably also for diseases like atherosclerosis. Modulation of TI is a promising area for new treatments.

  19. Transflammation: Innate Immune Signaling in Nuclear Reprogramming.

    PubMed

    Meng, Shu; Chanda, Palas; Thandavarayan, Rajarajan A; Cooke, John P

    2017-09-12

    Induction of pluripotency in somatic cells by retroviral overexpression of four transcription factors has revolutionized the field of stem cell biology and regenerative medicine. The efficient induction of pluripotency requires the activation of innate immune signaling in a process termed "transflammation" [1]. Specifically, the stimulation of pattern recognition receptors (PRRs) causes global alterations in the expression and activity of epigenetic modifiers to favor an open chromatin configuration. Activation of toll-like receptors (TLR) or RIG-1-like receptors (RLR) [2] trigger signaling cascades that result in NFκB or IRF-3 mediated changes in epigenetic plasticity that facilitate reprogramming. Another form of nuclear reprogramming is so-called direct reprogramming or transdifferentiation of one somatic cell to another lineage. We have shown that transdifferentiation of human fibroblasts to endothelial cells also involves transflammation [3]. Recently, we also identified reactive oxygen species (ROS) [4] and reactive nitrogen species (RNS) [5] as mediators of innate immune signaling in nuclear reprogramming. Innate immune signaling plays a key role in nuclear reprogramming by regulating DNA accessibility (Figure 1). Here, we review recent progress of innate immunity signaling in nuclear reprogramming and epigenetic plasticity. Copyright © 2017. Published by Elsevier B.V.

  20. Endocannabinoid signalling in innate and adaptive immunity

    PubMed Central

    Chiurchiù, Valerio; Battistini, Luca; Maccarrone, Mauro

    2015-01-01

    The immune system can be modulated and regulated not only by foreign antigens but also by other humoral factors and metabolic products, which are able to affect several quantitative and qualitative aspects of immunity. Among these, endocannabinoids are a group of bioactive lipids that might serve as secondary modulators, which when mobilized coincident with or shortly after first-line immune modulators, increase or decrease many immune functions. Most immune cells express these bioactive lipids, together with their set of receptors and of enzymes regulating their synthesis and degradation. In this review, a synopsis of the manifold immunomodulatory effects of endocannabinoids and their signalling in the different cell populations of innate and adaptive immunity is appointed, with a particular distinction between mice and human immune system compartments. PMID:25585882

  1. The Innate Immune Response Against Staphylococcus aureus.

    PubMed

    Bekeredjian-Ding, Isabelle; Stein, Christoph; Uebele, Julia

    2015-12-15

    The innate immune system harbors a multitude of different receptor systems and cells that are constantly prepared to sense and eliminate invading microbial pathogens. Staphylococcus aureus enters the body on its exposed epithelial surfaces, e.g., on skin and mucosa. The initial interaction with epithelial cells is governed by Toll-like receptor (TLR)-2-mediated local production of soluble mediators, including cytokines, chemokines, and antimicrobial peptides. The overall goal is to achieve a steady state of immune mediators and colonizing bacteria. Following cell and tissue invasion clearance of bacteria depends on intracellular microbial sensors and subsequent activation of the inflammasomes. Tissue-resident mast cells and macrophages recruit neutrophils, macrophages, and NK cells. This inflammatory response supports the generation of IL-17 producing NKT, γδ T cells, and T helper cells. Local dendritic cells migrate to the lymph nodes and fine-tune the adaptive immune response. The scope of this chapter is to provide an overview on the major cell types and receptors involved in innate immune defense against S. aureus. By segregating the different stages of infection from epithelial barrier to intracellular and systemic infection, this chapter highlights the different qualities of the innate immune response to S. aureus at different stages of invasiveness.

  2. CNS Remyelination and the Innate Immune System

    PubMed Central

    McMurran, Christopher E.; Jones, Clare A.; Fitzgerald, Denise C.; Franklin, Robin J. M.

    2016-01-01

    A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune–mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease. PMID:27200350

  3. Innate and Adaptive Immunity in Atherosclerosis

    PubMed Central

    Packard, René R. S.; Lichtman, Andrew H.; Libby, Peter

    2010-01-01

    Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk, and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis. PMID:19449008

  4. In this issue: autoimmunity and innate immunity.

    PubMed

    Bot, Adrian

    2014-01-01

    In this issue of the journal, we host a range of topics relevant to innate immunity as well as certain inflammatory diseases. More specifically, Sanz et al. cover a tantalizing form of death called pyroptosis that leads to inflammation. Samasca et al. provide a brief perspective on celiac disease. Singh and collaborators discuss in detail a newly designed leptin antagonist that could be applicable to colitis treatment. Through a meta-analysis, Wen et al. show that IL-18 gene polymorphism is associated with RA and SLE. Adenovirus-triggered innate immunity is discussed by Chen and Lee. Further, Zheng et al. provide a review of lectin receptors and their importance to anti-microbial immunity. Finally, Rojas et al. discuss tantalizing evidence supporting the fact that endogenous danger motifs such as advanced glycation end products are recognized via a TLR-like molecule and signaling pathway.

  5. Innate immunity modulation in virus entry.

    PubMed

    Faure, Mathias; Rabourdin-Combe, Chantal

    2011-07-01

    Entry into a cell submits viruses to detection by pattern recognition receptors (PRRs) leading to an early innate anti-viral response. Several viruses evolved strategies to avoid or subvert PRR recognition at the step of virus entry to promote infection. Whereas viruses mostly escape from soluble PRR detection, endocytic/phagocytic PRRs, such as the mannose receptor or DC-SIGN, are commonly used for virus entry. Moreover, virion-incorporated proteins may also offer viruses a way to dampen anti-viral innate immunity upon virus entry, and entering viruses might usurp autophagy to improve their own infectivity. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Deconstructing innate immune signaling in Myelodysplastic Syndromes

    PubMed Central

    Varney, Melinda E.; Melgar, Katelyn; Starczynowski, Daniel T.

    2015-01-01

    Overexpression of immune-related genes is widely reported in Myelodysplastic syndromes (MDS), and chronic immune stimulation increases the risk for developing MDS. Aberrant innate immune activation, such as due to increased Toll-like receptor (TLR) signaling, in MDS can contribute to systemic effects on hematopoiesis in addition to cell-intrinsic defects on hematopoietic stem/progenitor cell (HSPC) function. This review will deconstruct aberrant function of TLR signaling mediators within MDS HSPC that may contribute to cell intrinsic consequences on hematopoiesis and disease pathogenesis. We will discuss the contribution of chronic TLR signaling to the pathogenesis of MDS based on evidence from patients and mouse genetic models. PMID:26143580

  7. Roles of Toll-like receptors in innate immune responses.

    PubMed

    Takeda, K; Akira, S

    2001-09-01

    Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.

  8. Ubiquitin in Influenza Virus Entry and Innate Immunity

    PubMed Central

    Rudnicka, Alina; Yamauchi, Yohei

    2016-01-01

    Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular immunity. The role of ubiquitin is to regulate fundamental cellular processes such as endocytosis, protein degradation, and immune signaling. Many viruses including influenza A virus (IAV) usurp ubiquitination and ubiquitin-like modifications to establish infection. In this focused review, we discuss how ubiquitin and unanchored ubiquitin regulate IAV host cell entry, and how histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase with ubiquitin-binding activity, mediates IAV capsid uncoating. We also discuss the roles of ubiquitin in innate immunity and its implications in the IAV life cycle. PMID:27783058

  9. INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.

    PubMed

    Gaudet, Ryan G; Sintsova, Anna; Buckwalter, Carolyn M; Leung, Nelly; Cochrane, Alan; Li, Jianjun; Cox, Andrew D; Moffat, Jason; Gray-Owen, Scott D

    2015-06-12

    Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells. Detection of HBP within the host cytosol activated the nuclear facto κB pathway in vitro and induced innate and adaptive immune responses in vivo. Moreover, we used a genome-wide RNA interference screen to uncover an innate immune signaling axis, mediated by phosphorylation-dependent oligomerization of the TRAF-interacting protein with forkhead-associated domain (TIFA) that is triggered by HBP. Thus, HBP is a PAMP that activates TIFA-dependent immunity to Gram-negative bacteria.

  10. Pathogen recognition by innate immunity and its signaling

    PubMed Central

    Akira, Shizuo

    2009-01-01

    Mammalian immune response can be divided into innate and acquired immunity. Furthermore, much evidence has demonstrated that activation of innate immunity is a prerequisite to induction of acquired immunity. This paradigm shift has changed our thinking on the pathogenesis and treatment of infections, immune diseases, allergy, and cancers. PMID:19367086

  11. Prion Disease and the Innate Immune System

    PubMed Central

    Bradford, Barry M.; Mabbott, Neil A.

    2012-01-01

    Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis. PMID:23342365

  12. Innate immunity in alcoholic liver disease

    PubMed Central

    Seki, Ekihiro; Brenner, David A.; Friedman, Scott; Cohen, Jessica I.; Nagy, Laura; Szabo, Gyongyi; Zakhari, Samir

    2011-01-01

    Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease. PMID:21252049

  13. Innate immune responses to hepatitis C virus.

    PubMed

    Schoggins, John W; Rice, Charles M

    2013-01-01

    The innate immune response provides the first line of defense against invading viral pathogens. Incoming viruses are sensed by dedicated host factors that, when triggered, initiate multiple signal transduction pathways. Activation of these pathways leads to the induction of highly orchestrated transcriptional programs designed to limit virus replication and spread. In recent years, our understanding of innate immune responses targeting hepatitis C virus (HCV) has increased substantially, largely due to the development of new systems and methodologies to study HCV-host interactions in vitro and in vivo. However, significant gaps still remain. Here, we aim to provide a comprehensive view of the innate immune response to HCV, focusing primarily on knowledge gained from cell culture models of HCV infection, as well as data from human patients infected with HCV. While some paradigms of the host response to HCV revealed in cell culture translate to human infection in vivo, others are less clear. Further insight into the similarities and differences in these systems will not only reveal directions for future studies on HCV immunity, but may also guide the development of novel strategies to control HCV and other viral infections.

  14. Innate immunity of the ocular surface.

    PubMed

    Ueta, Mayumi; Kinoshita, Shigeru

    2010-02-15

    The ocular surface epithelium serves a critical function as the defensive front line of the innate immune system. While the detection of microbes is arguably its most important task, an exaggerated host defense reaction to endogenous bacterial flora may initiate and perpetuate inflammatory mucosal responses. The ability of cells to recognize pathogen-associated molecular patterns (PAMPs) mainly depends on the expression of a family of Toll-like receptors (TLRs). A healthy ocular surface is not inflammatory, even though ocular surface epithelium is in constant contact with bacteria and bacterial products. In this study, we show that human ocular surface epithelial cells, both corneal and conjuctival epithelial cells, respond to viral double-stranded RNA mimic polyI:C to produce pro-inflammatory cytokines through TLR3, while they fail to respond functionally to lipopolysaccharide, a TLR4 ligand. Moreover, human ocular surface epithelium responds to flagellins from ocular pathogenic, but not ocular non-pathogenic bacteria, to produce pro-inflammatory cytokines through TLR5. Thus, ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation; immune-competent cells can recognize microbial components through TLRs and induce the inflammation. The unique innate immune response of the ocular surface epithelium may contribute to its coexistence with commensal bacteria. Inflammatory bowel disease is thought to result from an abnormal response to the gut microbiota. Thus, we also considered the possibility of an association between ocular surface inflammation and a disordered innate immune response. IkappaBzeta is important for TLR signaling, in mice, its knock-out produced severe, spontaneous ocular surface inflammation, the eventual loss of goblet cells, and spontaneous perioral inflammation, suggesting that dysfunction/abnormality of innate immunity can lead to ocular surface inflammation. Copyright 2009 Elsevier Inc. All

  15. Natural innate and adaptive immunity to cancer.

    PubMed

    Vesely, Matthew D; Kershaw, Michael H; Schreiber, Robert D; Smyth, Mark J

    2011-01-01

    The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.

  16. Immunotherapy for cancer: promoting innate immunity.

    PubMed

    Lotfi, Ramin; Schrezenmeier, Hubert; Lotze, Michael Thomas

    2009-01-01

    Development of tumor over many years leads to reciprocal alterations in the host immune response and the tumor, enabling tumor growth seemingly paradoxically in the setting of necrosis and inflammation. Innate immune cells, granulocytes - neutrophils, eosinophils, basophils - and mast cells belong to the first line of defense sensing pathogen and damage associated molecular pattern (PAMPs, DAMPs) signals, initiating and modulating the subsequent inflammatory response. Nontheless, the prevailing contemporary strategies of immunotherapy for cancer have focused on the second line of the immune response, the adaptive immune response. We have determined that most highly evolved tumors in adults undergo necrosis, releasing DAMPs, promoting reactive angiogenesis, stromagenesis and reparative epithelial proliferation of the tumor cell. Means to aerobically eliminate such DAMPs by peroxidases released by innate immune effectors allows us to consider novel strategies for limiting tumor progression. Summarized here is our current understanding of acute and chronic inflammation and its impact on tumor development, the pathophysiology of immunity in cancer, and the influence of granulocytes and mast cells in this setting.

  17. Oral innate immunity in HIV infection in HAART era.

    PubMed

    Nittayananta, Wipawee; Tao, Renchuan; Jiang, Lanlan; Peng, Yuanyuan; Huang, Yuxiao

    2016-01-01

    Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces not only provide a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection, contributed to a global reduction of HIV-associated oral lesions. However, prolonged use of HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: (i) What are the roles of oral innate immunity in health and disease?, (ii) What are the effects of HIV infection on oral innate immunity?, (iii) What are the roles of oral innate immunity against other co-infections?, (iv) What are the effects of HAART on oral innate immunity?, and (v) Is oral innate immunity enhanced by HAART?

  18. Transcriptional analysis of the innate immune response using the avian innate immunity microarray

    USDA-ARS?s Scientific Manuscript database

    The avian innate immunity microarray (AIIM) is a genomics tool designed to study the transcriptional activity of the avian immune response (Cytogenet. Genome Res. 117:139-145, 2007). It is an avian cDNA microarray representing 4,959 avian genes spotted in triplicate. The AIIM contains 25 avian int...

  19. Innate Immunity Dysregulation in Myelodysplastic Syndromes

    DTIC Science & Technology

    2015-12-01

    Fernandez, Hagop M. Kantarjian, and Guillermo Garcia-Manero. American Society of Hematology (ASH) Annual Meeting, Nov 2012, Atlanta 2. Targeting...Garcia- Manero. 2012 National conference of Hematologic Malignancies, Oct 2012, Houston Poster Presentations: 1. Serum Amyloid Protein A 1 (hSAA1) Is...Guillermo Garcia-Manero. American Society of Hematology (ASH) Annual Meeting, Nov 2012, Atlanta 2. Deregulation of TLR2-JMJD3 Innate Immunity Signaling

  20. Innate Immunity Dysregulation in Myelodysplastic Syndromes

    DTIC Science & Technology

    2014-10-01

    Expression of Toll-40 like receptor 9 in bone marrow cells of myelodysplastic syndromes is down -regulated during 41 transformation to overt...Myelodysplastic Syndromes PRINCIPAL INVESTIGATOR: Yue Wei CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston TX...30 Sept 2013 – 29 Sept 2014 4. TITLE AND SUBTITLE “Innate Immunity Dysregulation in Myelodysplastic Syndromes ” 5a. CONTRACT NUMBER 5b

  1. Rosetta Stone of NLR Innate Immunity.

    PubMed

    Lechtenberg, Bernhard C; Riedl, Stefan J

    2016-01-01

    The formation of NLR inflammasomes is a central step in the initiation of the innate immune response. Two recent publications describe the structure of the NAIP2-NLRC4 inflammasome and derive an elegant model of NLR inflammasome formation, whereby binding of the pathogen-molecule-bound NLR NAIP2 to NLRC4 leads to the activation of NLRC4 and initiation of self-propagating NLRC4 inflammasome formation.

  2. Innate Immune Response to Burkholderia mallei

    DTIC Science & Technology

    2017-02-16

    infections. Lipopolysaccharide (LPS) is a major component of the outer membrane of gram- negative bacteria , and a potent stimulator of host innate...relapse or reinfection. Bacteria can become quiescent and subclinical to avoid host immune mechanisms of clearance. An earlier report indicated that non...autophagy correlate with intracellular persistence of bacteria with aerosol exposure not only of B. pseudomallei but also B. mallei in spleens of TR-17-034

  3. Diabetic complications and dysregulated innate immunity

    PubMed Central

    Graves, Dana T; Kayal, Rayyan A

    2011-01-01

    Diabetes mellitus is a metabolic disorder that leads to the development of a number of complications. The etiology of each diabetic complication is undoubtedly multifactorial. We will focus on one potential component that may be common in many diabetic complications, dysregulation of innate immunity associated with an increased inflammatory response. High glucose levels lead to shunting through the polyol pathway, an increase in diacylglycerol which activates protein kinase C, an increase in the release of electrons that react with oxygen molecules to form superoxides, and the non-enzymatic glycosylation of proteins that result in greater formation of advanced glycation end products. Each of these can lead to aberrant cell signalling that affects innate immunity for example, by activating the MAP kinase pathway or inducing activation of transcription factors such as NF-kappaB. This may be a common feature of several complications including periodontal disease, atherosclerosis, nephropathy, impaired healing and retinopathy. These complications are frequently associated with increased expression of inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 and enhanced generation of reactive oxygen species. Cause and effect relationship between dysregulation of key components of innate immunity and diabetic complications in many instances have been demonstrated with the use of cytokine blockers and antioxidants. PMID:17981625

  4. Heme on innate immunity and inflammation

    PubMed Central

    Dutra, Fabianno F.; Bozza, Marcelo T.

    2014-01-01

    Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases. PMID:24904418

  5. Innate Lymphoid Cells in Tumor Immunity

    PubMed Central

    van Beek, Jasper J. P.; Martens, Anne W. J.; Bakdash, Ghaith; de Vries, I. Jolanda M.

    2016-01-01

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring. PMID:28536374

  6. Innate Lymphoid Cells in Tumor Immunity.

    PubMed

    van Beek, Jasper J P; Martens, Anne W J; Bakdash, Ghaith; de Vries, I Jolanda M

    2016-02-25

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.

  7. Systems-Level Analysis of Innate Immunity

    PubMed Central

    Zak, Daniel E.; Tam, Vincent C.; Aderem, Alan

    2014-01-01

    Systems-level analysis of biological processes strives to comprehensively and quantitatively evaluate the interactions between the relevant molecular components over time, thereby enabling development of models that can be employed to ultimately predict behavior. Rapid development in measurement technologies (omics), when combined with the accessible nature of the cellular constituents themselves, is allowing the field of innate immunity to take significant strides toward this lofty goal. In this review, we survey exciting results derived from systems biology analyses of the immune system, ranging from gene regulatory networks to influenza pathogenesis and systems vaccinology. PMID:24655298

  8. Hepatitis C and Innate Immunity – Recent Advances

    PubMed Central

    Szabo, Gyongyi; Dolganiuc, Angela

    2008-01-01

    Eradication of HCV infection requires a complex and coordinated interplay between innate and adaptive immune responses that, when it fails, leads to chronic infection. Increasing evidence suggest that defects in innate immune recognition and in innate immunity-induced activation of adaptive immune responses play a critical role in failure of HCV clearance. The evolutionarily preserved receptors of viral recognition in immune cells and in hepatocytes sense invading pathogens that results in induction of Type I IFNs, the central players in antiviral immunity. In this review the innate immune mechanisms by which HCV is sensed and by which HCV undermines host defense are discussed. The critical role of dendritic cells in antigen presentation/T cell activation and IFNα-production as well as interference of HCV with innate immune cell functions are reviewed. Finally, current and emerging therapeutic approaches targeting innate immune pathways will be evaluated. PMID:18625434

  9. Innate Immune Responses to AAV Vectors.

    PubMed

    Rogers, Geoffrey L; Martino, Ashley T; Aslanidi, George V; Jayandharan, Giridhara R; Srivastava, Arun; Herzog, Roland W

    2011-01-01

    Gene replacement therapy by in vivo delivery of adeno-associated virus (AAV) is attractive as a potential treatment for a variety of genetic disorders. However, while AAV has been used successfully in many models, other experiments in clinical trials and in animal models have been hampered by undesired responses from the immune system. Recent studies of AAV immunology have focused on the elimination of transgene-expressing cells by the adaptive immune system, yet the innate immune system also has a critical role, both in the initial response to the vector and in prompting a deleterious adaptive immune response. Responses to AAV vectors are primarily mediated by the TLR9-MyD88 pathway, which induces the production of pro-inflammatory cytokines by activating the NF-κB pathways and inducing type I IFN production; self-complementary AAV vectors enhance these inflammatory processes. Additionally, the alternative NF-κB pathway influences transgene expression in cells transduced by AAV. This review highlights these recent discoveries regarding innate immune responses to AAV and discusses strategies to ablate these potentially detrimental signaling pathways.

  10. The innate and adaptive immune response to avian influenza virus

    USDA-ARS?s Scientific Manuscript database

    Protective immunity against viruses is mediated by the early innate immune responses and later on by the adaptive immune responses. The early innate immunity is designed to contain and limit virus replication in the host, primarily through cytokine and interferon production. Most all cells are cap...

  11. The innate immune system of the perinatal lung and responses to respiratory syncytial virus infection.

    PubMed

    Derscheid, R J; Ackermann, M R

    2013-09-01

    The response of the preterm and newborn lung to airborne pathogens, particles, and other insults is initially dependent on innate immune responses since adaptive responses may not fully mature and require weeks for sufficient responses to antigenic stimuli. Foreign material and microbial agents trigger soluble, cell surface, and cytoplasmic receptors that activate signaling cascades that invoke release of surfactant proteins, defensins, interferons, lactoferrin, oxidative products, and other innate immune substances that have antimicrobial activity, which can also influence adaptive responses. For viral infections such as respiratory syncytial virus (RSV), the pulmonary innate immune responses has an essential role in defense as there are no fully effective vaccines or therapies for RSV infections of humans and reinfections are common. Understanding the innate immune response by the preterm and newborn lung may lead to preventive strategies and more effective therapeutic regimens.

  12. [The role of the innate immune system in atopic dermatitis].

    PubMed

    Volz, T; Kaesler, S; Skabytska, Y; Biedermann, T

    2015-02-01

    The mechanisms how the innate immune system detects microbes and mounts a rapid immune response have been more and more elucidated in the past years. Subsequently it has been shown that innate immunity also shapes adaptive immune responses and determines their quality that can be either inflammatory or tolerogenic. As atopic dermatitis is characterized by disturbances of innate and adaptive immune responses, colonization with pathogens and defects in skin barrier function, insight into mechanisms of innate immunity has helped to understand the vicious circle of ongoing skin inflammation seen in atopic dermatitis patients. Elucidating general mechanisms of the innate immune system and its functions in atopic dermatitis paves the way for developing new therapies. Especially the novel insights into the human microbiome and potential functional consequences make the innate immune system a very fundamental and promising target. As a result atopic dermatitis manifestations can be attenuated or even resolved. These currently developed strategies will be introduced in the current review.

  13. Role of innate immunity in neonatal infection.

    PubMed

    Cuenca, Alex G; Wynn, James L; Moldawer, Lyle L; Levy, Ofer

    2013-02-01

    Newborns are at increased risk of infection due to genetic, epigenetic, and environmental factors. Herein we examine the roles of the neonatal innate immune system in host defense against bacterial and viral infections. Full-term newborns express a distinct innate immune system biased toward T(H)2-/T(H)17-polarizing and anti-inflammatory cytokine production with relative impairment in T(H)1-polarizing cytokine production that leaves them particularly vulnerable to infection with intracellular pathogens. In addition to these distinct features, preterm newborns also have fragile skin, impaired T(H)17-polarizing cytokine production, and deficient expression of complement and of antimicrobial proteins and peptides (APPs) that likely contribute to susceptibility to pyogenic bacteria. Ongoing research is identifying APPs, including bacterial/permeability-increasing protein and lactoferrin, as well as pattern recognition receptor agonists that may serve to enhance protective newborn and infant immune responses as stand-alone immune response modifiers or vaccine adjuvants. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  14. Fish innate immunity against intestinal helminths.

    PubMed

    Dezfuli, B S; Bosi, G; DePasquale, J A; Manera, M; Giari, L

    2016-03-01

    Most individual fish in farmed and wild populations are infected with parasites. Upon dissection of fish, helminths from gut are often easily visible. Enteric helminths include several species of digeneans, cestodes, acanthocephalans and nematodes. Some insights into biology, morphology and histopathological effects of the main fish enteric helminths taxa will be described here. The immune system of fish, as that of other vertebrates, can be subdivided into specific and aspecific types, which in vivo act in concert with each other and indeed are interdependent in many ways. Beyond the small number of well-described models that exist, research focusing on innate immunity in fish against parasitic infections is lacking. Enteric helminths frequently cause inflammation of the digestive tract, resulting in a series of chemical and morphological changes in the affected tissues and inducing leukocyte migration to the site of infection. This review provides an overview on the aspecific defence mechanisms of fish intestine against helminths. Emphasis will be placed on the immune cellular response involving mast cells, neutrophils, macrophages, rodlet cells and mucous cells against enteric helminths. Given the relative importance of innate immunity in fish, and the magnitude of economic loss in aquaculture as a consequence of disease, this area deserves considerable attention and support. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Natural antibodies bridge innate and adaptive immunity.

    PubMed

    Panda, Saswati; Ding, Jeak L

    2015-01-01

    Natural Abs, belonging to isotypes IgM, IgG3, and IgA, were discovered nearly half a century ago. Despite knowledge about the role of the polyreactive natural IgM in pathogen elimination, B cell survival and homeostasis, inflammatory diseases, and autoimmunity, there is a lack of clarity about the physiological role of natural IgG and natural IgA because they appear incapable of recognizing Ags on their own and are perceived as nonreactive. However, recent research revealed exciting functions of natural IgG in innate immunity. Natural IgG:lectin collaboration swiftly and effectively kills invading pathogens. These advances prompt further examination of natural Abs in immune defense and homeostasis, with the potential for developing novel therapeutics. This review provides new insights into the interaction between natural Abs and lectins, with implications on how interactions between molecules of the innate and adaptive immune systems bridge these two arms of immunity. Copyright © 2014 by The American Association of Immunologists, Inc.

  16. Innate immune dysfunction in inflammatory bowel disease.

    PubMed

    Gersemann, M; Wehkamp, J; Stange, E F

    2012-05-01

    The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.

  17. Innate immunity and primary biliary cirrhosis.

    PubMed

    Selmi, Carlo; Lleo, Ana; Pasini, Simone; Zuin, Massimo; Gershwin, M Eric

    2009-02-01

    There has been a rapid growth in our understanding of the molecular bases of primary biliary cirrhosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mechanisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts. Most recently, there have been experimental data suggesting that innate immunity changes may be critical to the initiation and perpetuation of the autoimmune injury, as in the case of the enhanced response of monocytes and memory B cells to infectious stimulation and environmental mimics. These observations are important as they help fill in the many gaps which remain on the most difficult subject of autoimmunity, etiology. Indeed, based on the available data, several experimental models of PBC have been developed. These models illustrate and suggest that PBC can be initiated by several mechanisms, all of which lead to loss of tolerance to the mitochondrial antigens. However, once this adaptive response develops, it appears that much of the subsequent pathology is exacerbated by innate responses. We suggest that future therapeutic efforts in PBC will depend heavily on understanding the nature of this innate immune responses and methodology to blunt their cytotoxicity.

  18. Acquired and innate immunity to polyaromatic hydrocarbons

    SciTech Connect

    Yusuf, Nabiha Timares, Laura; Seibert, Megan D.; Xu Hui; Elmets, Craig A.

    2007-11-01

    Polyaromatic hydrocarbons are ubiquitous environmental pollutants that are potent mutagens and carcinogens. Researchers have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. When applied to the skin of mice, several carcinogenic polyaromatic hydrocarbons have also been shown to interact with the immune system, stimulating immune responses and resulting in the development of antigen-specific T-cell-mediated immunity. Development of cell-mediated immunity is strain-specific and is governed by Ah receptor genes and by genes located within the major histocompatibility complex. CD8{sup +} T cells are effector cells in the response, whereas CD4{sup +} T cells down-regulate immunity. Development of an immune response appears to have a protective effect since strains of mice that develop a cell-mediated immune response to carcinogenic polyaromatic hydrocarbons are less likely to develop tumors when subjected to a polyaromatic hydrocarbon skin carcinogenesis protocol than mice that fail to develop an immune response. With respect to innate immunity, TLR4-deficient C3H/HeJ mice are more susceptible to polyaromatic hydrogen skin tumorigenesis than C3H/HeN mice in which TLR4 is normal. These findings support the hypothesis that immune responses, through their interactions with chemical carcinogens, play an active role in the prevention of chemical skin carcinogenesis during the earliest stages. Efforts to augment immune responses to the chemicals that cause tumors may be a productive approach to the prevention of tumors caused by these agents.

  19. Interactions between Innate Immunity, Microbiota, and Probiotics.

    PubMed

    Giorgetti, GianMarco; Brandimarte, Giovanni; Fabiocchi, Federica; Ricci, Salvatore; Flamini, Paolo; Sandri, Giancarlo; Trotta, Maria Cristina; Elisei, Walter; Penna, Antonio; Lecca, Piera Giuseppina; Picchio, Marcello; Tursi, Antonio

    2015-01-01

    The term "microbiota" means genetic inheritance associated with microbiota, which is about 100 times larger than the guest. The tolerance of the resident bacterial flora is an important key element of immune cell function. A key role in the interaction between the host and the microbiota is played by Paneth cell, which is able to synthesize and secrete proteins and antimicrobial peptides, such as α/β defensins, cathelicidin, 14 β-glycosidases, C-type lectins, and ribonuclease, in response to various stimuli. Recent studies found probiotics able to preserve intestinal homeostasis by downmodulating the immune response and inducing the development of T regulatory cells. Specific probiotic strain, as well as probiotic-driven metabolic products called "postbiotics," has been recently recognized and it is able to influence innate immunity. New therapeutic approaches based on probiotics are now available, and further treatments based on postbiotics will come in the future.

  20. Innate immunity in Drosophila: Pathogens and pathways.

    PubMed

    Govind, Shubha

    2008-02-01

    Following in the footsteps of traditional developmental genetics, research over the last 15 years has shown that innate immunity against bacteria and fungi is governed largely by two NF-kappaB signal transduction pathways, Toll and IMD. Antiviral immunity appears to stem from RNA interference, whereas resistance against parasitoids is conferred by Toll signaling. The identification of these post-transcriptional regulatory mechanisms and the annotation of most Drosophila immunity genes have derived from functional genomic studies using "model" pathogens, intact animals and cell lines. The D. melanogaster host has thus provided the core information that can be used to study responses to natural microbial and metazoan pathogens as they become identified, as well as to test ideas of selection and evolutionary change. These analyses are of general importance to understanding mechanisms of other insect host-pathogen interactions and determinants of variation in host resistance.

  1. Innate immunity in Drosophila: Pathogens and pathways

    PubMed Central

    Govind, Shubha

    2009-01-01

    Following in the footsteps of traditional developmental genetics, research over the last 15 years has shown that innate immunity against bacteria and fungi is governed largely by two NF-κB signal transduction pathways, Toll and IMD. Antiviral immunity appears to stem from RNA interference, whereas resistance against parasitoids is conferred by Toll signaling. The identification of these post-transcriptional regulatory mechanisms and the annotation of most Drosophila immunity genes have derived from functional genomic studies using “model” pathogens, intact animals and cell lines. The D. melanogaster host has thus provided the core information that can be used to study responses to natural microbial and metazoan pathogens as they become identified, as well as to test ideas of selection and evolutionary change. These analyses are of general importance to understanding mechanisms of other insect host–pathogen interactions and determinants of variation in host resistance. PMID:20485470

  2. Hantaan virus triggers TLR4-dependent innate immune responses.

    PubMed

    Yu, Hai-Tao; Jiang, Hong; Zhang, Ye; Nan, Xue-Ping; Li, Yu; Wang, Wei; Jiang, Wei; Yang, Dong-Qiang; Su, Wen-Jing; Wang, Jiu-Ping; Wang, Ping-Zhong; Bai, Xue-Fan

    2012-10-01

    The innate immune response induced by Hantavirus is responsible for endothelial cell dysfunction and viral pathogenicity. Recent studies demonstrate that TLR4 expression is upregulated and mediates the secretion of several cytokines in Hantaan virus (HTNV)-infected endothelial cells. To examine viral interactions with host endothelial cells and characterize the innate antiviral responses associated with Toll-like receptors, we selected TLR4 as the target molecule to investigate anti-hantavirus immunity. TLR4 mRNA-silenced EVC-304 (EVC-304 TLR4-) cells and EVC-304 cells were used to investigate signaling molecules downstream of TLR4. The expression of the adaptor protein TRIF was higher in HTNV-infected EVC-304 cells than in EVC-304 TLR4- cells. However, there was no apparent difference in the expression of MyD88 in either cell line. The transcription factors for NF-κB and IRF-3 were translocated from the cytoplasm into the nucleus in HTNV-infected EVC-304 cells, but not in HTNV-infected EVC-304 TLR4- cells. Our results demonstrate that TLR4 may play an important role in the antiviral immunity of the host against HTNV infection through an MyD88-independent signaling pathway.

  3. How the Innate Immune System Senses Trouble and Causes Trouble.

    PubMed

    Hato, Takashi; Dagher, Pierre C

    2015-08-07

    The innate immune system is the first line of defense in response to nonself and danger signals from microbial invasion or tissue injury. It is increasingly recognized that each organ uses unique sets of cells and molecules that orchestrate regional innate immunity. The cells that execute the task of innate immunity are many and consist of not only "professional" immune cells but also nonimmune cells, such as renal epithelial cells. Despite a high level of sophistication, deregulated innate immunity is common and contributes to a wide range of renal diseases, such as sepsis-induced kidney injury, GN, and allograft dysfunction. This review discusses how the innate immune system recognizes and responds to nonself and danger signals. In particular, the roles of renal epithelial cells that make them an integral part of the innate immune apparatus of the kidney are highlighted.

  4. OASL – a new player in controlling antiviral innate immunity

    PubMed Central

    Zhu, Jianzhong; Ghosh, Arundhati; Sarkar, Saumendra N.

    2015-01-01

    The cellular innate immune system plays a critical role in mounting the initial resistance to virus infection. It is comprised of various pattern-recognition receptors that induce type I interferon production, which further shapes the adaptive immunity. However, to overcome this resistance and promote replication, viruses have evolved mechanisms to evade this host innate immune response. Here we discuss a recently described mechanism of boosting the innate immunity by oligoadenylate synthetase-like (OASL) protein, which can potentially be used to overcome viral evasion and enhance innate immunity. PMID:25676874

  5. A Role for PML in Innate Immunity

    PubMed Central

    Lunardi, Andrea; Gaboli, Mirella; Giorgio, Marco; Rivi, Roberta; Bygrave, Anne; Antoniou, Michael; Drabek, Dubravka; Dzierzak, Elaine; Fagioli, Marta; Salmena, Leonardo; Botto, Marina; Cordon-Cardo, Carlos; Luzzatto, Lucio; Pelicci, Pier Giuseppe; Grosveld, Frank; Pandolfi, Pier Paolo

    2011-01-01

    The promyelocytic leukemia gene (PML) of acute promyelocytic leukemia is an established tumor suppressor gene with critical functions in growth suppression, induction of apoptosis, and cellular senescence. Interestingly, although less studied, PML seems to play a key role also in immune response to viral infection. Herein, we report that Pml −/− mice spontaneously develop an atypical invasive and lethal granulomatous lesion known as botryomycosis (BTM). In Pml −/− mice, BTM is the result of impaired function of macrophages, whereby they fail to become activated and are thus unable to clear pathogenic microorganisms. Accordingly, Pml −/− mice are resistant to lipopolysaccharide (LPS)–induced septic shock as a result of an ineffective production of cytokines and chemokines, suggesting a role for PML in the innate immune Toll-like receptor (TLR)/NF-κB prosurvival pathway. These results not only shed light on a new fundamental function of PML in innate immunity, but they also point to a proto-oncogenic role for PML in certain cellular and pathological contexts. PMID:21779477

  6. Pulmonary contusion primes systemic innate immunity responses.

    PubMed

    Hoth, J Jason; Martin, R S; Yoza, Barbara K; Wells, Jonathan D; Meredith, J W; McCall, Charles E

    2009-07-01

    Traumatic injury may result in an exaggerated response to subsequent immune stimuli such as nosocomial infection. This "second hit" phenomenon and molecular mechanism(s) of immune priming by traumatic lung injury, specifically, pulmonary contusion, remain unknown. We used an animal model of pulmonary contusion to determine whether the injury resulted in priming of the innate immune response and to test the hypothesis that resuscitation fluids could attenuate the primed response to a second hit. Male, 8 to 9 weeks, C57/BL6 mice with a pulmonary contusion were challenged by a second hit of intratracheal administration of the Toll-like receptor 4 agonist, lipopolysaccharide (LPS, 50 microg) 24 hours after injury (injury + LPS). Other experimental groups were injury + vehicle or LPS alone. A separate group was injured and resuscitated by 4 cc/kg of hypertonic saline (HTS) or Lactated Ringer's (LR) resuscitation before LPS challenge. Mice were killed 4 hours after LPS challenge and blood, bronchoalveolar lavage, and tissue were isolated and analyzed. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest for significant differences (*p < or = 0.05). Injury + LPS showed immune priming observed by lung injury histology and increased bronchoalveolar lavage neutrophilia, lung myeloperoxidase and serum IL-6, CXCL1, and MIP-2 levels when compared with injury + vehicle or LPS alone. After injury, resuscitation with HTS, but not Lactated Ringer's was more effective in attenuating the primed response to a second hit. Pulmonary contusion primes innate immunity for an exaggerated response to a second hit with the Toll-like receptor 4 agonist, LPS. We observed synergistic increases in inflammatory mediator expression in the blood and a more severe lung injury in injured animals challenged with LPS. This priming effect was reduced when HTS was used to resuscitate the animal after lung contusion.

  7. Pulmonary contusion primes systemic innate immunity responses

    PubMed Central

    Hoth, JJ; Martin, RS; Yoza, BK; Wells, JD; Meredith, JW; McCall, CE

    2010-01-01

    Introduction Traumatic injury may result in an exaggerated response to subsequent immune stimuli such as nosocomial infection. This “second hit” phenomenon, and molecular mechanism(s) of immune priming by traumatic lung injury, specifically pulmonary contusion, remains unknown. We used an animal model of pulmonary contusion to determine if the injury resulted in priming of the innate immune response and to test the hypothesis that resuscitation fluids could attenuate the primed response to a second hit. Methods Male, 8-9 wk, C57/BL6 mice with a pulmonary contusion were challenged by a second hit of intratracheal administration of the Toll like receptor (TLR) 4 agonist, lipopolysaccharide (LPS, 50mcg) 24hrs after injury (injury+LPS). Other experimental groups were injury+vehicle or LPS alone. A separate group were injured and resuscitated by 4cc/kg of hypertonic saline (HTS) or Lactated Ringer's (LR) resuscitation prior to LPS challenge. Mice were euthanized 4hrs after LPS challenge and blood, bronchoalveolar lavage (BAL), and tissue were isolated and analyzed. Data were analyzed using one way ANOVA with Bonferroni multiple comparison post-test for significant differences (*, p≤0.05). Results Injury+LPS showed immune priming observed by lung injury histology and increased BAL neutrophilia, lung myeloperoxidase, and serum IL-6, CXCL1 and MIP-2 levels when compared to injury+vehicle or LPS alone. After injury, resuscitation with HTS, but not LR was more effective in attenuating the primed response to a second hit. Conclusion Pulmonary contusion primes innate immunity for an exaggerated response to a second hit with the TLR4 agonist, LPS. We observed synergistic increases in inflammatory mediator expression in the blood and a more severe lung injury in injured animals challenged with LPS. This priming effect was reduced when HTS was used to resuscitate the animal after lung contusion. PMID:19590302

  8. Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

    PubMed Central

    Navarro, Rocío; Compte, Marta; Álvarez-Vallina, Luis; Sanz, Laura

    2016-01-01

    Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on. PMID:27867386

  9. A prime time for trained immunity: innate immune memory in newborns and infants.

    PubMed

    Levy, Ofer; Wynn, James L

    2014-01-01

    The newborn and infant periods of early life are associated with heightened vulnerability to infection. Limited antigen exposure and distinct adaptive immune function compared to the adult places a greater burden on innate immunity for host defense to microbial challenge during this time. Trained immunity describes the phenomenon of augmented innate immune function following a stimulus that is not specific to the original stimulus. We review the concept of trained immunity in the context of the newborn's unique innate immune system function, the preclinical and clinical evidence that supports the tenet of innate immune memory in early life, and potential consequences of altered innate immune host responses. © 2013 S. Karger AG, Basel.

  10. Ocular Surface as Barrier of Innate Immunity

    PubMed Central

    Bolaños-Jiménez, Rodrigo; Navas, Alejandro; López-Lizárraga, Erika Paulina; de Ribot, Francesc March; Peña, Alexandra; Graue-Hernández, Enrique O; Garfias, Yonathan

    2015-01-01

    Sight is one of the most important senses that human beings possess. The ocular system is a complex structure equipped with mechanisms that prevent or limit damage caused by physical, chemical, infectious and environmental factors. These mechanisms include a series of anatomical, cellular and humoral factors that have been a matter of study. The cornea is not only the most powerful and important lens of the optical system, but also, it has been involved in many other physiological and pathological processes apart from its refractive nature; the morphological and histological properties of the cornea have been thoroughly studied for the last fifty years; drawing attention in its molecular characteristics of immune response. This paper will review the anatomical and physiological aspects of the cornea, conjunctiva and lacrimal apparatus, as well as the innate immunity at the ocular surface. PMID:26161163

  11. Ocular Surface as Barrier of Innate Immunity.

    PubMed

    Bolaños-Jiménez, Rodrigo; Navas, Alejandro; López-Lizárraga, Erika Paulina; de Ribot, Francesc March; Peña, Alexandra; Graue-Hernández, Enrique O; Garfias, Yonathan

    2015-01-01

    Sight is one of the most important senses that human beings possess. The ocular system is a complex structure equipped with mechanisms that prevent or limit damage caused by physical, chemical, infectious and environmental factors. These mechanisms include a series of anatomical, cellular and humoral factors that have been a matter of study. The cornea is not only the most powerful and important lens of the optical system, but also, it has been involved in many other physiological and pathological processes apart from its refractive nature; the morphological and histological properties of the cornea have been thoroughly studied for the last fifty years; drawing attention in its molecular characteristics of immune response. This paper will review the anatomical and physiological aspects of the cornea, conjunctiva and lacrimal apparatus, as well as the innate immunity at the ocular surface.

  12. Innate and acquired bacteriophage-mediated immunity

    PubMed Central

    Barr, Jeremy J.; Youle, Merry; Rohwer, Forest

    2013-01-01

    We recently described a novel, non-host-derived, phage-mediated immunity active at mucosal surfaces, the main site of pathogen entry in metazoans. In that work, we showed that phage T4 adheres to mucus glycoproteins via immunoglobulin-like domains displayed on its capsid. This adherence positions the phage in mucus surfaces where they are more likely to encounter and kill bacteria, thereby benefiting both the phage and its metazoan host. We presented this phage-metazoan symbiosis based on an exclusively lytic model of phage infection. Here we extend our bacteriophage adherence to mucus (BAM) model to consider the undoubtedly more complex dynamics in vivo. We hypothesize how mucus-adherent phages, both lytic and temperate, might impact the commensal microbiota as well as protect the metazoan epithelium from bacterial invasion. We suggest that BAM may provide both an innate and an acquired antimicrobial immunity. PMID:24228227

  13. Innate immunity in resistance to HIV infection.

    PubMed

    Biasin, Mara; Clerici, Mario; Piacentini, Luca

    2010-11-01

    Resistance to human immunodeficiency virus (HIV) infection in subjects who do not seroconvert despite multiple exposures to the virus and to the progression to AIDS in HIV‐infected individuals depends on multiple factors involving both the innate and the adaptive immune system. The contribution of natural immunity in preventing HIV infection has so far received little attention, but many recently published articles suggest a key role for Toll‐like receptors, natural killer cells, interleukin‐22, acute‐phase amyloid A protein, and APOBEC3G in conferring resistance to HIV infection. The study of these factors will shed light on HIV pathogenesis and contribute to the development of new therapeutic approaches to this elusive disease.

  14. [Perinatal innate immune activation and neuropsychological development].

    PubMed

    Nagai, Taku

    2013-08-01

    Development of animal models is a crucial issue in biological psychiatry for the search of novel drug targets as well as the screening of candidate compounds. Epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. Recently, we have developed a novel mouse model of viral infection during the perinatal stage by injecting polyriboinosinic-polyribocytidilic acid (polyI:C) into neonatal mice. Neonatal treatment of mice with polyI:C, an inducer of innate immune responses via toll-like receptor 3, caused a significant increase in interferon-induced transmembrane protein 3 (IFITM3) levels in the astrocytes of the hippocampus, which resulted in long-lasting brain dysfunction, including cognitive and emotional impairments as well as a deficit in depolarization-evoked glutamate release in the hippocampus in adulthood. Neonatal polyI:C-induced neuronal impairments have not been observed in IFITM3-KO mice. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of neurodevelopment has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

  15. Innate immunity's path to the Nobel Prize 2011 and beyond.

    PubMed

    Wagner, Hermann

    2012-05-01

    The 2011 Nobel Prize in Physiology/Medicine to Ralph Steinmann, Jules Hoffmann, and Bruce Beutler recognized a paradigm shift in our understanding of innate immunity, and its impact on adaptive immunity. The Prize highlighted the initial discoveries of Toll's role in immunity in flies, Toll-like receptors in mammals, and the establishment of dendritic cells as the initiators of adaptive immunity. This historical Commentary focuses on the developments in our understanding of innate immunity.

  16. Dengue Virus Perturbs Mitochondrial Morphodynamics to Dampen Innate Immune Responses.

    PubMed

    Chatel-Chaix, Laurent; Cortese, Mirko; Romero-Brey, Inés; Bender, Silke; Neufeldt, Christopher John; Fischl, Wolfgang; Scaturro, Pietro; Schieber, Nicole; Schwab, Yannick; Fischer, Bernd; Ruggieri, Alessia; Bartenschlager, Ralf

    2016-09-14

    With no antiviral drugs or widely available vaccines, Dengue virus (DENV) constitutes a public health concern. DENV replicates at ER-derived cytoplasmic structures that include substructures called convoluted membranes (CMs); however, the purpose of these membrane alterations remains unclear. We determine that DENV nonstructural protein (NS)4B, a promising drug target with unknown function, associates with mitochondrial proteins and alters mitochondria morphology to promote infection. During infection, NS4B induces elongation of mitochondria, which physically contact CMs. This restructuring compromises the integrity of mitochondria-associated membranes, sites of ER-mitochondria interface critical for innate immune signaling. The spatio-temporal parameters of CM biogenesis and mitochondria elongation are linked to loss of activation of the fission factor Dynamin-Related Protein-1. Mitochondria elongation promotes DENV replication and alleviates RIG-I-dependent activation of interferon responses. As Zika virus infection induces similar mitochondria elongation, this perturbation may protect DENV and related viruses from innate immunity and create a favorable replicative environment.

  17. Innate immune response development in nestling tree swallows

    USGS Publications Warehouse

    Stambaugh, T.; Houdek, B.J.; Lombardo, M.P.; Thorpe, P.A.; Caldwell, Hahn D.

    2011-01-01

    We tracked the development of innate immunity in nestling Tree Swallows (Tachycineta bicolor) and compared it to that of adults using blood drawn from nestlings during days 6, 12, and 18 of the ???20-day nestling period and from adults. Innate immunity was characterized using an in vitro assay of the ability of whole blood to kill Escherichia coli. The ability of whole blood to kill E. coli increased as nestlings matured. Neither this component of innate immunity nor right wing chord length on day18 were as developed as in adults indicating that development of the innate immune system and growth both continued after fledging. Narrow sense heritability analyses suggest that females with strong immune responses produced nestlings with strong immune responses. These data suggest nestling Tree Swallows allocated sufficient energy to support rapid growth to enable fledging by day 18, but that further development of innate immunity occurred post-fledging. ?? 2011 by the Wilson Ornithological Society.

  18. Oral innate immunity in HIV infection in HAART era

    PubMed Central

    Nittayananta, Wipawee; Tao, Renchuan; Jiang, Lanlan; Peng, Yuanyuan; Huang, Yuxiao

    2015-01-01

    Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces provide not only a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection contributed to a global reduction of HIV-associated oral lesions. However, prolonged treatment by HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: 1) What are the roles of oral innate immunity in health and disease?, 2) What are the effects of HIV infection on oral innate immunity?, 3) What are the roles of oral innate immunity against other co-infections?, 4) What are the effects of HAART on oral innate immunity?, and 5) Is oral innate immunity enhanced by HAART? PMID:25639844

  19. Alzheimer's disease: Innate immunity gone awry?

    PubMed

    VanItallie, Theodore B

    2017-01-11

    Inflammation is an immune activity designed to protect the host from pathogens and noxious agents. In its low-intensity form, presence of an inflammatory process must be inferred from appropriate biomarkers. Occult neuroinflammation is not just secondary to Alzheimer's disease (AD) but may contribute to its pathogenesis and promote its progression. A leaky blood-brain barrier (BBB) has been observed in early AD and may play a role in its initiation and development. Studies of the temporal evolution of AD's biomarkers have shown that, in AD, the brain's amyloid burden correlates poorly with cognitive decline. In contrast, cognitive deficits in AD correlate well with synapse loss. Oligomeric forms of amyloid-beta (oAβs) can be synaptotoxic and evidence of their deposition inside synaptic terminals of cognition-associated neurons explains early memory loss in AD better than formation of extracellular Aβ plaques. Among innate immune cells that reside in the brain, microglia sense danger signals represented by proteins like oAβ and become activated by neuronal damage such as that caused by bacterial endotoxins. The resulting reactive microgliosis has been implicated in generating the chronic form of microglial activation believed to promote AD's development. Genome-wide association studies (GWASs) have yielded data from patients with sporadic AD indicating that its causes include genetic variation in the innate immune system. Recent preclinical studies have reported that β-hydroxybutyrate (βOHB) may protect the brain from the adverse effects of both the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and the deacetylation of histone. Consequently, there is an urgent need for clinical investigations designed to test whether an orally administered βOHB preparation, such as a ketone ester, can have a similar beneficial effect in human subjects.

  20. Are innate immune signaling pathways in plants and animals conserved?

    PubMed

    Ausubel, Frederick M

    2005-10-01

    Although adaptive immunity is unique to vertebrates, the innate immune response seems to have ancient origins. Common features of innate immunity in vertebrates, invertebrate animals and plants include defined receptors for microbe-associated molecules, conserved mitogen-associated protein kinase signaling cascades and the production of antimicrobial peptides. It is commonly reported that these similarities in innate immunity represent a process of divergent evolution from an ancient unicellular eukaryote that pre-dated the divergence of the plant and animal kingdoms. However, at present, data suggest that the seemingly analogous regulatory modules used in plant and animal innate immunity are a consequence of convergent evolution and reflect inherent constraints on how an innate immune system can be constructed.

  1. Cell-autonomous stress responses in innate immunity.

    PubMed

    Moretti, Julien; Blander, J Magarian

    2017-01-01

    The innate immune response of phagocytes to microbes has long been known to depend on the core signaling cascades downstream of pattern recognition receptors (PRRs), which lead to expression and production of inflammatory cytokines that counteract infection and induce adaptive immunity. Cell-autonomous responses have recently emerged as important mechanisms of innate immunity. Either IFN-inducible or constitutive, these processes aim to guarantee cell homeostasis but have also been shown to modulate innate immune response to microbes and production of inflammatory cytokines. Among these constitutive cell-autonomous responses, autophagy is prominent and its role in innate immunity has been well characterized. Other stress responses, such as metabolic stress, the ER stress/unfolded protein response, mitochondrial stress, or the DNA damage response, seem to also be involved in innate immunity, although the precise mechanisms by which they regulate the innate immune response are not yet defined. Of importance, these distinct constitutive cell-autonomous responses appear to be interconnected and can also be modulated by microbes and PRRs, which add further complexity to the interplay between innate immune signaling and cell-autonomous responses in the mediation of an efficient innate immune response.

  2. Manipulation of Innate and Adaptive Immunity through Cancer Vaccines

    PubMed Central

    Mitchell, Duane A.

    2017-01-01

    Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens. PMID:28265580

  3. Innate Immune Gene Polymorphisms in Tuberculosis

    PubMed Central

    Sadee, Wolfgang

    2012-01-01

    Tuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C-type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB. PMID:22825450

  4. Innate Immune Pattern Recognition: A Cell Biological Perspective

    PubMed Central

    Brubaker, Sky W.; Bonham, Kevin S.; Zanoni, Ivan

    2016-01-01

    Receptors of the innate immune system detect conserved determinants of microbial and viral origin. Activation of these receptors initiates signaling events that culminate in an effective immune response. Recently, the view that innate immune signaling events rely on and operate within a complex cellular infrastructure has become an important framework for understanding the regulation of innate immunity. Compartmentalization within this infrastructure provides the cell with the ability to assign spatial information to microbial detection and regulate immune responses. Several cell biological processes play a role in the regulation of innate signaling responses; at the same time, innate signaling can engage cellular processes as a form of defense or to promote immunological memory. In this review, we highlight these aspects of cell biology in pattern-recognition receptor signaling by focusing on signals that originate from the cell surface, from endosomal compartments, and from within the cytosol. PMID:25581309

  5. The innate immune system in human systemic lupus erythematosus.

    PubMed

    Weidenbusch, Marc; Kulkarni, Onkar P; Anders, Hans-Joachim

    2017-04-25

    Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

  6. Post-Translational Modification Control of Innate Immunity.

    PubMed

    Liu, Juan; Qian, Cheng; Cao, Xuetao

    2016-07-19

    A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Innate immunity and inflammation: a transcriptional paradigm.

    PubMed

    Hawiger, J

    2001-01-01

    The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or superantigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proinflammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and superantigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-kappaB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-kappaB allows transcriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-kappaB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-kappaB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFalpha and interferon gamma) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation ofcytokine genes that are controlled by NF-kappaB and other SRTFs.

  8. Innate immune receptors in solid organ transplantation.

    PubMed

    Georgel, Philippe

    2016-11-01

    The discovery of Pattern Recognition Receptors (PRRs) followed by that of their role in the early detection of pathogens and the ignition of the innate immune response has been a formidable progress for immunological research in the past 15years. This has massively fueled investigations aiming at developing better strategies to fight off infectious diseases and/or to prevent their occurrence. However, infected individuals are for most part outliers in a given population and therefore, the primary function of these receptors should be considered in pathogen-free conditions. Our current understanding indicates that an important physiological function of PRRs resides in their capacity to maintain epithelial homeostasis in response to colonizing commensals. In addition, endogenous host-derived ligands, expressed under stressed, albeit sterile, conditions (called DAMPs for Danger-Associated Molecular Patterns) are also able to trigger PRR signaling. Solid organ transplantation represents a unique situation where both contributions of PRRs signaling can be studied. Indeed, dysbiosis (either caused by antibiotherapy preceding organ transplantation or simply due to the microbiota differences between the transplanted organ and the recipient host) is a characteristic feature of this situation, which is also marked by a massive synthesis and liberation of DAMPs as a result of hypoxia/reperfusion injury. Therefore, in the transplanted organ, at least two compartments (epithelial and that composed of immune cells) participate in graft rejection/acceptance depending on the activation status of expressed PRRs.

  9. Cooperativity of adaptive and innate immunity: implications for cancer therapy

    PubMed Central

    Marincola, Francesco M.

    2012-01-01

    The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control. PMID:21656157

  10. Enhancing Cancer Immunotherapy Via Activation of Innate Immunity

    PubMed Central

    Goldberg, Jacob L.; Sondel, Paul M.

    2015-01-01

    Given recent technological advances and advances in our understanding of cancer, immunotherapy of cancer is being used with clear clinical benefit. The immunosuppression accompanying cancer itself, as well as with current cancer treatment with radiation or chemotherapy, impairs adaptive immune effectors to a greater extent than innate effector cells. In addition to being less suppressed, innate immune cells are capable of being enhanced via immune-stimulatory regimens. Most strategies being investigated to promote innate immune responses against cancer do not require complex, patient-specific, ex-vivo cellular or molecular creation of therapeutic agents; thus they can, generally, be used as “off the shelf” therapeutics that could be administered by most cancer clinics. Successful applications of innate immunotherapy in the clinic have effectively targeted components of the innate immune response. Preclinical data demonstrate how initiation of innate immune responses can lead to subsequent adaptive long-term cancer immunity. We hypothesize that integration of innate immune activation strategies into combination therapies for cancer treatment will lead to more effective and long term clinical benefit. PMID:26320061

  11. Enhancing Cancer Immunotherapy Via Activation of Innate Immunity.

    PubMed

    Goldberg, Jacob L; Sondel, Paul M

    2015-08-01

    Given recent technological advances and advances in our understanding of cancer, immunotherapy of cancer is being used with clear clinical benefit. The immunosuppression accompanying cancer itself, as well as with current cancer treatment with radiation or chemotherapy, impairs adaptive immune effectors to a greater extent than innate effector cells. In addition to being less suppressed, innate immune cells are capable of being enhanced via immune-stimulatory regimens. Most strategies being investigated to promote innate immune responses against cancer do not require complex, patient-specific, ex vivo cellular or molecular creation of therapeutic agents; thus they can, generally, be used as "off the shelf" therapeutics that could be administered by most cancer clinics. Successful applications of innate immunotherapy in the clinic have effectively targeted components of the innate immune response. Preclinical data demonstrate how initiation of innate immune responses can lead to subsequent adaptive long-term cancer immunity. We hypothesize that integration of innate immune activation strategies into combination therapies for cancer treatment will lead to more effective and long-term clinical benefit.

  12. Innate immune targets of hepatitis B virus infection

    PubMed Central

    Zou, Zhi-Qiang; Wang, Li; Wang, Kai; Yu, Ji-Guang

    2016-01-01

    Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection. PMID:27330680

  13. Innate immune targets of hepatitis B virus infection.

    PubMed

    Zou, Zhi-Qiang; Wang, Li; Wang, Kai; Yu, Ji-Guang

    2016-06-18

    Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.

  14. Effects of engineered nanoparticles on the innate immune system.

    PubMed

    Liu, Yuanchang; Hardie, Joseph; Zhang, Xianzhi; Rotello, Vincent M

    2017-10-03

    Engineered nanoparticles (NPs) have broad applications in industry and nanomedicine. When NPs enter the body, interactions with the immune system are unavoidable. The innate immune system, a non-specific first line of defense against potential threats to the host, immediately interacts with introduced NPs and generates complicated immune responses. Depending on their physicochemical properties, NPs can interact with cells and proteins to stimulate or suppress the innate immune response, and similarly activate or avoid the complement system. NPs size, shape, hydrophobicity and surface modification are the main factors that influence the interactions between NPs and the innate immune system. In this review, we will focus on recent reports about the relationship between the physicochemical properties of NPs and their innate immune response, and their applications in immunotherapy. Copyright © 2017. Published by Elsevier Ltd.

  15. Toll-like receptors in antiviral innate immunity

    PubMed Central

    Lester, Sandra N.; Li, Kui

    2014-01-01

    Toll-like receptors (TLRs) are fundamental sensor molecules of the host innate immune system, which detect conserved molecular signatures of a wide range of microbial pathogens and initiate innate immune responses via distinct signaling pathways. Various TLRs are implicated in the early interplay of host cells with invading viruses, which regulates viral replication and/or host responses, ultimately impacting on viral pathogenesis. To survive the host innate defense mechanisms, many viruses have developed strategies to evade or counteract signaling through the TLR pathways, creating an advantageous environment for their propagation. Here we review the current knowledge of the roles TLRs play in antiviral innate immune responses, discuss examples of TLR-mediated viral recognition, and describe strategies used by viruses to antagonize the host antiviral innate immune responses. PMID:24316048

  16. A role for innate immunity in type 1 diabetes?

    PubMed

    Beyan, H; Buckley, L R; Yousaf, N; Londei, M; Leslie, R D G

    2003-01-01

    Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.

  17. Stress hyperglycemia, insulin treatment, and innate immune cells.

    PubMed

    Xiu, Fangming; Stanojcic, Mile; Diao, Li; Jeschke, Marc G

    2014-01-01

    Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

  18. Innate Immunity and Immune Evasion by Enterovirus 71

    PubMed Central

    Pathinayake, Prabuddha S.; Hsu, Alan C-Y.; Wark, Peter A.B.

    2015-01-01

    Enterovirus 71 (EV71) is a major infectious disease affecting millions of people worldwide and it is the main etiological agent for outbreaks of hand foot and mouth disease (HFMD). Infection is often associated with severe gastroenterological, pulmonary, and neurological diseases that are most prevalent in children. Currently, no effective vaccine or antiviral drugs exist against EV71 infection. A lack of knowledge on the molecular mechanisms of EV71 infection in the host and the virus-host interactions is a major constraint to developing specific antiviral strategies against this infection. Previous studies have identified and characterized the function of several viral proteins produced by EV71 that interact with the host innate immune proteins, including type I interferon signaling and microRNAs. These interactions eventually promote efficient viral replication and increased susceptibility to the disease. In this review we discuss the functions of EV71 viral proteins in the modulation of host innate immune responses to facilitate viral replication. PMID:26694447

  19. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells

    PubMed Central

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines. PMID:26258152

  20. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells.

    PubMed

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines.

  1. Innate immunity, insulin resistance and type 2 diabetes.

    PubMed

    Fernández-Real, José Manuel; Pickup, John C

    2008-01-01

    Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.

  2. Population genetic tools to dissect innate immunity in humans

    PubMed Central

    Quintana-Murci, Lluis; Clark, Andrew G.

    2014-01-01

    Innate immunity involves direct interactions between the host and the microbial world, both pathogenic and symbiotic, so natural selection is expected to strongly influence genes involved in these processes. Population genetics investigates the impact of past natural selection events on the genome of present-day human populations, and complements immunological, and clinical and epidemiological genetic studies. Recent data show that the impact of selection on the different families of innate immune receptors and their downstream signalling molecules varies considerably. This Review discusses these findings and highlights how they help delineate the relative functional importance of innate immune pathways, which can range from being essential to being redundant. PMID:23470320

  3. [Innate Lymphoid Cells: new actors of immunity].

    PubMed

    Cypowyj, Sophie; Vivier, Éric

    2016-03-01

    The world of lymphocytes has recently expanded. A new group of cells, innate lymphoid cells (ILCs) has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells, and lymphoid tissue--inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as interferon-γ). (IFN-γ). Advances in our understanding of NK cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens in the absence of specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples.

  4. Estrogen receptors regulate innate immune cells and signaling pathways.

    PubMed

    Kovats, Susan

    2015-04-01

    Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ERs) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Innate cell communication kick-starts pathogen-specific immunity

    PubMed Central

    Rivera, Amariliz; Siracusa, Mark C.; Yap, George S.; Gause, William C.

    2016-01-01

    Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells. Rather than acting as isolated effector cells, innate cells are in constant communication with other responding cells of the immune system, locally and distally. These interactions are critically important for the efficient control of primary infections as well for the development of ‘trained’ innate cells that facilitate the rapid elimination of homologous or heterologous infections. PMID:27002843

  6. Innate immune control and regulation of influenza virus infections

    PubMed Central

    McGill, Jodi; Heusel, Jonathan W.; Legge, Kevin L.

    2009-01-01

    Adaptive immune responses are critical for the control and clearance of influenza A virus (IAV) infection. However, in recent years, it has become increasingly apparent that innate immune cells, including natural killer cells, alveolar macrophages (aMφ), and dendritic cells (DC) are essential following IAV infection in the direct control of viral replication or in the induction and regulation of virus-specific adaptive immune responses. This review will discuss the role of these innate immune cells following IAV infection, with a particular focus on DC and their ability to induce and regulate the adaptive IAV-specific immune response. PMID:19643736

  7. [Bacterial proteases and bacterial resistance against human innate immunity factors].

    PubMed

    Tiurin, Iu A; Mustafin, I G; Fassakhov, R S

    2011-01-01

    The molecular and cell-mediated mechanisms that are developed by certain opportunistic and pathogenic bacteria and were obtained over the course of evolution to preserve resistance against principal components of human body innate immunity are summarized.

  8. The Innate Immune-Related Genes in Catfish

    PubMed Central

    Gao, Lei; He, Chongbo; Liu, Xueguang; Su, Hao; Gao, Xianggang; Li, Yunfeng; Liu, Weidong

    2012-01-01

    Catfish is one of the most important aquaculture species in America (as well as in Asia and Africa). In recent years, the production of catfish has suffered massive financial losses due to pathogen spread and breakouts. Innate immunity plays a crucial role in increasing resistance to pathogenic organisms and has generated increasing interest in the past few years. This review summarizes the current understanding of innate immune-related genes in catfish, including pattern recognition receptors, antimicrobial peptides, complements, lectins, cytokines, transferrin and gene expression profiling using microarrays and next generation sequencing technologies. This review will benefit the understanding of innate immune system in catfish and further efforts in studying the innate immune-related genes in fish. PMID:23203058

  9. Influenza A Virus Infection, Innate Immunity, and Childhood

    PubMed Central

    Coates, Bria M.; Staricha, Kelly L.; Wiese, Kristin M.; Ridge, Karen M.

    2016-01-01

    Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population. PMID:26237589

  10. Innate Immunity and antimicrobial defense systems in psoriasis

    PubMed Central

    Büchau, Amanda S.; Gallo, Richard L.

    2009-01-01

    Psoriasis is a chronic inflammatory disorder that is mediated by elements of the innate and adaptive immune systems. Its characteristic features in the skin consist of inflammatory changes in both dermis and epidermis, with abnormal keratinocyte differentiation and proliferation. Despite the elucidation of many aspects of psoriasis pathogenesis, some puzzling questions remain to be answered. A major question currently debated is if psoriasis is a primary abnormality of the epidermal keratinocyte or a reflection of dysregulated bone-marrow derived immunocytes. In this review we will focus on understanding the role of the innate immune system in psoriasis and how this provides a rational solution to address the origin of this multifactorial disease. Innate immunity is non-specific and genetically-based. It protects the body against the constant risk of pathogens through the use of rapidly mobilized defenses that are able to recognize and kill a wide variety of threats (bacteria, fungi, viruses, etc.). The key mechanisms of innate immune responses are the existence of receptors to recognize pathogens, and the production of factors that kill pathogens, such as antimicrobial peptides and proteins. Any combination of excessive sensitivity of the innate detection system, or dysregulation of the response system, can manifest both an epidermal phenotype and abnormal T-cell function. Thus, the multidimensional action of the innate immune system, its triggers, and its recently understood role in T-cell function, argue for an important role for innate mechanisms of recognition and response in the pathogenesis of psoriasis. PMID:18021900

  11. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

    PubMed Central

    Czarnewski, Paulo; Das, Srustidhar; Parigi, Sara M.; Villablanca, Eduardo J.

    2017-01-01

    Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs. PMID:28098786

  12. Innate immunity to mycobacteria: vitamin D and autophagy.

    PubMed

    Jo, Eun-Kyeong

    2010-08-01

    Autophagy is an ancient mechanism of protein degradation and a novel antimicrobial strategy. With respect to host defences against mycobacteria, autophagy plays a crucial role in antimycobacterial resistance, and contributes to immune surveillance of intracellular pathogens and vaccine efficacy. Vitamin D3 contributes to host immune responses against Mycobacterium tuberculosis through LL-37/hCAP-18, which is the only cathelicidin identified to date in humans. In this review, we discuss recent advances in our understanding of host immune strategies against mycobacteria, including vitamin D-mediated innate immunity and autophagy activation. This review also addresses our current understanding regarding the autophagy connection to principal innate machinery, such as ubiquitin- or inflammasome-involved pathways. Integrated dialog between autophagy and innate immunity may contribute to adequate host immune defences against mycobacterial infection.

  13. Pentraxins as a key component of innate immunity.

    PubMed

    Bottazzi, Barbara; Garlanda, Cecilia; Salvatori, Giovanni; Jeannin, Pascale; Manfredi, Angelo; Mantovani, Alberto

    2006-02-01

    Pentraxins are a complex superfamily of multifunctional molecules characterized by a multimeric structure. C-reactive protein and pentraxin 3 (PTX3) are prototypic molecules of the short and long pentraxin family, respectively. PTX3 is conserved in evolution and produced by innate immune cells. Evidence suggests that PTX3 acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation.

  14. Fungal Surface and Innate Immune Recognition of Filamentous Fungi

    PubMed Central

    Figueiredo, Rodrigo T.; Carneiro, Leticia A. M.; Bozza, Marcelo T.

    2011-01-01

    The innate immune system performs specific detection of molecules from infectious agents through pattern recognition receptors. This recognition triggers inflammatory responses and activation of microbicidal mechanisms by leukocytes. Infections caused by filamentous fungi have increased in incidence and represent an important cause of mortality and morbidity especially in individuals with immunosuppression. This review will discuss the innate immune recognition of filamentous fungi molecules and its importance to infection control and disease. PMID:22194732

  15. Innate immunity in the Aegean: ancient pathways for today's survival.

    PubMed

    Vasta, G R; Lambris, J D

    2002-04-01

    A workshop on innate immunity that took place this past autumn in Fira, Santorini, as part of the Aegean Conferences, provided tantalizing evidence about the early origin and evolutionary conservation of humoral and cellular components of innate immunity from sponges, flies and sea squirts to man, uncovered mechanistic aspects of its fundamental role in defense against disease, as well as the serious consequences of misdirected responses, and revealed the untapped potential of novel therapeutic approaches.

  16. Innate immune reconstitution with suppression of HIV-1

    PubMed Central

    Scully, Eileen P.; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M.; Bosch, Ronald J.

    2016-01-01

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. PMID:27158667

  17. Hepatocytes: a key cell type for innate immunity

    PubMed Central

    Zhou, Zhou; Xu, Ming-Jiang; Gao, Bin

    2016-01-01

    Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors (e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins), pro-inflammatory mediators (e.g. interleukin (IL)-6, IL-22, IL-1β and tumor necrosis factor-α), and downstream signaling pathways (e.g. signal transducer and activator of transcription factor 3 and nuclear factor-κB) that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceptibility to bacterial infection in patients with cirrhosis. PMID:26685902

  18. Beyond empiricism: informing vaccine development through innate immunity research.

    PubMed

    Levitz, Stuart M; Golenbock, Douglas T

    2012-03-16

    Although a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and have informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection.

  19. Emerging Roles of Protein Deamidation in Innate Immune Signaling

    PubMed Central

    Zhao, Jun; Li, Junhua; Xu, Simin

    2016-01-01

    Protein deamidation has been considered a nonenzymatic process associated with protein functional decay or “aging.” Recent studies implicate protein deamidation in regulating signal transduction in fundamental biological processes, such as innate immune responses. Work investigating gammaherpesviruses and bacterial pathogens indicates that microbial pathogens deploy deamidases or enzyme-deficient homologues (pseudoenzymes) to induce deamidation of key signaling components and evade host immune responses. Here, we review studies on protein deamidation in innate immune signaling and present several imminent questions concerning the roles of protein deamidation in infection and immunity. PMID:26889032

  20. Targeting Innate Immunity for Type 1 Diabetes Prevention.

    PubMed

    Needell, James C; Zipris, Danny

    2017-09-27

    Despite immense research efforts, type 1 diabetes (T1D) remains an autoimmune disease without a known trigger or approved intervention. Over the last three decades, studies have primarily focused on delineating the role of the adaptive immune system in the mechanism of T1D. The discovery of Toll-like receptors in the 1990s has advanced the knowledge on the role of the innate immune system in host defense as well as mechanisms that regulate adaptive immunity including the function of autoreactive T cells. Recent investigations suggest that inflammation plays a key role in promoting a large number of autoimmune disorders including T1D. Data from the LEW1.WR1 rat model of virus-induced disease and the RIP-B7.1 mouse model of diabetes suggest that innate immune signaling plays a key role in triggering disease progression. There is also evidence that innate immunity may be involved in the course of T1D in humans; however, a small number of clinical trials have shown that interfering with the function of the innate immune system following disease onset exerts only a modest effect on β-cell function. The data implying that innate immune pathways are linked with mechanisms of islet autoimmunity hold great promise for the identification of novel disease pathways that may be harnessed for clinical intervention. Nevertheless, more work needs to be done to better understand mechanisms by which innate immunity triggers β-cell destruction and assess the therapeutic value in blocking innate immunity for diabetes prevention.

  1. Cheetahs have a stronger constitutive innate immunity than leopards

    PubMed Central

    Heinrich, Sonja K.; Hofer, Heribert; Courtiol, Alexandre; Melzheimer, Jörg; Dehnhard, Martin; Czirják, Gábor Á.; Wachter, Bettina

    2017-01-01

    As a textbook case for the importance of genetics in conservation, absence of genetic variability at the major histocompatibility complex (MHC) is thought to endanger species viability, since it is considered crucial for pathogen resistance. An alternative view of the immune system inspired by life history theory posits that a strong response should evolve in other components of the immune system if there is little variation in the MHC. In contrast to the leopard (Panthera pardus), the cheetah (Acinonyx jubatus) has a relatively low genetic variability at the MHC, yet free-ranging cheetahs are healthy. By comparing the functional competence of the humoral immune system of both species in sympatric populations in Namibia, we demonstrate that cheetahs have a higher constitutive innate but lower induced innate and adaptive immunity than leopards. We conclude (1) immunocompetence of cheetahs is higher than previously thought; (2) studying both innate and adaptive components of immune systems will enrich conservation science. PMID:28333126

  2. Innate Immune Signaling Activated by MDR Bacteria in the Airway

    PubMed Central

    Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

    2015-01-01

    Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation. PMID:26582515

  3. Innate Immune Signaling Activated by MDR Bacteria in the Airway.

    PubMed

    Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

    2016-01-01

    Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation.

  4. Commensal bacteria calibrate the activation threshold of innate antiviral immunity.

    PubMed

    Abt, Michael C; Osborne, Lisa C; Monticelli, Laurel A; Doering, Travis A; Alenghat, Theresa; Sonnenberg, Gregory F; Paley, Michael A; Antenus, Marcelo; Williams, Katie L; Erikson, Jan; Wherry, E John; Artis, David

    2012-07-27

    Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.

  5. Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

    PubMed Central

    Abt, Michael C.; Osborne, Lisa C.; Monticelli, Laurel A.; Doering, Travis A.; Alenghat, Theresa; Sonnenberg, Gregory F.; Paley, Michael A.; Antenus, Marcelo; Williams, Katie L.; Erikson, Jan; Wherry, E. John; Artis, David

    2013-01-01

    SUMMARY Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity. PMID:22705104

  6. The STING pathway and regulation of innate immune signaling in response to DNA pathogens.

    PubMed

    Ishikawa, Hiroki; Barber, Glen N

    2011-04-01

    The innate immune system has evolved a variety of sensing mechanisms to detect and counter microbial invasion. These include the Toll-like receptor (TLR), cytoplasmic, nucleotide binding oligomerization domain (NOD)-like receptor and RIG-I-like helicase (RLH) pathways. However, how the cell detects pathogen-associated DNA to trigger host defense, including the production of interferon, remains to be fully clarified. Understanding these processes could have profound implications into how we understand and treat a variety of microbial-related disease, including viral-associated cancers, as well as autoimmune disorders. Recently, an endoplasmic reticulum-associated molecule referred to as STING (for stimulator of interferon genes) was isolated and shown to be critical for regulating the production of IFN in response to cytoplasmic DNA. Here, we review recent discoveries relating to the detection of foreign DNA, including the importance of the STING and inflammasome pathways and the triggering of innate signaling processes.

  7. Dengue and soluble mediators of the innate immune system.

    PubMed

    Espada-Murao, Lyre Anni; Morita, Kouichi

    2011-12-01

    Huge emphasis has been placed on the role of the adaptive immune system in dengue pathogenesis. Yet there is increasing evidence for the importance of the innate immune system in regulating dengue infection and possibly influencing the disease. This review focuses on the interplay between the innate immune system and dengue and highlights the role of soluble immunological mediators. Type I and type II interferons of the innate immune system demonstrate non-overlapping roles in dengue infection. Furthermore, while some IFN responses to dengue are protective, others may exert disease-related effects on the host. But aside from interferons, a number of cytokines have also been implicated in dengue pathogenesis. Our expanding knowledge of cytokines indicates that these soluble mediators act upon a complicated network of events to provoke the disease. This cytokine storm is generally attributed to massive T cell activation as an outcome of secondary infection. However, there is reason to believe that innate immune response-derived cytokines also have contributory effects, especially in the context of severe cases of primary dengue infection. Another less popular but interesting perspective on dengue pathogenesis is the effect of mosquito feeding on host immune responses and viral infection. Various studies have shown that soluble factors from vector saliva have the capacity to alter immune reactions and thereby influence pathogen transmission and establishment. Hence, modulation of the innate immune system at various levels of infection is a critical component of dengue disease. In the absence of an approved drug or vaccine for dengue, soluble mediators of the innate immune system could be a strategic foothold for developing anti-viral therapeutics and improving clinical management.

  8. The Critical Role of Innate Immunity in Kidney Transplantation.

    PubMed

    Cucchiari, David; Podestà, Manuel Alfredo; Ponticelli, Claudio

    2016-01-01

    For a long time now, kidney transplant rejection has been considered the consequence of either cellular or antibody-mediated reaction as a part of adaptive immunity response. The role of innate immunity, on the other hand, had been unclear for many years and was thought to be only ancillary. There is now consistent evidence that innate immune response is a condition necessary to activate the machinery of rejection. In this setting, the communication between antigen-presenting cells and T lymphocytes is of major importance. Indeed, T cells are unable to cause rejection if innate immunity is not activated. This field is currently being explored and several experiments in animal models have proved that blocking innate immunity activation can promote tolerance of the graft instead of rejection. The aim of this review is to systematically describe all the steps of innate immunity response in kidney transplant rejection, from antigen recognition to T-cells activation, with a focus on clinical consequences and possible future perspectives.

  9. Induction of adaptive immunity by flagellin does not require robust activation of innate immunity.

    PubMed

    Sanders, Catherine J; Franchi, Luigi; Yarovinsky, Felix; Uematsu, Satoshi; Akira, Shizuo; Núñez, Gabriel; Gewirtz, Andrew T

    2009-02-01

    The ability of TLR agonists to promote adaptive immune responses is attributed to their ability to robustly activate innate immunity. However, it has been observed that, for adjuvants in actual use in research and vaccination, TLR signaling is dispensable for generating humoral immunity. Here, we examined the role of TLR5 and MyD88 in promoting innate and humoral immunity to flagellin using a prime/boost immunization regimen. We observed that eliminating TLR5 greatly reduced flagellin-induced cytokine production, except for IL-18, and ablated DC maturation but did not significantly impact flagellin's ability to promote humoral immunity. Elimination of MyD88, which will ablate signaling through TLR and IL-1beta/IL-18 generated by Nod-like receptors, reduced, but did not eliminate flagellin's promotion of humoral immunity. In contrast, loss of the innate immune receptor for profilin-like protein (PLP), TLR11, greatly reduced the ability of PLP to elicit humoral immunity. Together, these results indicate that, firstly, the degree of innate immune activation induced by TLR agonists may be in great excess of that needed to promote humoral immunity and, secondly, there is considerable redundancy in mechanisms that promote the humoral immune response upon innate immune recognition of flagellin. Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation.

  10. 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.…

  11. 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.…

  12. Endogenous opioid peptides in regulation of innate immunity cell functions.

    PubMed

    Gein, S V; Baeva, T A

    2011-03-01

    Endogenous opioid peptides comprise a group of bioregulatory factors involved in regulation of functional activity of various physiological systems of an organism. One of most important functions of endogenous opioids is their involvement in the interaction between cells of the nervous and immune systems. Summary data on the effects of opioid peptides on regulation of functions of innate immunity cells are presented.

  13. Collectins and collectin receptors in innate immunity.

    PubMed

    Holmskov, U L

    2000-01-01

    This thesis is based on nine papers and a review on the collectins and collectin receptors in innate immunity. The collectins are a family of proteins in which the individual chains consist of a C-type lectin domain attached to a collagen domain via an alpha-coiled neck region. The chains are organized into a triple collagen helix and oligomerized through N-terminally located cysteines. The collectins have a dual function: one is to bind specifically to carbohydrate structures on the surface of a pathogen; the other is subsequently to recruit other cells and molecules to destroy the pathogen. The C-type lectin domains contain 110-130 amino-acid residues arranged in a conserved sequence pattern which allows the domain to fold into a well-defined tertiary structure. Five collectins have been described. Lung surfactant proteins A and D (SP-A and SP-D) are mainly found in the surfactant coating the luminal surface of the pulmonary epithelial cells, but are also produced by cells lining the gastrointestinal tract. Mannan-binding lectin (MBL), conglutinin and collectin-43 (CL-43) are serum proteins produced by the liver. Conglutinin and CL-43 have so far only been found in Bovidae. The collectins are involved in innate, nonadaptive immune defense. They bind to microbial surface carbohydrates, inducing aggregation and thereby impeding infectivity or mediating phagocytosis through specific receptors on the phagocytes. After binding microbial carbohydrate, MBL can activate the complement system through a newly discovered pathway which makes use of two serine proteases (MASP-1 and MASP-2) to activate the complement factors C4 and C2. In man, low serum MBL concentrations resulting from mutations in the collagen region are associated with a common opsonic defect. CL-43 was identified as a new collectin by its calcium-dependent binding to mannan and by its M(r) of 43 kDa in the reduced state on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The lectin was

  14. DNA damage and innate immunity: links and trade-offs.

    PubMed

    Chatzinikolaou, Georgia; Karakasilioti, Ismene; Garinis, George A

    2014-09-01

    To counteract DNA damage, cells employ genome maintenance pathways that are directed inward, relentlessly to scan and repair the genome. Adaptive and innate immune mechanisms are often directed outward, protecting self against pathogens. Recent work has revealed direct links between innate immune signaling and the DNA damage response (DDR). Here we review current understanding of the mechanism by which cells sense damaged and foreign DNA. We examine the functional role of DNA damage signaling in immune activation and discuss the relevance of these processes to DNA damage-driven chronic inflammation in disease and in aging. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Innate immune mediators in cancer: between defense and resistance.

    PubMed

    Berraondo, Pedro; Minute, Luna; Ajona, Daniel; Corrales, Leticia; Melero, Ignacio; Pio, Ruben

    2016-11-01

    Chronic inflammation in the tumor microenvironment and evasion of the antitumor effector immune response are two of the emerging hallmarks required for oncogenesis and cancer progression. The innate immune system not only plays a critical role in perpetuating these tumor-promoting hallmarks but also in developing antitumor adaptive immune responses. Thus, understanding the dual role of the innate system in cancer immunology is required for the design of combined immunotherapy strategies able to tackle established tumors. Here, we review recent advances in the understanding of the role of cell populations and soluble components of the innate immune system in cancer, with a focus on complement, the adapter molecule Stimulator of Interferon Genes, natural killer cells, myeloid cells, and B cells. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Innate immune mechanisms in vitiligo: danger from within.

    PubMed

    Richmond, Jillian M; Frisoli, Michael L; Harris, John E

    2013-12-01

    Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.

  17. Innate immune mechanisms in vitiligo: Danger from within

    PubMed Central

    Richmond, Jillian M.; Frisoli, Michael L.; Harris, John E.

    2013-01-01

    Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. While adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo. PMID:24238922

  18. The respiratory microbiome and innate immunity in asthma

    PubMed Central

    Huang, Yvonne J.

    2015-01-01

    Purpose of review The purpose of this study is to summarize recent studies of the lower respiratory microbiome in asthma, the role of innate immunity in asthma and strategies to understand complex microbiome–immune interactions in asthma. Recent findings Recent evidence indicates that the composition of lower respiratory microbiota in asthmatic individuals, across a spectrum of disease severity, is altered compared with healthy individuals. Attributes of this altered airway microbiome have been linked to clinical and inflammatory features of asthma. The importance of innate immune cells and mucosal defense systems in asthma is increasingly appreciated and may be dysregulated in the disease. Summary Interactions between the respiratory microbiome and innate mucosal immunity in asthma are complex and a challenge to dissect. Multiple avenues of investigation, leveraging a variety of methodologies, will need to be pursued to understand functional relationships to clinical and inflammatory phenotypes seen in asthma. PMID:25405668

  19. RNAs Containing Modified Nucleotides Fail To Trigger RIG-I Conformational Changes for Innate Immune Signaling

    PubMed Central

    Durbin, Ann Fiegen; Wang, Chen; Marcotrigiano, Joseph

    2016-01-01

    ABSTRACT Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling. The experiments were based on a model innate immune activating RNA molecule, the polyU/UC RNA domain of hepatitis C virus, which was transcribed in vitro with canonical nucleotides or with one of eight modified nucleotides. The approach revealed signature assay responses associated with individual modified nucleotides or classes of modified nucleotides. For example, while both N-6-methyladenosine (m6A) and pseudouridine nucleotides correlate with diminished signaling, RNA containing m6A modifications bound RIG-I poorly, while RNA containing pseudouridine bound RIG-I with high affinity but failed to trigger the canonical RIG-I conformational changes associated with robust signaling. These data advance understanding of RNA-mediated innate immune signaling, with additional relevance for applying nucleotide modifications to RNA therapeutics. PMID:27651356

  20. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans.

    PubMed

    Solana, Rafael; Tarazona, Raquel; Gayoso, Inmaculada; Lesur, Olivier; Dupuis, Gilles; Fulop, Tamas

    2012-10-01

    Components of the innate immune response, including neutrophils and macrophages, are the first line of defense against infections. Their role is to initiate an inflammatory response, phagocyte and kill pathogens, recruit natural killer cells (NK), and facilitate the maturation and migration of dendritic cells that will initiate the adaptive immune response. Extraordinary advances have been made in the last decade on the knowledge of the receptors and mechanisms used by cells of the innate immunity not only to sense and eliminate the pathogen but also to communicate each other and collaborate with cells of adaptive immunity to mount an effective immune response. The analysis of innate immunity in elderly humans has evidenced that aging has a profound impact on the phenotype and functions of these cells. Thus altered expression and/or function of innate immunity receptors and signal transduction leading to defective activation and decreased chemotaxis, phagocytosis and intracellular killing of pathogens have been described. The phenotype and function of NK cells from elderly individuals show significant changes that are compatible with remodeling of the different NK subsets, with a decrease in the CD56bright subpopulation and accumulation of the CD56dim cells, in particular those differentiated NK cells that co-express CD57, as well as a decreased expression of activating natural cytotoxicity receptors. These alterations can be responsible of the decreased production of cytokines and the lower per-cell cytotoxicity observed in the elderly. Considering the relevance of these cells in the initiation of the immune response, the possibility to reactivate the function of innate immune cells should be considered in order to improve the response to pathogens and to vaccination in the elderly.

  1. Innate Immune Function of TH2 Cells in vivo

    PubMed Central

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F.; Paul, William E.

    2015-01-01

    Type 2 helper T (TH) cells produce interleukin 13 (IL-13) when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2s) are the dominant innate producers of IL-13 in naïve animals, we show here that in helminth-infected mice, TH2 cell numbers increased and became major mediators of innate type II responses. TH2 cells made important contributions to HDM-induced antigen–non-specific eosinophilic inflammation and protected mice recovering from Ascaris suum infection against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role of effector TH2 cells during TCR-independent innate-like immune responses. PMID:26322482

  2. Viral degradasome hijacks mitochondria to suppress innate immunity

    PubMed Central

    Goswami, Ramansu; Majumdar, Tanmay; Dhar, Jayeeta; Chattopadhyay, Saurabh; Bandyopadhyay, Sudip K; Verbovetskaya, Valentina; Sen, Ganes C; Barik, Sailen

    2013-01-01

    The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named “NS-degradasome” (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity. PMID:23877405

  3. The role of innate immunity in donor organ procurement.

    PubMed

    McKay, Dianne B

    2011-03-01

    Solid organ transplantation is a life saving procedure for patients with end-stage organ disease, and great care is taken to ensure that healthy organs are procured from deceased or live donors. Despite rigorous efforts to avoid injury, all organs experience some degree of damage from a process called ischemia reperfusion injury (IRI). The first part of the injury (ischemia) occurs when the donor organ's blood supply is compromised, and the second part (reperfusion) occurs when the blood supply is reestablished. The pathophysiology of the IRI is complex, but data from many laboratories have demonstrated that the inciting events of ischemia/reperfusion injury are triggered through a phylogenetically conserved system called the innate immune system. The innate immune system is a complex array of molecules, receptors and cellular elements present in species as diverse as plants to humans. This review discusses the role of the innate immune system in renal IRI and focuses on mechanisms of injury during organ procurement and transplantation. Although there are overlapping complex mechanisms, blockade of the innate immune system will likely provide a novel approach to preventing the earliest events associated with renal ischemia. Potentially, blockade of innate immune activation will provide the opportunity to increase the use marginal donors, especially those from patients deceased after cardiac death.

  4. Role of the innate immune system in acute viral myocarditis.

    PubMed

    Huang, Chien-Hua; Vallejo, Jesus G; Kollias, George; Mann, Douglas L

    2009-05-01

    Although the adaptive immune system is thought to play an important role in the pathogenesis of viral myocarditis, the role of the innate immune system has not been well defined. To address this deficiency, we employed a unique line of mice that harbor a genomic "knock in" of a mutated TNF gene lacking the AU rich element (TNF(ARE/ARE)) that is critical for TNF mRNA stability and translation, in order to examine the contribution of the innate immune system in encephalomyocarditis-induced myocarditis (EMCV). Heterozygous mice (TNF(ARE/+)) were infected with 500 plaque-forming units of EMCV. TNF(ARE/+)mice had a significantly higher 14-day mortality and myocardial inflammation when compared to littermate control mice. Virologic studies showed that the viral load at 14 days was significantly lower in the hearts of TNF(ARE/+) mice. TNF(ARE/+) mice had an exaggerated proinflammatory cytokine and chemokine response in the heart following EMCV infection. Modulation of the innate immune response in TNF(ARE/+) mice by the late administration of prednisolone resulted in a significant improvement in survival and decreased cardiac inflammation, whereas early administration of prednisolone resulted in a blunted innate response and increased mortality in littermate control mice. Viewed together, these data suggest that the duration and degree of activation of the innate immune system plays a critical role in determining host outcomes in experimental viral myocarditis.

  5. Innate and adaptive immunity in inflammatory bowel disease

    PubMed Central

    Siegmund, Britta; Zeitz, Martin

    2011-01-01

    Inflammatory bowel diseases are the consequence of a dysregulated mucosal immune system. The mucosal immune system consists of two arms, innate and adaptive immunity, that have been studied separately for a long time. Functional studies from in vivo models of intestinal inflammation as well as results from genome-wide association studies strongly suggest a cross-regulation of both arms. The present review will illustrate this interaction by selecting examples from innate immunity and adaptive immunity, and their direct impact on each other. Broadening our view by focusing on the cross-regulated areas of the mucosal immune system will not only facilitate our understanding of disease, but furthermore will allow identification of future therapeutic targets. PMID:21912465

  6. Evolution of innate and adaptive immune systems in jawless vertebrates.

    PubMed

    Kasamatsu, Jun

    2013-01-01

    Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates. © 2012 The Societies and Wiley Publishing Asia Pty Ltd.

  7. Rainbow Trout Innate Immunity against Flavobacterium psychrophilum

    USDA-ARS?s Scientific Manuscript database

    Flavobacterium psychrophilum infection is associated with significant loss of rainbow trout production in the U.S. and other parts of the world. In 2005, a selective breeding program was initiated at the National Center for Cool and Cold Water Aquaculture to improve rainbow trout innate resistance ...

  8. Did the molecules of adaptive immunity evolve from the innate immune system?

    PubMed

    Bartl, Simona; Baish, Meredith; Weissman, Irving L; Diaz, Marilyn

    2003-04-01

    The antigen receptors on cells of innate immune systems recognize broadly expressed markers on non-host cells while the receptors on lymphocytes of the adaptive immune system display a higher level of specificity. Adaptive immunity, with its exquisite specificity and immunological memory, has only been found in the jawed vertebrates, which also display innate immunity. Jawless fishes and invertebrates only have innate immunity. In the adaptive immune response, T and B-lymphocytes detect foreign agents or antigens using T cell receptors (TCR) or immunoglobulins (Ig), respectively. While Ig can bind free intact antigens, TCR only binds processed antigenic fragments that are presented on molecules encoded in the major histocompatibility complex (MHC). MHC molecules display variation through allelic polymorphism. A diverse repertoire of Ig and TCR molecules is generated by gene rearrangement and junctional diversity, processes carried out by the recombinase activating gene (RAG) products and terminal deoxynucleotidyl transferase (TdT). Thus, the molecules that define adaptive immunity are TCR, Ig, MHC molecules, RAG products and TdT. No direct predecessors of these molecules have been found in the jawless fishes or invertebrates. In contrast, the complement cascade can be activated by either adaptive or innate immune systems and contains examples of molecules that gradually evolved from non-immune functions to being part of the innate and then adaptive immune system. In this paper we examine the molecules of the adaptive immune system and speculate on the existence of direct predecessors that were part of innate immunity.

  9. Innate and Adaptive Immune Responses in Wound Epithelialization

    PubMed Central

    Strbo, Natasa; Yin, Natalie; Stojadinovic, Olivera

    2014-01-01

    Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross-talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident γδT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases. PMID:25032069

  10. Protective cancer immunotherapy: what can the innate immune system contribute?

    PubMed

    Schmitz, Frank; Heit, Antje

    2008-01-01

    Despite significant efforts to induce protection against malignant diseases, the clinical effects of antitumour vaccines are poor. However, recent studies on a quadrivalent human papilloma virus vaccine suggest that protection against secondary tumour development is feasible. While this scenario benefits rather from antiviral protection than from direct antitumour responses, immunisation against cancers of non-viral origin demands strategies that rely on the circumvention of intrinsic regulatory mechanisms. Strong activation of innate immune cells seems to be key and, thus, the choice of adjuvant determines vaccination efficacy. The recently acquired knowledge about molecular and cellular recognition of microbial molecules suggests how one can modulate innate and adaptive immune reactions to potentially induce robust T- and B-cell reactions capable of prohibiting tumour development and progression. Here, the authors review the present knowledge of innate immune reactions, which may help to define rationales on the design of novel antitumour vaccines.

  11. Probiotics promote gut health through stimulation of epithelial innate immunity.

    PubMed

    Pagnini, Cristiano; Saeed, Rubina; Bamias, Giorgos; Arseneau, Kristen O; Pizarro, Theresa T; Cominelli, Fabio

    2010-01-05

    Probiotic formulations are widely available and have a variety of proposed beneficial effects, including promotion of gut health. The mechanisms of action of probiotic bacteria in the intestine are still unclear but are generally attributed to an antiinflammatory effect. Here, we demonstrate that the multiple probiotic formulation VSL#3 prevents the onset of intestinal inflammation by local stimulation of epithelial innate immune responses (i.e., increased production of epithelial-derived TNF-alpha and restoration of epithelial barrier function in vivo). We also demonstrate that probiotic bacteria stimulate epithelial production of TNF-alpha and activate NF-kappaB in vitro. Our results support the hypothesis that probiotics promote gut health through stimulation, rather than suppression, of the innate immune system. Furthermore, our findings provide the perspective that defects in innate immunity may play a critical role in the pathogenesis and progression of intestinal disorders, such as inflammatory bowel disease.

  12. Postnatal Innate Immune Development: From Birth to Adulthood

    PubMed Central

    Georgountzou, Anastasia; Papadopoulos, Nikolaos G.

    2017-01-01

    It is well established that adaptive immune responses are deficient in early life, contributing to increased mortality and morbidity. The developmental trajectories of different components of innate immunity are only recently being explored. Individual molecules, cells, or pathways of innate recognition and signaling, within different compartments/anatomical sites, demonstrate variable maturation patterns. Despite some discrepancies among published data, valuable information is emerging, showing that the developmental pattern of cytokine responses during early life is age and toll-like receptor specific, and may be modified by genetic and environmental factors. Interestingly, specific environmental exposures have been linked both to innate function modifications and the occurrence of chronic inflammatory disorders, such as respiratory allergies. As these conditions are on the rise, our knowledge on innate immune development and its modulating factors needs to be expanded. Improved understanding of the sequence of events associated with disease onset and persistence will lead toward meaningful interventions. This review describes the state-of-the-art on normal postnatal innate immune ontogeny and highlights research areas that are currently explored or should be further addressed. PMID:28848557

  13. The activation and suppression of plant innate immunity by parasitic nematodes.

    PubMed

    Goverse, Aska; Smant, Geert

    2014-01-01

    Plant-parasitic nematodes engage in prolonged and intimate relationships with their host plants, often involving complex alterations in host cell morphology and function. It is puzzling how nematodes can achieve this, seemingly without activating the innate immune system of their hosts. Secretions released by infective juvenile nematodes are thought to be crucial for host invasion, for nematode migration inside plants, and for feeding on host cells. In the past, much of the research focused on the manipulation of developmental pathways in host plants by plant-parasitic nematodes. However, recent findings demonstrate that plant-parasitic nematodes also deliver effectors into the apoplast and cytoplasm of host cells to suppress plant defense responses. In this review, we describe the current insights in the molecular and cellular mechanisms underlying the activation and suppression of host innate immunity by plant-parasitic nematodes along seven critical evolutionary and developmental transitions in plant parasitism.

  14. Innate immune activation in neutrophilic asthma and bronchiectasis

    PubMed Central

    Simpson, Jodie L; Grissell, Terry V; Douwes, Jeroen; Scott, Rodney J; Boyle, Michael J; Gibson, Peter G

    2007-01-01

    Background The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre‐programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. Aim To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. Methods Induced sputum was obtained from non‐smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll‐like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. Results Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro‐inflammatory cytokines IL8 and IL1β, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. Conclusion There is evidence of activation of the innate immune system in asthma which results in the production of pro‐inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma. PMID:16844729

  15. Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

    PubMed Central

    Rus, Florentina; Flatt, Thomas; Tong, Mei; Aggarwal, Kamna; Okuda, Kendi; Kleino, Anni; Yates, Elisabeth; Tatar, Marc; Silverman, Neal

    2013-01-01

    Throughout the animal kingdom, steroid hormones have been implicated in the defense against microbial infection, but how these systemic signals control immunity is unclear. Here, we show that the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial infection. We identify a group of steroid-regulated transcription factors as well as two GATA transcription factors that act as repressors and activators of the immune response and are required for the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that Drosophila use complex mechanisms to modulate innate immune responses, and identify a transcriptional hierarchy that integrates steroid signalling and immunity in animals. PMID:23652443

  16. Antiviral defense in shrimp: from innate immunity to viral infection.

    PubMed

    Wang, Pei-Hui; Huang, Tianzhi; Zhang, Xiaobo; He, Jian-Guo

    2014-08-01

    The culture of penaeid shrimp is rapidly developing as a major business endeavor worldwide. However, viral diseases have caused huge economic loss in penaeid shrimp culture industries. Knowledge of shrimp innate immunity and antiviral responses has made important progress in recent years, allowing the design of better strategies for the prevention and control of shrimp diseases. In this study, we have updated information on shrimp antiviral immunity and interactions between shrimp hosts and viral pathogens. Current knowledge and recent progress in immune signaling pathways (e.g., Toll/IMD-NF-κB and JAK-STAT signaling pathways), RNAi, phagocytosis, and apoptosis in shrimp antiviral immunity are discussed. The mechanism of viral infection in shrimp hosts and the interactions between viruses and shrimp innate immune systems are also analyzed. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. The innate immune response during urinary tract infection and pyelonephritis.

    PubMed

    Spencer, John David; Schwaderer, Andrew L; Becknell, Brian; Watson, Joshua; Hains, David S

    2014-07-01

    Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides-a ubiquitous component of the innate immune response.

  18. The innate immune response during urinary tract infection and pyelonephritis

    PubMed Central

    Spencer, John David; Schwaderer, Andrew L.; Becknell, Brian; Watson, Joshua; Hains, David S.

    2013-01-01

    Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides – a ubiquitous component of the innate immune response. PMID:23732397

  19. Recognition of Streptococcus pneumoniae by the innate immune system.

    PubMed

    Koppe, Uwe; Suttorp, Norbert; Opitz, Bastian

    2012-04-01

    Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection.

  20. Innate immunity, coagulation and placenta-related adverse pregnancy outcomes.

    PubMed

    Li, Min; Huang, S Joseph

    2009-12-01

    Maternal immunity undergoes subtle adjustment in order to tolerate the semi-allogeneic embryo and maintain the host defense against potential pathogens. Concomitantly, coagulation systems change from an anti-coagulant state to a pro-coagulant state to meet the hemostatic challenge of placentation and delivery. Innate immunity and blood coagulation systems are the first line of defense to protect a host against exogenous challenges, including alloantigens and mechanical insults, and preserve the integrity of an organism. The interactions between coagulation and immune systems have been extensively studied. Immune cells play a pivotal role in the initiation of the coagulation cascade, whereas coagulation proteases display substantial immuno-modulatory effects. Upon exogenous challenges, the immune and coagulation systems are capable of potentiating each other leading to a vicious cycle. Natural killer (NK) cells, macrophages (Mphis) and dendritic cells (DCs) are three major innate immune cells that have been demonstrated to play essential roles in early pregnancy. However, immune maladaptation and hemostatic imbalance have been suggested to be responsible for adverse pregnant outcomes, such as preeclampsia (PE), miscarriage, recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). In this review, we will summarize the mutual regulation between blood coagulation and innate immune systems as well as their roles in the maintenance of normal pregnancy and in the pathogenesis of adverse pregnancy outcomes.

  1. The Influence of Innate and Adaptive Immune Responses on Atherosclerosis

    PubMed Central

    Witztum, Joseph L.; Lichtman, Andrew H.

    2014-01-01

    Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID:23937439

  2. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

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

    2014-01-01

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

  3. The Innate Immune System in Acute and Chronic Wounds

    PubMed Central

    MacLeod, Amanda S.; Mansbridge, Jonathan N.

    2016-01-01

    Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing. PMID:26862464

  4. Innate immune responses in hepatitis C virus infection.

    PubMed

    Li, Kui; Lemon, Stanley M

    2013-01-01

    Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV.

  5. Innate immune responses in raccoons after raccoon rabies virus infection.

    PubMed

    Srithayakumar, Vythegi; Sribalachandran, Hariharan; Rosatte, Rick; Nadin-Davis, Susan A; Kyle, Christopher J

    2014-01-01

    Zoonotic wildlife diseases pose significant health risks not only to their primary vectors but also to humans and domestic animals. Rabies is a lethal encephalitis caused by rabies virus (RV). This RNA virus can infect a range of terrestrial mammals but each viral variant persists in a particular reservoir host. Active management of these host vectors is needed to minimize the negative impacts of this disease, and an understanding of the immune response to RV infection aids strategies for host vaccination. Current knowledge of immune responses to RV infection comes primarily from rodent models in which an innate immune response triggers activation of several genes and signalling pathways. It is unclear, however, how well rodent models represent the immune response of natural hosts. This study investigates the innate immune response of a primary host, the raccoon, to a peripheral challenge using the raccoon rabies virus (RRV). The extent and temporal course of this response during RRV infection was analysed using genes predicted to be upregulated during infection (IFNs; IFN regulatory factors; IL-6; Toll like receptor-3; TNF receptor). We found that RRV activated components of the innate immune system, with changes in levels of transcripts correlated with presence of viral RNA. Our results suggest that natural reservoirs of rabies may not mimic the immune response triggered in rodent models, highlighting the need for further studies of infection in primary hosts.

  6. PGE2 suppression of innate immunity during mucosal bacterial infection

    PubMed Central

    Agard, Mallory; Asakrah, Saja; Morici, Lisa A.

    2013-01-01

    Prostaglandin E2 (PGE2) is an important lipid mediator in inflammatory and immune responses during acute and chronic infections. Upon stimulation by various proinflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, PGE2 synthesis is upregulated by the expression of cyclooxygenases. Biologically active PGE2 is then able to signal through four primary receptors to elicit a response. PGE2 is a critical molecule that regulates the activation, maturation, migration, and cytokine secretion of several immune cells, particularly those involved in innate immunity such as macrophages, neutrophils, natural killer cells, and dendritic cells. Both Gram-negative and Gram-positive bacteria can induce PGE2 synthesis to regulate immune responses during bacterial pathogenesis. This review will focus on PGE2 in innate immunity and how bacterial pathogens influence PGE2 production during enteric and pulmonary infections. The conserved ability of many bacterial pathogens to promote PGE2 responses during infection suggests a common signaling mechanism to deter protective pro-inflammatory immune responses. Inhibition of PGE2 production and signaling during infection may represent a therapeutic alternative to treat bacterial infections. Further study of the immunosuppressive effects of PGE2 on innate immunity will lead to a better understanding of potential therapeutic targets within the PGE2 pathway. PMID:23971009

  7. Innate immune responses of Drosophila melanogaster are altered by spaceflight.

    PubMed

    Marcu, Oana; Lera, Matthew P; Sanchez, Max E; Levic, Edina; Higgins, Laura A; Shmygelska, Alena; Fahlen, Thomas F; Nichol, Helen; Bhattacharya, Sharmila

    2011-01-11

    Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of 330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was downregulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways.

  8. Innate Immune Responses of Drosophila melanogaster Are Altered by Spaceflight

    PubMed Central

    Marcu, Oana; Lera, Matthew P.; Sanchez, Max E.; Levic, Edina; Higgins, Laura A.; Shmygelska, Alena; Fahlen, Thomas F.; Nichol, Helen; Bhattacharya, Sharmila

    2011-01-01

    Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of 330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was downregulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways. PMID:21264297

  9. The innate immune system and inflammatory bowel disease.

    PubMed

    Davies, Julie M; Abreu, Maria T

    2015-01-01

    The innate immune system is a key factor in understanding the pathogenesis of inflammatory bowel disease (IBD) and in the hopes of improving its treatment. NOD2, a pattern recognition receptor, was one of the first major susceptibility genes identified in Crohn's disease (CD). This discovery has been followed by genome-wide association studies that have identified other genes involved in innate immune responses. Most notably, polymorphisms in the interleukin (IL)-23 receptor have also been linked to IBD - both CD and ulcerative colitis. At the core of the innate immune defects associated with IBD is a lack of generating a robust response to control invasive commensal or pathogenic bacteria. The defect sometimes lies in a failure of the epithelium to express antimicrobial peptides or in defective control of intracellular bacteria by phagocytic cells such as dendritic cells, macrophages, or neutrophils. The recent identification of innate lymphoid cells that express the IL-23 receptor and generate both proinflammatory and protective or regulatory responses to commensal or pathogenic bacteria provides another layer of complexity to the interplay of host protection and dysregulated inflammation. Although inhibition of tumor necrosis factor has been highly successful as a strategy in treating IBD, we must better understand the nuanced role of other innate cytokines before we may incorporate these in the treatment of IBD.

  10. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis

    PubMed Central

    Ahmetspahic, Diana; Ruck, Tobias; Schulte-Mecklenbeck, Andreas; Schwarte, Kathrin; Jörgens, Silke; Scheu, Stefanie; Windhagen, Susanne; Graefe, Bettina; Melzer, Nico; Klotz, Luisa; Arolt, Volker; Wiendl, Heinz; Meuth, Sven G.

    2016-01-01

    Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. Results: In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS. PMID:27766281

  11. Cytokines as a link between innate and adaptive antitumor immunity.

    PubMed

    Belardelli, Filippo; Ferrantini, Maria

    2002-04-01

    Recent studies indicate that cytokines produced by cells of the innate defense system play an essential role in influencing the immune response towards protective antitumor immunity. These cytokines might act as first 'danger signals' in alerting the immune system. By promoting the differentiation and activation of dendritic cells, antigen presentation and T-cell-mediated immune responses, these cytokines could be powerful natural adjuvants for the development of cancer vaccines. With regard to type I interferons - cytokines with a long history of clinical use - this new knowledge could be translated easily into novel strategies for the prevention and treatment of human malignancies.

  12. Beta-glucan recognition by the innate immune system.

    PubMed

    Goodridge, Helen S; Wolf, Andrea J; Underhill, David M

    2009-07-01

    Beta-glucans are recognized by the innate immune system. This recognition plays important roles in host defense and presents specific opportunities for clinical modulation of the host immune response. Neutrophils, macrophages, and dendritic cells among others express several receptors capable of recognizing beta-glucan in its various forms. This review explores what is currently known about beta-glucan recognition and how this recognition stimulates immune responses. Special emphasis is placed on Dectin-1, as we know the most about how this key beta-glucan receptor translates recognition into intracellular signaling, stimulates cellular responses, and participates in orchestrating the adaptive immune response.

  13. Regulation of the adaptive immune system by innate lymphoid cells

    PubMed Central

    Hepworth, Matthew R.; Sonnenberg, Gregory F.

    2014-01-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid tissues and epithelial cells at barrier surfaces. In this review we summarize the current understanding of how ILCs modulate the magnitude and quality of adaptive immune cell responses, and in particular focus on recent evidence suggesting that ILCs can also directly regulate CD4+ T cells. Further, we discuss the implications that these pathways may have on human health and disease. PMID:24594491

  14. Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

    PubMed Central

    Raineri, Davide; Boggio, Elena; Favero, Francesco; Soluri, Maria Felicia

    2016-01-01

    Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases. PMID:28097158

  15. HIV-1 evades innate immune recognition through specific cofactor recruitment

    NASA Astrophysics Data System (ADS)

    Rasaiyaah, Jane; Tan, Choon Ping; Fletcher, Adam J.; Price, Amanda J.; Blondeau, Caroline; Hilditch, Laura; Jacques, David A.; Selwood, David L.; James, Leo C.; Noursadeghi, Mahdad; Towers, Greg J.

    2013-11-01

    Human immunodeficiency virus (HIV)-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double-stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors. We reasoned that if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors then manipulation of specific interactions between HIV-1 capsid and host factors that putatively regulate these processes should trigger pattern recognition receptors and stimulate type 1 interferon (IFN) secretion. Here we show that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NF-κB and IRF3, the production of soluble type 1 IFN and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allows wild-type virus to trigger innate sensors and IFN production. In each case, suppressed replication is rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, we show that we can pharmacologically induce wild-type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.

  16. Trauma: the role of the innate immune system

    PubMed Central

    Hietbrink, F; Koenderman, L; Rijkers, GT; Leenen, LPH

    2006-01-01

    Immune dysfunction can provoke (multiple) organ failure in severely injured patients. This dysfunction manifests in two forms, which follow a biphasic pattern. During the first phase, in addition to the injury by trauma, organ damage is caused by the immune system during a systemic inflammatory response. During the second phase the patient is more susceptible for sepsis due to host defence failure (immune paralysis). The pathophysiological model outlined in this review encompasses etiological factors and the contribution of the innate immune system in the end organ damage. The etiological factors can be divided into intrinsic (genetic predisposition and physiological status) and extrinsic components (type of injury or "traumaload" and surgery or "intervention load"). Of all the factors, the intervention load is the only one which, can be altered by the attending emergency physician. Adjustment of the therapeutic approach and choice of the most appropriate treatment strategy can minimize the damage caused by the immune response and prevent the development of immunological paralysis. This review provides a pathophysiological basis for the damage control concept, in which a staged approach of surgery and post-traumatic immunomonitoring have become important aspects of the treatment protocol. The innate immune system is the main objective of immunomonitoring as it has the most prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-cells of the innate immune system in the processes that lead to organ failure. These cells are controlled by cytokines, chemokines, complement factors and specific tissue signals. The contribution of tissue barrier integrity and its interaction with the innate immune system is further evaluated. PMID:16759367

  17. Innate Immunity and the Role of Defensins in Otitis Media

    PubMed Central

    Underwood, Mark; Bakaletz, Lauren

    2011-01-01

    Otitis media is the most common pediatric disease in developed countries and a significant cause of morbidity and hearing loss in developing countries. The innate immune system is essential to protecting the middle ear from infection. Defensins, broad-spectrum cationic antimicrobial peptides, have been implicated in prevention of and the early response to acute otitis media; however, the mechanisms by which defensins and other antimicrobial molecules mediate this protection have not been completely elucidated. In both animal otitis media models and human middle ear epithelial cell culture models, β-defensins are highly induced and effectively kill the common pathogens associated with otitis media. We review the importance of innate immunity in protecting the middle ear and recent advances in understanding the roles of defensins and other antimicrobial molecules in the prevention and treatment of otitis media. The extremely high prevalence of otitis media, in spite of sophisticated innate and adaptive immune systems, is a vexing problem for clinicians and scientists. We therefore also review mechanisms by which bacteria evade innate immune defenses. PMID:21901304

  18. RNA Editing, ADAR1, and the Innate Immune Response

    PubMed Central

    Wang, Qingde; Li, Xiaoni; Qi, Ruofan; Billiar, Timothy

    2017-01-01

    RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1–3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field. PMID:28106799

  19. Innate immune responses of temperamental and calm cattle after transportation

    USDA-ARS?s Scientific Manuscript database

    The objective was to investigate measures of cellular innate immune responses among calm and temperamental Brahman bulls in response to handling and transportation. Sixteen Brahman bulls (344 ± 37 days of age; 271.6 ± 45.5 kg BW) classified as either calm (n = 8) or temperamental (n = 8) were loaded...

  20. Role of innate immunity in the pathogenesis of otitis media

    PubMed Central

    Mittal, Rahul; Kodiyan, Joyson; Gerring, Robert; Mathee, Kalai; Li, Jian-Dong; Grati, M’hamed; Liu, Xue Zhong

    2015-01-01

    Summary Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects. PMID:25447732

  1. Role of innate immunity in the pathogenesis of otitis media.

    PubMed

    Mittal, Rahul; Kodiyan, Joyson; Gerring, Robert; Mathee, Kalai; Li, Jian-Dong; Grati, M'hamed; Liu, Xue Zhong

    2014-12-01

    Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects.

  2. Origin of Toll-like receptor-mediated innate immunity.

    PubMed

    Kanzok, Stefan M; Hoa, Ngo T; Bonizzoni, Mariangela; Luna, Coralia; Huang, Yaming; Malacrida, Anna R; Zheng, Liangbiao

    2004-04-01

    Toll-related receptors (TLR) have been found in four animal phyla: Nematoda, Arthropoda, Echinodermata, and Chordata. No TLR has been identified thus far in acoelomates. TLR genes play a pivotal role in the innate immunity in both fruit fly and mammals. The prevailing view is that TLR-mediated immunity is ancient. The two pseudocoelomate TLRs, one each from Caenorhabditis elegans and Strongyloides stercoralis, were distinct from the coelomate ones. Further, the only TLR gene (Tol-1) in Ca. elegans did not appear to play a role in innate immunity. We argue that TLR-mediated innate immunity developed only in the coelomates, after they split from pseudocoelomates and acoelomates. We hypothesize that the function of TLR-mediated immunity is to prevent microbial infection in the body cavity present only in the coelomates. Phylogenetic analysis showed that almost all arthropod TLRs form a separate cluster from the mammalian counterparts. We further hypothesize that TLR-mediated immunity developed independently in the protostomia and deuterostomia coelomates.

  3. Acute stress elicited by bungee jumping suppresses human innate immunity.

    PubMed

    van Westerloo, David J; Choi, Goda; Löwenberg, Ester C; Truijen, Jasper; de Vos, Alex F; Endert, Erik; Meijers, Joost C M; Zhou, Lu; Pereira, Manuel P F L; Queiroz, Karla C S; Diks, Sander H; Levi, Marcel; Peppelenbosch, Maikel P; van der Poll, Tom

    2011-01-01

    Although a relation between diminished human immunity and stress is well recognized both within the general public and the scientific literature, the molecular mechanisms by which stress alters immunity remain poorly understood. We explored a novel model for acute human stress involving volunteers performing a first-time bungee jump from an altitude of 60 m and exploited this model to characterize the effects of acute stress in the peripheral blood compartment. Twenty volunteers were included in the study; half of this group was pretreated for 3 d with the β-receptor blocking agent propranolol. Blood was drawn 2 h before, right before, immediately after and 2 h after the jump. Plasma catecholamine and cortisol levels increased significantly during jumping, which was accompanied by significantly reduced ex vivo inducibility of proinflammatory cytokines as well as activation of coagulation and vascular endothelium. Kinome profiles obtained from the peripheral blood leukocyte fraction contained a strong noncanonical glucocorticoid receptor signal transduction signature after jumping. In apparent agreement, jumping down-regulated Lck/Fyn and cellular innate immune effector function (phagocytosis). Pretreatment of volunteers with propranolol abolished the effects of jumping on coagulation and endothelial activation but left the inhibitory effects on innate immune function intact. Taken together, these results indicate that bungee jumping leads to a catecholamine-independent immune suppressive phenotype and implicate noncanonical glucocorticoid receptor signal transduction as a major pathway linking human stress to impaired functioning of the human innate immune system.

  4. Acute Stress Elicited by Bungee Jumping Suppresses Human Innate Immunity

    PubMed Central

    van Westerloo, David J; Choi, Goda; Löwenberg, Ester C; Truijen, Jasper; de Vos, Alex F; Endert, Erik; Meijers, Joost C M; Zhou, Lu; Pereira, Manuel PFL; Queiroz, Karla CS; Diks, Sander H; Levi, Marcel; Peppelenbosch, Maikel P; van der Poll, Tom

    2011-01-01

    Although a relation between diminished human immunity and stress is well recognized both within the general public and the scientific literature, the molecular mechanisms by which stress alters immunity remain poorly understood. We explored a novel model for acute human stress involving volunteers performing a first-time bungee jump from an altitude of 60 m and exploited this model to characterize the effects of acute stress in the peripheral blood compartment. Twenty volunteers were included in the study; half of this group was pretreated for 3 d with the β-receptor blocking agent propranolol. Blood was drawn 2 h before, right before, immediately after and 2 h after the jump. Plasma catecholamine and cortisol levels increased significantly during jumping, which was accompanied by significantly reduced ex vivo inducibility of proinflammatory cytokines as well as activation of coagulation and vascular endothelium. Kinome profiles obtained from the peripheral blood leukocyte fraction contained a strong noncanonical glucocorticoid receptor signal transduction signature after jumping. In apparent agreement, jumping down-regulated Lck/Fyn and cellular innate immune effector function (phagocytosis). Pretreatment of volunteers with propranolol abolished the effects of jumping on coagulation and endothelial activation but left the inhibitory effects on innate immune function intact. Taken together, these results indicate that bungee jumping leads to a catecholamine-independent immune suppressive phenotype and implicate noncanonical glucocorticoid receptor signal transduction as a major pathway linking human stress to impaired functioning of the human innate immune system. PMID:21203694

  5. Zinc in innate and adaptive tumor immunity

    PubMed Central

    2010-01-01

    Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order. PMID:21087493

  6. Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

    PubMed Central

    Cui, Xiuji; Clark, Daniel N.; Liu, Kuancheng; Xu, Xiao-Dong; Guo, Ju-Tao

    2015-01-01

    ABSTRACT Hepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication. IMPORTANCE Chronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes. Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was

  7. Regulation of innate immunity by extracellular nucleotides

    PubMed Central

    Gorini, Stefania; Gatta, Lucia; Pontecorvo, Laura; Vitiello, Laura; la Sala, Andrea

    2013-01-01

    Extracellular ATP (eATP) is the most abundant among extracellular nucleotides and is commonly considered as a classical danger signal, which stimulates immune responses in the presence of tissue injury. In fact, increased nucleotide concentration in the extracellular space is generally closely associated with tissue stress or damage. However non-lytic nucleotide release may also occur in many cell types under a variety of conditions. Extracellular nucleotides are sensed by a class of plasma membrane receptors called P2 purinergic receptors (P2Rs). P2 receptors are expressed by all immunological cells and their activation elicits different responses. Extracellular ATP can act as an initiator or terminator of immune responses being able to induce different effects on immune cells depending on the pattern of P2 receptors engaged, the duration of the stimulus and its concentration in the extracellular milieu. Millimolar (high) concentrations of extracellular ATP, induce predominantly proinflammatory effects, while micromolar (low) doses exert mainly tolerogenic/immunosuppressive action. Moreover small, but significant differences in the pattern of P2 receptor expression in mice and humans confer diverse capacities of ATP in regulating the immune response. PMID:23358447

  8. Toward understanding of rice innate immunity against Magnaporthe oryzae.

    PubMed

    Azizi, P; Rafii, M Y; Abdullah, S N A; Nejat, N; Maziah, M; Hanafi, M M; Latif, M A; Sahebi, M

    2016-01-01

    The blast fungus, Magnaporthe oryzae, causes serious disease on a wide variety of grasses including rice, wheat and barley. The recognition of pathogens is an amazing ability of plants including strategies for displacing virulence effectors through the adaption of both conserved and variable pathogen elicitors. The pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) were reported as two main innate immune responses in plants, where PTI gives basal resistance and ETI confers durable resistance. The PTI consists of extracellular surface receptors that are able to recognize PAMPs. PAMPs detect microbial features such as fungal chitin that complete a vital function during the organism's life. In contrast, ETI is mediated by intracellular receptor molecules containing nucleotide-binding (NB) and leucine rich repeat (LRR) domains that specifically recognize effector proteins produced by the pathogen. To enhance crop resistance, understanding the host resistance mechanisms against pathogen infection strategies and having a deeper knowledge of innate immunity system are essential. This review summarizes the recent advances on the molecular mechanism of innate immunity systems of rice against M. oryzae. The discussion will be centered on the latest success reported in plant-pathogen interactions and integrated defense responses in rice.

  9. Meeting the demand for innate and adaptive immunities during evolution.

    PubMed

    Du Pasquier, L

    2005-07-01

    An ideal immune system should provide each individual with rapid and efficient responses, a diverse repertoire of recognition and effector molecules and a certain flexibility to match the changing internal and external environment. It should be economic in cells and genes. Specific memory would be useful. It should not be autoreactive. These requirements, a mixture of innate and adaptive immunity features, are modulated in function of the dominant mode of selection for each species of metazoa during evolution (K or r). From sponges to man, a great diversity of receptors and effector mechanisms, some of them shared with plants, are articulated around conserved signalling cascades. Multiple attempts at combining innate and adaptive immunity somatic features can be observed as new somatic mechanisms provide individualized repertoires of receptors throughout metazoa, in agnathans, prochordates, echinoderms and mollusks. The adaptive immunity of vertebrates with lymphocytes and their specific receptors of the immunoglobulin superfamily, the major histocompatibility complex, developed from innate immunity evolutionary lines that can be traced back in earlier deuterostomes.

  10. Innate Immune Memory: The Latest Frontier of Adjuvanticity.

    PubMed

    Töpfer, Elfi; Boraschi, Diana; Italiani, Paola

    2015-01-01

    Recent findings in the field of immune memory have demonstrated that B and T cell mediated immunity following infections are enhanced by the so-called trained immunity. This effect has been most extensively investigated for the tuberculosis vaccine strain Bacillus Calmette-Guérin (BCG). Epidemiological studies suggest that this vaccine is associated with a substantial reduction in overall child mortality that cannot be solely explained by prevention of the target disease but that it seems to rely on inducing resistance to other infections. Upon infection or vaccination, monocytes/macrophages can be functionally reprogrammed so as to display an enhanced defensive response against unrelated infections. Epigenetic modifications seem to play a key role in the induction of this "innate memory." These findings are revolutionising our knowledge of the immune system, introducing the concept of memory also for mammalian innate immunity. Thus, vaccines are likely to nonspecifically affect the overall immunological status of individuals in a clinically relevant manner. As a consequence, future vaccine strategies ought to take into account the contribution of innate memory through appropriate design of formulations and administration scheduling.

  11. Strength in numbers: "Omics" studies of C. elegans innate immunity.

    PubMed

    Simonsen, Karina T; Gallego, Sandra F; Færgeman, Nils J; Kallipolitis, Birgitte H

    2012-10-01

    For more than ten years the nematode Caenorhabditis elegans has proven to be a valuable model for studies of the host response to various bacterial and fungal pathogens. When exposed to a pathogenic organism, a clear response is elicited in the nematode, which is characterized by specific alterations on the transcriptional and translational levels. Early on, researchers took advantage of the possibility to conduct large-scale investigations of the C. elegans immune response. Multiple studies demonstrated that C. elegans does indeed mount a protective response against invading pathogens, thus rendering this small nematode a very useful and simple host model for the study of innate immunity and host-pathogen interactions. Here, we provide an overview of key aspects of innate immunity in C. elegans revealed by recent whole-genome transcriptomics and proteomics studies of the global response of C. elegans to various bacterial and fungal pathogens.

  12. Innate immune sensing of nucleic acids from pathogens.

    PubMed

    Oliveira, Sergio C

    2014-12-01

    The innate immune system is important as the first line of defense to sense invading pathogens. Nucleic acids represent critical pathogen signatures that trigger a host proinflammatory immune response. Much progress has been made in understanding how DNA and RNA trigger host defense countermeasures, however, several aspects of how cytosolic nucleic acids are sensed remain unclear. This special issue reviews how the host innate immune system senses nucleic acids from Brucella abortus, Mycobacterium sp and Legionella pneumophila, viral DNA, the role of STING in DNA sensing and inflammatory diseases and the mechanism of viral RNA recognition by the small interfering RNA pathway in Drosophila melanogaster. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  13. Innate immune recognition of DNA: A recent history.

    PubMed

    Dempsey, Alan; Bowie, Andrew G

    2015-05-01

    Innate immune DNA sensing underpins many physiological and pathological responses to DNA, including anti-viral immunity to DNA viruses. Although it has been appreciated for many years that cytosolic DNA can evoke a type I interferon response, it is only within the past decade that the cellular mechanisms responsible for such a response have been defined. Here we review the discoveries that led to an appreciation of the existence of cytosolic DNA sensor proteins, and discuss two key such sensors, cGAS and IFI16, in detail. DNA sensors operate via STING, a protein shown to have a central role in controlling altered gene induction in response to DNA in vivo, and as such to be central to a rapidly expanding list of both protective and harmful responses to DNA. We also discuss recent insights into how and when DNA stimulates innate immunity, and highlight current outstanding questions in the DNA sensing field.

  14. Boosting innate immunity to sustainably control diseases in crops.

    PubMed

    Nicaise, Valerie

    2017-08-10

    Viruses cause epidemics in all major crops, threatening global food security. The development of efficient and durable resistance able to withstand viral attacks represents a major challenge for agronomy, and relies greatly on the understanding of the molecular dialogue between viral pathogens and their hosts. Research over the last decades provided substantial advances in the field of plant-virus interactions. Remarkably, the advent of studies of plant innate immunity has recently offered new strategies exploitable in the field. This review summarizes the recent breakthroughs that define the mechanisms underlying antiviral innate immunity in plants, and emphasizes the importance of integrating that knowledge into crop improvement actions, particularly by exploiting the insights related to immune receptors. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Crosstalk between microbiota, pathogens and the innate immune responses.

    PubMed

    Günther, Claudia; Josenhans, Christine; Wehkamp, Jan

    2016-08-01

    Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.

  16. Innate or adaptive immunity? The example of natural killer cells.

    PubMed

    Vivier, Eric; Raulet, David H; Moretta, Alessandro; Caligiuri, Michael A; Zitvogel, Laurence; Lanier, Lewis L; Yokoyama, Wayne M; Ugolini, Sophie

    2011-01-07

    Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.

  17. Enhancing crop innate immunity: new promising trends

    PubMed Central

    Huang, Pin-Yao; Zimmerli, Laurent

    2014-01-01

    Plants are constantly exposed to potentially pathogenic microbes present in their surrounding environment. Due to the activation of the pattern-triggered immunity (PTI) response that largely relies on accurate detection of pathogen- or microbe-associated molecular patterns by pattern-recognition receptors (PRRs), plants are resistant to the majority of potential pathogens. However, adapted pathogens may avoid recognition or repress plant PTI and resulting diseases significantly affect crop yield worldwide. PTI provides protection against a wide range of pathogens. Reinforcement of PTI through genetic engineering may thus generate crops with broad-spectrum field resistance. In this review, new approaches based on fundamental discoveries in PTI to improve crop immunity are discussed. Notably, we highlight recent studies describing the interfamily transfer of PRRs or key regulators of PTI signaling. PMID:25414721

  18. Innate immunity in the lung regulates the development of asthma.

    PubMed

    DeKruyff, Rosemarie H; Yu, Sanhong; Kim, Hye Young; Umetsu, Dale T

    2014-07-01

    The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin-4 (IL-4), IL-5, IL-13, interferon-γ, IL-17, and IL-22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non-allergic asthma phenotypes develop.

  19. Interleukin-17 and innate immunity in infections and chronic inflammation.

    PubMed

    Isailovic, Natasa; Daigo, Kenji; Mantovani, Alberto; Selmi, Carlo

    2015-06-01

    Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. The immunobiology of Campylobacter jejuni: Innate immunity and autoimmune diseases.

    PubMed

    Phongsisay, Vongsavanh

    2016-04-01

    The Gram-negative bacterium Campylobacter jejuni causes gastroenteritis and Guillain-Barré syndrome in humans. Recent advances in the immunobiology of C. jejuni have been made. This review summarizes C. jejuni-binding innate receptors and highlights the role of innate immunity in autoimmune diseases. This human pathogen produces a variety of glycoconjugates, including human ganglioside-like determinants and multiple activators of Toll-like receptors (TLRs). Furthermore, C. jejuni targets MyD88, NLRP3 inflammasome, TIR-domain-containing adapter-inducing interferon-β (TRIF), sialic acid-binding immunoglobulin-like lectins (Siglecs), macrophage galactose-type lectin (MGL), and immunoglobulin-like receptors (TREM2, LMIR5/CD300b). The roles of these innate receptors and signaling molecules have been extensively studied. MyD88-mediated TLR activation or inflammasome-dependent IL-1β secretion is essential for autoimmune induction. TRIF mediates the production of type I interferons that promote humoral immune responses and immunoglobulin class-switching. Siglec-1 and Siglec-7 interact directly with gangliosides. Siglec-1 activation enhances phagocytosis and inflammatory responses. MGL internalizes GalNAc-containing glycoconjugates. TREM2 is well-known for its role in phagocytosis. LMIR5 recognizes C. jejuni components and endogenous sulfoglycolipids. Several lines of evidence from animal models of autoimmune diseases suggest that simultaneous activation of innate immunity in the presence of autoreactive lymphocytes or antigen mimicry may link C. jejuni to immunopathology. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Innate and adaptive immune responses in neurodegeneration and repair.

    PubMed

    Amor, Sandra; Woodroofe, M Nicola

    2014-03-01

    Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases.

  2. Long noncoding RNAs in Innate and Adaptive Immunity

    PubMed Central

    Fitzgerald, Katherine A.; Caffrey, Daniel R.

    2014-01-01

    The differentiation and activation of both innate and adaptive immune cells is highly dependent on a coordinated set of transcriptional and post-transcriptional events. Chromatin-modifiers and transcription factors regulate the accessibility and transcription of immune genes, respectively. Immune cells also express miRNA and RNA-binding proteins that provide an additional layer of regulation at the mRNA level. However, long noncoding RNA (lncRNA), which have been primarily studied in the context of genomic imprinting, cancer, and cell differentiation, are now emerging as important regulators of immune cell differentiation and activation. In this review, we provide a brief overview of lncRNA, their known functions in immunity, and discuss their potential to be more broadly involved in other aspects of the immune response. PMID:24556411

  3. Innate and adaptive immune cells in the tumor microenvironment

    PubMed Central

    Gajewski, Thomas F; Schreiber, Hans; Fu, Yang-Xin

    2014-01-01

    Most tumor cells express antigens that can mediate recognition by host CD8+ T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell–inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system–suppressive pathways. The other major phenotype lacks this T cell–inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect. PMID:24048123

  4. Innate immune cell response upon Candida albicans infection

    PubMed Central

    Qin, Yulin; Zhang, Lulu; Xu, Zheng; Zhang, Jinyu; Jiang, Yuan-ying; Cao, Yongbing; Yan, Tianhua

    2016-01-01

    abstract Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity. PMID:27078171

  5. Innate immune cell response upon Candida albicans infection.

    PubMed

    Qin, Yulin; Zhang, Lulu; Xu, Zheng; Zhang, Jinyu; Jiang, Yuan-Ying; Cao, Yongbing; Yan, Tianhua

    2016-07-03

    Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity.

  6. Innate and adaptive immune responses in neurodegeneration and repair

    PubMed Central

    Amor, Sandra; Woodroofe, M Nicola

    2014-01-01

    Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases. PMID:23758741

  7. Innate lymphoid cell function in the context of adaptive immunity

    PubMed Central

    Bando, Jennifer K.; Colonna, Marco

    2016-01-01

    Innate lymphoid cells (ILCs) are a family of innate immune cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror polarized T helper subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant in comparison to T cells. Here, we discuss genetic mouse models that have been used to dissect the contributions of ILCs versus T cells, and review our current understanding of the specialized in vivo functions of ILCs. PMID:27328008

  8. 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

  9. Mesenchymal stromal cells and the innate immune response.

    PubMed

    Le Blanc, Katarina; Davies, Lindsay C

    2015-12-01

    Mesenchymal stromal cells (MSC) have been exploited for their immunomodulatory properties in the treatment of a number of immune-based disorders, including Graft versus Host Disease (GvHD) and type 1 diabetes. The mechanisms for inducing therapeutic effect still remain largely unknown however, with research focused on understanding how MSCs interact with individual immune cell subsets. Within this review we address what is known about the interactions of MSCs with cells of the innate immune system, how they respond to their microenvironment and how this relates to therapeutic effects we see both within in vivo animal models and in clinical trials.

  10. Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity

    PubMed Central

    Rodriguez, Paulo C.; Ochoa, Augusto C.; Al-Khami, Amir A.

    2017-01-01

    Arginine metabolism has been a key catabolic and anabolic process throughout the evolution of the immune response. Accruing evidence indicates that arginine-catabolizing enzymes, mainly nitric oxide synthases and arginases, are closely integrated with the control of immune response under physiological and pathological conditions. Myeloid cells are major players that exploit the regulators of arginine metabolism to mediate diverse, although often opposing, immunological and functional consequences. In this article, we focus on the importance of arginine catabolism by myeloid cells in regulating innate and adaptive immunity. Revisiting this matter could result in novel therapeutic approaches by which the immunoregulatory nodes instructed by arginine metabolism can be targeted. PMID:28223985

  11. New insights into innate immune control of systemic candidiasis.

    PubMed

    Lionakis, Michail S

    2014-08-01

    Systemic infection caused by Candida species is the fourth leading cause of nosocomial bloodstream infection in modern hospitals and carries high morbidity and mortality despite antifungal therapy. A recent surge of immunological studies in the mouse models of systemic candidiasis and the parallel discovery and phenotypic characterization of inherited genetic disorders in antifungal immune factors that are associated with enhanced susceptibility or resistance to the infection have provided new insights into the cellular and molecular basis of protective innate immune responses against Candida. In this review, the new developments in our understanding of how the mammalian immune system responds to systemic Candida challenge are synthesized and important future research directions are highlighted.

  12. Molecular insights on the cerebral innate immune system.

    PubMed

    Rivest, Serge

    2003-02-01

    All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.

  13. Trained immunity: A program of innate immune memory in health and disease.

    PubMed

    Netea, Mihai G; Joosten, Leo A B; Latz, Eicke; Mills, Kingston H G; Natoli, Gioacchino; Stunnenberg, Hendrik G; O'Neill, Luke A J; Xavier, Ramnik J

    2016-04-22

    The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases. Copyright © 2016, American Association for the Advancement of Science.

  14. Trained immunity: a program of innate immune memory in health and disease

    PubMed Central

    Netea, Mihai G.; Joosten, Leo A.B.; Latz, Eicke; Mills, Kingston H.G.; Natoli, Gioacchino; Stunnenberg, Hendrik G.; O’Neill, Luke A.J.; Xavier, Ramnik J.

    2016-01-01

    The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed trained immunity or innate immune memory. Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases. PMID:27102489

  15. Innate Immunity Dysregulation in Myelodysplastic Syndromes

    DTIC Science & Technology

    2013-10-01

    expression of JMJD3 was examined using immune- histochemical staining in primary BM CD34+ cytospins of patients with MDS (N=7) and healthy controls (N=2...of activated NF-KB complex, 18 in primary MOS and control BM (034 + cell cytospins. This staining confi rmed increase levels of p-p65 in MOS cells...characterize JMJ03 expression in MOS BM CD34 + cells, we performed immuno- histochemical staining of JMJ03 protein in primary BM C034 + cytospins of

  16. Innate immune cells for immunotherapy of autoimmune and cancer disorders.

    PubMed

    Schäfer, Carolina; Ascui, Gabriel; Ribeiro, Carolina H; López, Mercedes; Prados-Rosales, Rafael; González, Pablo A; Bueno, Susan M; Riedel, Claudia A; Baena, Andrés; Kalergis, Alexis M; Carreño, Leandro J

    2017-09-21

    Modulation of the immune system has been widely targeted for the treatment of several immune-related diseases, such as autoimmune disorders and cancer, due to its crucial role in these pathologies. Current available therapies focus mainly on symptomatic treatment and are often associated with undesirable secondary effects. For several years, remission of disease and subsequently recovery of immune homeostasis has been a major goal for immunotherapy. Most current immunotherapeutic strategies are aimed to inhibit or potentiate directly the adaptive immune response by modulating antibody production and B cell memory, as well as the effector potential and memory of T cells. Although these immunomodulatory approaches have shown some success in the clinic with promising therapeutic potential, they have some limitations related to their effectiveness in disease models and clinical trials, as well as elevated costs. In the recent years, a renewed interest has emerged on targeting innate immune cells for immunotherapy, due to their high plasticity and ability to exert a potent and extremely rapid response, which can influence the outcome of the adaptive immune response. In this review, we discuss the immunomodulatory potential of several innate immune cells, as well as they use for immunotherapy, especially in autoimmunity and cancer.

  17. MicroRNAs in Rice Innate Immunity.

    PubMed

    Baldrich, Patricia; San Segundo, Blanca

    2016-12-01

    MicroRNAs (miRNAs) are short regulatory non-coding RNAs that guide gene silencing in most eukaryotes. They regulate gene expression by triggering sequence-specific cleavage or translational repression of target transcripts. Plant miRNAs are known to play important roles in a wide range of developmental processes. Increasing evidence also supports that the modulation of miRNA levels plays an important role in reprogramming plant responses to abiotic stress (drought, cold, salinity and nutrient deficiency) and biotic stress (antibacterial resistance). Most of these studies were carried out in the model plant Arabidopsis thaliana. During the last years, the adoption of high-throughput sequencing technologies has significantly contributed to uncover multiple miRNAs while allowing miRNA profiling in plants. However, although a plethora of rice miRNAs have been shown to be regulated by pathogen infection, the biological function remains largely unknown for most of them. In this review, we summarize our current understanding on the contribution of miRNAs to rice immunity and discuss their potential applications in rice biotechnology. A better understanding of the miRNA species controlling rice immunity may lead to practical biotechnological applications leading to the development of appropriate strategies for rice protection.

  18. Platelet Interaction with Innate Immune Cells

    PubMed Central

    Kral, Julia Barbara; Schrottmaier, Waltraud Cornelia; Salzmann, Manuel; Assinger, Alice

    2016-01-01

    Summary Beyond their traditional role in haemostasis and thrombosis, platelets are increasingly recognised as immune modulatory cells. Activated platelets and platelet-derived microparticles can bind to leukocytes, which stimulates mutual activation and results in rapid, local release of platelet-derived cytokines. Thereby platelets modulate leukocyte effector functions and contribute to inflammatory and immune responses to injury or infection. Platelets enhance leukocyte extravasation, differentiation and cytokine release. Platelet-neutrophil interactions boost oxidative burst, neutrophil extracellular trap formation and phagocytosis and play an important role in host defence. Platelet interactions with monocytes propagate their differentiation into macrophages, modulate cytokine release and attenuate macrophage functions. Depending on the underlying pathology, platelets can enhance or diminish leukocyte cytokine production, indicating that platelet-leukocyte interactions represent a fine balanced system to restrict excessive inflammation during infection. In atherosclerosis, platelet interaction with neutrophils, monocytes and dendritic cells accelerates key steps of atherogenesis by promoting leukocyte extravasation and foam cell formation. Platelet-leukocyte interactions at sites of atherosclerotic lesions destabilise atherosclerotic plaques and promote plaque rupture. Leukocytes in turn also modulate platelet function and production, which either results in enhanced platelet destruction or increased platelet production. This review aims to summarise the key effects of platelet-leukocyte interactions in inflammation, infection and atherosclerosis. PMID:27226790

  19. Nlrp6 regulates intestinal antiviral innate immunity

    PubMed Central

    Wang, Penghua; Zhu, Shu; Yang, Long; Cui, Shuang; Pan, Wen; Jackson, Ruaidhri; Zheng, Yunjiang; Rongvaux, Anthony; Sun, Qiangming; Yang, Guang; Gao, Shandian; Lin, Rongtuan; You, Fuping; Flavell, Richard; Fikrig, Erol

    2016-01-01

    The nucleotide-binding oligomerization domain-like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6−/− and control mice systemically challenged with encephalomyocarditis virus had similar mortality, however, the gastrointestinal tract of Nlrp6−/− mice exhibited increased viral loads. Nlrp6−/− mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared to controls. Similar results were observed with murine norovirus 1. Nlrp6 bound viral RNA via the RNA helicase Dhx15 and interacted with Mavs to induce type I/III interferons (IFNs) and IFN-stimulated genes (ISGs). These data demonstrate that Nlrp6 functions with Dhx15 as a viral RNA sensor to induce ISGs, and this effect is especially important in the intestinal tract. PMID:26494172

  20. Innate immunity at the forefront of psychoneuroimmunology.

    PubMed

    Dantzer, Robert

    2004-01-01

    The last 15 years of research in psychoneuroimmunology have been marked by a renewed interest in the mechanisms of inflammation and participation of the brain in these mechanisms. Peripheral proinflammatory cytokines produced by activated accessory immune cells act in the brain to trigger sickness, in the form of fever, pituitary-adrenal axis activation, and sickness behavior. Communication between the periphery and brain takes place via both neural and humoral pathways. Recognition of the role of local production of cytokines and their downstream messengers in the central nervous system opens important new vistas for understanding and treating non-specific neurovegetative and psychiatric symptoms of diseases. In this presidential address, I present the main methodological and conceptual developments that have allowed such progress.

  1. Mitochondria in the regulation of innate and adaptive immunity.

    PubMed

    Weinberg, Samuel E; Sena, Laura A; Chandel, Navdeep S

    2015-03-17

    Mitochondria are well appreciated for their role as biosynthetic and bioenergetic organelles. In the past two decades, mitochondria have emerged as signaling organelles that contribute critical decisions about cell proliferation, death, and differentiation. Mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and their function. Mitochondria can rapidly switch from primarily being catabolic organelles generating ATP to anabolic organelles that generate both ATP and building blocks for macromolecule synthesis. This enables them to fulfill appropriate metabolic demands of different immune cells. Mitochondria have multiple mechanisms that allow them to activate signaling pathways in the cytosol including altering in AMP/ATP ratio, the release of ROS and TCA cycle metabolites, as well as the localization of immune regulatory proteins on the outer mitochondrial membrane. In this Review, we discuss the evidence and mechanisms that mitochondrial dependent signaling controls innate and adaptive immune responses.

  2. Cytosolic nucleic acid sensors and innate immune regulation.

    PubMed

    Ori, Daisuke; Murase, Motoya; Kawai, Taro

    2017-03-04

    During viral and bacterial infections, pathogen-derived cytosolic nucleic acids are recognized by the intracellular RNA sensors retinoic acid-inducible gene I and melanoma-differentiated gene 5 and intracellular DNA sensors, including cyclic-di-GMP-AMP synthase, absent in melanoma 2, interferon (IFN)-gamma inducible protein 16, polymerase III, and so on. Binding of intracellular nucleic acids to these sensors activates downstream signaling cascades, resulting in the production of type I IFNs and pro-inflammatory cytokines to induce appropriate systematic immune responses. While these sensors also recognize endogenous nucleic acids and activate immune responses, they can discriminate between self- and non-self-nucleic acids. However, dysfunction of these sensors or failure of regulatory mechanisms causes aberrant activation of immune response and autoimmune disorders. In this review, we focus on how intracellular immune sensors recognize exogenous nucleic acids and activate the innate immune system, and furthermore, how autoimmune diseases result from dysfunction of these sensors.

  3. Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

    PubMed Central

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F.

    2015-01-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor–ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  4. Innate Immune Responses and Chronic Obstructive Pulmonary Disease

    PubMed Central

    Schleimer, Robert P.

    2005-01-01

    Innate immune responses appear to be partially responsible for maintaining inflammation and tissue destruction in chronic obstructive pulmonary disease. In the early stages of the disease in smokers, the airways are bombarded with large quantities of particulate material, and activation of phagocytic cells results in the release of many of the mediators believed to remodel the airways. Ironically, failure of the innate immune defense system, either by inherited deficiency or as a result of chronic smoke inhalation, is likely to result in increased susceptibility to infectious disease and exacerbations of chronic obstructive pulmonary disease. It is well known that deficiencies in the production of collectins, pentraxins, and complement can lead to increased infections, and several studies indicate that deficiency in one or another innate defense component is associated with increased exacerbations. Corticosteroids reduce exacerbations in part because of their ability to boost the production of innate host-defense molecules. Therapeutic approaches that stimulate the generation of antimicrobial molecules in the lungs might be able to reduce disease exacerbations. PMID:16267360

  5. When less means more: dehydration improves innate immunity in rattlesnakes.

    PubMed

    Brusch, George A; DeNardo, Dale F

    2017-04-12

    Immune function can vary based on availability of resources, and most studies of such influences have focused on the co-investment of energy into immune and other physiological functions. When energy resources are limited, trade-offs exist, which can compromise immunity for other functions. As with energy, water limitation can also alter various physiological processes, yet water has received little consideration for its role in possibly modulating immune functions. We examined the relationship between immunocompetence and hydration state using the western diamond-backed rattlesnake (Crotalus atrox). This species is known to undergo substantial seasonal fluctuations in water availability with extreme limitations during the hot, dry season. We collected blood samples from free-ranging C. atrox to compare osmolality and innate immune function (lysis, agglutination, bacterial growth inhibition) during the milder and relatively moister early spring season, the hot-dry season, and the hot-wet season. To isolate effects of dehydration from other possible seasonal influences, we complemented this field study with a laboratory study in which we withheld food and water from individually housed adult C. atrox for up to 16 weeks. We collected blood samples from each snake as it dehydrated and collected a final sample after the snake was given ad lib water at the end of the experiment. Our results demonstrate that C. atrox experience significant dehydration during the hot-dry season, and that, in general, innate immune function is highly correlated with osmolality, whether natural or artificially manipulated.

  6. Innate immunity prevents tissue invasion by Entamoeba histolytica.

    PubMed

    Shibayama, Mineko; Rivera-Aguilar, Víctor; Barbosa-Cabrera, Elizabeth; Rojas-Hernández, Saúl; Jarillo-Luna, Adriana; Tsutsumi, Víctor; Pacheco-Yepez, Judith; Campos-Rodríguez, Rafael

    2008-12-01

    Although innate and adaptive immunity both play a role in amoebiasis, the mechanisms involved in the elimination of Entamoeba histolytica are poorly understood. To provide more information about the innate immune mechanisms that may confer protection against invasive amoebiasis, we administered inflammatory substances (bacillus Calmette-Guérin, lipopolysaccharide, complete Freund's adjuvant, or mineral oil) into the peritoneum of hamsters. The animals were then challenged with pathogenic trophozoites of E. histolytica and, after 7 days, the protective host response was analysed. We found that the nonspecific inflammatory response induced in the peritoneum was sufficient to prevent liver invasion by E. histolytica. In vitro experiments showed that the killing of trophozoites was mediated by peritoneal macrophages and a protein of 68 kDa with peroxidase activity.

  7. Innate immune programing by endotoxin and its pathological consequences.

    PubMed

    Morris, Matthew C; Gilliam, Elizabeth A; Li, Liwu

    2014-01-01

    Monocytes and macrophages play pivotal roles in inflammation and homeostasis. Recent studies suggest that dynamic programing of macrophages and monocytes may give rise to distinct "memory" states. Lipopolysaccharide (LPS), a classical pattern recognition molecule, dynamically programs innate immune responses. Emerging studies have revealed complex dynamics of cellular responses to LPS, with high doses causing acute, resolving inflammation, while lower doses are associated with low-grade and chronic non-resolving inflammation. These phenomena hint at dynamic complexities of intra-cellular signaling circuits downstream of the Toll-like receptor 4 (TLR4). In this review, we examine pathological effects of varying LPS doses with respect to the dynamics of innate immune responses and key molecular regulatory circuits responsible for these effects.

  8. Innate Immunity in Alzheimer’s disease: a Complex Affair

    PubMed Central

    Guillot-Sestier, Marie-Victoire; Town, Terrence

    2013-01-01

    Alzheimer’s disease (AD) is characterized by three major histopathological hallmarks: β-amyloid plaques, neurofibrillary tangles and gliosis. While neglected for decades, neuroinflammatory processes coordinated by microglia are now accepted as etiologic events in AD evolution. Microglial cells are found in close vicinity to amyloid plaques and display various activation phenotypes determined by expression of a wide range of cytokines, chemokines, and innate immune cell surface receptors. During the development of AD pathology, microglia fail to restrict amyloid plaques and may contribute to neurotoxicity and cognitive deficit. Nevertheless, under specific conditions, microglia can participate in cerebral amyloid clearance. This review focuses on the complex relationship between microglia and Aβ pathology, and highlights both deleterious and beneficial roles of microglial activation in the context of AD. A deeper understanding of microglial biology will hopefully pave the way for next-generation AD therapeutic approaches aimed at harnessing these enigmatic innate immune cells of the central nervous system. PMID:23574177

  9. Innate immunity: actuating the gears of celiac disease pathogenesis.

    PubMed

    Kim, Sangman Michael; Mayassi, Toufic; Jabri, Bana

    2015-06-01

    Celiac disease is a T cell mediated immune disorder characterized by the loss of oral tolerance to dietary gluten and the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells, leading to villous atrophy. Innate immunity plays a critical role in both of these processes and cytokines such as interleukin-15 and interferon-α can modulate innate processes such as polarization of dendritic cells as well as intraepithelial lymphocyte function. These cytokines can be modulated by host microbiota, which can also influence dendritic cell function and intraepithelial lymphocyte homeostasis. We will elaborate on the role of interleukin-15, interferon-α, and the microbiota in modulating the processes that lead to loss of tolerance to gluten and tissue destruction in celiac disease.

  10. Defining the subcellular sites of innate immune signal transduction.

    PubMed

    Kagan, Jonathan C

    2012-09-01

    Innate immune activation by microbial detection receptors is a complex process involving at least 100 proteins and multiple signaling pathways. Although there continues to be a need to identify additional regulators of host-microbe interactions, a larger conceptual challenge is our lack of understanding of how the known regulators interact in space and time. This review offers a framework to explain the long appreciated (but poorly understood) observation that innate immune signaling pathways are activated from multiple organelles. Using the Toll-like receptors (TLRs) and the retinoic acid-inducible gene 1 protein (RIG-I)-like receptors (RLRs) as examples, I propose that the receptors do not necessarily define the sites of signaling. Rather, a structurally unrelated class of proteins called 'sorting adaptors' functions in this capacity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Mechanisms of innate immunity in C. elegans epidermis

    PubMed Central

    Taffoni, Clara; Pujol, Nathalie

    2015-01-01

    The roundworm C. elegans has been successfully used for more than 50 y as a genetically tractable invertebrate model in diverse biological fields such as neurobiology, development and interactions. C. elegans feeds on bacteria and can be naturally infected by a wide range of microorganisms, including viruses, bacteria and fungi. Most of these pathogens infect C. elegans through its gut, but some have developed ways to infect the epidermis. In this review, we will mainly focus on epidermal innate immunity, in particular the signaling pathways and effectors activated upon wounding and fungal infection that serve to protect the host. We will discuss the parallels that exist between epidermal innate immune responses in nematodes and mammals. PMID:26716073

  12. TLR signaling: an emerging bridge from innate immunity to atherogenesis.

    PubMed

    Michelsen, Kathrin S; Doherty, Terence M; Shah, Prediman K; Arditi, Moshe

    2004-11-15

    Chronic inflammation and disordered lipid metabolism represent hallmarks of atherosclerosis. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to development of arterial plaques. The preponderance of such evidence has been indirect clinical and epidemiologic studies, with some support from experimental animal models of atherosclerosis. However, recent data now directly implicate signaling by TLR4 in the pathogenesis of atherosclerosis, establishing a key link between atherosclerosis and defense against both foreign pathogens and endogenously generated inflammatory ligands. In this study, we briefly review these and closely related studies, highlighting areas that should provide fertile ground for future studies aimed at a more comprehensive understanding of the interplay between innate immune defense mechanisms, atherosclerosis, and related vascular disorders.

  13. Pathogen recognition or homeostasis? APC receptor functions in innate immunity.

    PubMed

    Gordon, Siamon

    2004-06-01

    Myeloid cells (macrophages, neutrophils, dendritic cells) express a repertoire of plasma membrane receptors able to recognize all classes of macromolecules. The concept of pattern recognition has emphasized microbial ligands and host defence. However, these receptors play a broader role in tissue homeostasis within multicellular hosts, clearing the extracellular environment of potential undesirable ligands arising endogenously as well as from without. This article will evaluate one of the paradigms that underlie innate immunity.

  14. Construction and validation of a Bovine Innate Immune Microarray

    PubMed Central

    Donaldson, Laurelea; Vuocolo, Tony; Gray, Christian; Strandberg, Ylva; Reverter, Antonio; McWilliam, Sean; Wang, YongHong; Byrne, Keren; Tellam, Ross

    2005-01-01

    Background Microarray transcript profiling has the potential to illuminate the molecular processes that are involved in the responses of cattle to disease challenges. This knowledge may allow the development of strategies that exploit these genes to enhance resistance to disease in an individual or animal population. Results The Bovine Innate Immune Microarray developed in this study consists of 1480 characterised genes identified by literature searches, 31 positive and negative control elements and 5376 cDNAs derived from subtracted and normalised libraries. The cDNA libraries were produced from 'challenged' bovine epithelial and leukocyte cells. The microarray was found to have a limit of detection of 1 pg/μg of total RNA and a mean slide-to-slide correlation co-efficient of 0.88. The profiles of differentially expressed genes from Concanavalin A (ConA) stimulated bovine peripheral blood lymphocytes were determined. Three distinct profiles highlighted 19 genes that were rapidly up-regulated within 30 minutes and returned to basal levels by 24 h; 76 genes that were up-regulated between 2–8 hours and sustained high levels of expression until 24 h and 10 genes that were down-regulated. Quantitative real-time RT-PCR on selected genes was used to confirm the results from the microarray analysis. The results indicate that there is a dynamic process involving gene activation and regulatory mechanisms re-establishing homeostasis in the ConA activated lymphocytes. The Bovine Innate Immune Microarray was also used to determine the cross-species hybridisation capabilities of an ovine PBL sample. Conclusion The Bovine Innate Immune Microarray has been developed which contains a set of well-characterised genes and anonymous cDNAs from a number of different bovine cell types. The microarray can be used to determine the gene expression profiles underlying innate immune responses in cattle and sheep. PMID:16176586

  15. Prognostic value of innate and adaptive immunity in colorectal cancer

    PubMed Central

    Grizzi, Fabio; Bianchi, Paolo; Malesci, Alberto; Laghi, Luigi

    2013-01-01

    Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit. PMID:23345940

  16. Prognostic value of innate and adaptive immunity in colorectal cancer.

    PubMed

    Grizzi, Fabio; Bianchi, Paolo; Malesci, Alberto; Laghi, Luigi

    2013-01-14

    Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit.

  17. Interactions between bile salts, gut microbiota, and hepatic innate immunity.

    PubMed

    Schubert, Kristin; Olde Damink, Steven W M; von Bergen, Martin; Schaap, Frank G

    2017-09-01

    Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Antimicrobial Peptides as Mediators of Innate Immunity in Teleosts

    PubMed Central

    Katzenback, Barbara A.

    2015-01-01

    Antimicrobial peptides (AMPs) have been identified throughout the metazoa suggesting their evolutionarily conserved nature and their presence in teleosts is no exception. AMPs are short (18–46 amino acids), usually cationic, amphipathic peptides. While AMPs are diverse in amino acid sequence, with no two AMPs being identical, they collectively appear to have conserved functions in the innate immunity of animals towards the pathogens they encounter in their environment. Fish AMPs are upregulated in response to pathogens and appear to have direct broad-spectrum antimicrobial activity towards both human and fish pathogens. However, an emerging role for AMPs as immunomodulatory molecules has become apparent—the ability of AMPs to activate the innate immune system sheds light onto the multifaceted capacity of these small peptides to combat pathogens through direct and indirect means. Herein, this review focuses on the role of teleost AMPs as modulators of the innate immune system and their regulation in response to pathogens or other exogenous molecules. The capacity to regulate AMP expression by exogenous factors may prove useful in modulating AMP expression in fish to prevent disease, particularly in aquaculture settings where crowded conditions and environmental stress pre-dispose these fish to infection. PMID:26426065

  19. Reovirus activates human dendritic cells to promote innate antitumor immunity.

    PubMed

    Errington, Fiona; Steele, Lynette; Prestwich, Robin; Harrington, Kevin J; Pandha, Hardev S; Vidal, Laura; de Bono, Johann; Selby, Peter; Coffey, Matt; Vile, Richard; Melcher, Alan

    2008-05-01

    Oncolytic viruses can exert their antitumor activity via direct oncolysis or activation of antitumor immunity. Although reovirus is currently under clinical investigation for the treatment of localized or disseminated cancer, any potential immune contribution to its efficacy has not been addressed. This is the first study to investigate the ability of reovirus to activate human dendritic cells (DC), key regulators of both innate and adaptive immune responses. Reovirus induced DC maturation and stimulated the production of the proinflammatory cytokines IFN-alpha, TNF-alpha, IL-12p70, and IL-6. Activation of DC by reovirus was not dependent on viral replication, while cytokine production (but not phenotypic maturation) was inhibited by blockade of PKR and NF-kappaB signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-gamma production and increased NK cytolytic activity. Moreover, short-term coculture of reovirus-activated DC with autologous T cells also enhanced T cell cytokine secretion (IL-2 and IFN-gamma) and induced non-Ag restricted tumor cell killing. These data demonstrate for the first time that reovirus directly activates human DC and that reovirus-activated DC stimulate innate killing by not only NK cells, but also T cells, suggesting a novel potential role for T cells in oncolytic virus-induced local tumor cell death. Hence reovirus recognition by DC may trigger innate effector mechanisms to complement the virus's direct cytotoxicity, potentially enhancing the efficacy of reovirus as a therapeutic agent.

  20. B cells enhance early innate immune responses during bacterial sepsis

    PubMed Central

    Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Weinstein, Jason S.; Delano, Matthew J.; Cuenca, Alex G.; Nacionales, Dina C.; Wynn, James L.; Lee, Pui Y.; Kumagai, Yutaro; Efron, Philip A.; Akira, Shizuo; Wasserfall, Clive; Atkinson, Mark A.

    2011-01-01

    Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis. PMID:21746813

  1. Innate Immune Memory: Implications for Microglial Function and Neuroprogression.

    PubMed

    Salam, Alex P; Pariante, Carmine M; Zunszain, Patricia

    2017-01-01

    Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression. © 2017 S. Karger AG, Basel.

  2. The genetics of innate immunity sensors and human disease.

    PubMed

    Pothlichet, Julien; Quintana-Murci, Lluis

    2013-04-01

    Since their discovery, innate immunity microbial sensors have been increasingly studied and shown to play a critical role in innate responses to microbes in several experimental in vitro, ex vivo, and animal models. However, their role in the human response to infection in natural conditions has just started to be deciphered, by means of clinical studies of primary immunodeficiencies and epidemiological genetic studies. Here, we summarize the major findings concerning the genetic diversity of the various families of microbial sensors in humans, and of other molecules involved in the signaling pathways they trigger. Specifically, we review the genetic associations, revealed by both clinical and epidemiological genetics studies, of microbial sensors from five different families: Toll-like receptors, C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. In particular, we consider the relationships between variation at the genes encoding these molecules and susceptibility to and the severity of infectious diseases and other clinical conditions associated with immune dysfunction, including autoimmunity, inflammation, allergy, and cancer. Despite the fact that the genetic links between innate immunity sensors and human disorders remain still limited, human genetics studies are increasingly improving our understanding of the genuine functions of microbial sensors and downstream signaling molecules in the natural setting.

  3. Innate immune recognition of flagellin limits systemic persistence of Brucella.

    PubMed

    Terwagne, Matthieu; Ferooz, Jonathan; Rolán, Hortensia G; Sun, Yao-Hui; Atluri, Vidya; Xavier, Mariana N; Franchi, Luigi; Núñez, Gabriel; Legrand, Thomas; Flavell, Richard A; De Bolle, Xavier; Letesson, Jean-Jacques; Tsolis, Renée M

    2013-06-01

    Brucella are facultative intracellular bacteria that cause chronic infections by limiting innate immune recognition. It is currently unknown whether Brucella FliC flagellin, the monomeric subunit of flagellar filament, is sensed by the host during infection. Here, we used two mutants of Brucella melitensis, either lacking or overexpressing flagellin, to show that FliC hinders bacterial replication in vivo. The use of cells and mice genetically deficient for different components of inflammasomes suggested that FliC was a target of the cytosolic innate immune receptor NLRC4 in vivo but not in macrophages in vitro where the response to FliC was nevertheless dependent on the cytosolic adaptor ASC, therefore suggesting a new pathway of cytosolic flagellin sensing. However, our work also suggested that the lack of TLR5 activity of Brucella flagellin and the regulation of its synthesis and/or delivery into host cells are both part of the stealthy strategy of Brucella towards the innate immune system. Nevertheless, as a flagellin-deficient mutant of B. melitensis wasfound to cause histologically demonstrable injuries in the spleen of infected mice, we suggested that recognition of FliC plays a role in the immunological stand-off between Brucella and its host, which is characterized by a persistent infection with limited inflammatory pathology.

  4. Self/not self, innate immunity, danger, cancer potential

    NASA Astrophysics Data System (ADS)

    Cooper, Edwin L.

    2010-03-01

    Self/not self is an important hypothesis that has guided research in immunology. It is closely connected to adaptive immunity (restricted to vertebrates) and innate immunity (found in vertebrates and invertebrates). Self/not self is now being challenged and investigators are turning to the danger hypothesis to guide and open new areas of research. Emerging information suggests that genes involved in development of cancer are present in Drosophila and C. elegans. Short life span may not preclude the presence of genes that are related to the development of cancer.

  5. [Association of ocular inflammation and innate immune response].

    PubMed

    Sonoda, Koh-Hei

    2008-03-01

    Immune response has been divided into innate immunity and acquired immunity. We focused on the role of innate immunity during the formation of uveitis and choroidal neovascularization (CNV)-related diseases. To carry out a comprehensive analysis of ocular inflammatory responses in patients with uveitis, vitreous fluid was analyzed using a microbead-based multiplex ELIZA system. We found that cytokines which were related with innate immunity were elevated, but cytokines which were related with acquired immunity were not. We also found that the role of IL-17 was to produce Th17 cells in the chronic phase of experimental uveitis. Next, we investigated the role of the natural killer (NK) T cells which restrict CD1 and participate in the innate immune response in laser-induced experimental CNV. We studied the CNV formation in two independent NK T cell-deficient strains of mice, CD1 knockout (KO) mice and Jalpha18 KO mice, and found that both KO mice showed significant reduction of the effects of experimental CNV. After laser treatment, both CD1 KO mice and Jalpha18 KO mice showed a decrease in the expression of vascular endothelial growth factor (VEGF) expression in retina and choroid. Interestingly, intravitreous inoculation of a galactosylceramide (alphaGalCer), which is the ligand of NK Tcells, inhibited CNV in C57BL6 mice. Collectively, we conclude that NK T cells play an important role in forming CNV as one of the inducers of VEGS. Because NK T cells bear the potential to regulate immune response, alphaGalCer might activate NK T cells differently to produce angiostatic factors and have a therapeutic potential in vivo. During the clinical process of CNV-related diseases, not only CNV formation, but also subretinal scarring is thought to be another important step. We thus established the experimental model of subretinal scaring by injecting peritoneal exudating macrophases into the subretinal space. This scaring was inhibited by inoculation of anti-IL-6 antibody and

  6. Insights on adaptive and innate immunity in canine leishmaniosis.

    PubMed

    Hosein, Shazia; Blake, Damer P; Solano-Gallego, Laia

    2017-01-01

    Canine leishmaniosis (CanL) is caused by the parasite Leishmania infantum and is a systemic disease, which can present with variable clinical signs, and clinicopathological abnormalities. Clinical manifestations can range from subclinical infection to very severe systemic disease. Leishmaniosis is categorized as a neglected tropical disease and the complex immune responses associated with Leishmania species makes therapeutic treatments and vaccine development challenging for both dogs and humans. In this review, we summarize innate and adaptive immune responses associated with L. infantum infection in dogs, and we discuss the problems associated with the disease as well as potential solutions and the future direction of required research to help control the parasite.

  7. The role of nuclear macromolecules in innate immunity.

    PubMed

    Pisetsky, David S

    2007-07-01

    Nuclear macromolecules, in addition to their intracellular role in regulating cell function, can translocate into the extracellular space where they can activate innate immunity. This translocation can occur in various settings and reflects the dynamic nature of nuclear structure. Of nuclear molecules, DNA and the DNA-binding protein, HMGB1, display distinct patterns of immune activity. For DNA, immune activity depends on sequence, base methylation, and context. While bacterial DNA is an immune activator, mammalian DNA is either inert or inhibitory when free. In contrast, mammalian DNA in the form of immune complexes can trigger immune cell activation. As shown in in vivo and in vitro studies, DNA can exit cells during apoptotic as well as necrotic cell death in a process that may depend on the presence of macrophages. Like DNA, HMGB1 can exit cells and acquire immune properties. For HMGB1, the translocation occurs in macrophages that have been stimulated by Toll-like receptor (TLR) ligands as well as cytokines; HMGB1 release can also occur with apoptotic as well as necrotic death. While HMGB1 alone can display cytokine activity, it may also activate cells in conjunction with other immune stimulators such as TLR ligands. For both DNA and HMGB1, the immune properties may therefore reflect the array of other endogenous as well as exogenous molecules present.

  8. INSIDE-OUT SIGNALING PATHWAYS FROM NUCLEAR ROS CONTROL PULMONARY INNATE IMMUNITY

    PubMed Central

    Choudhary, Sanjeev; Brasier, Allan R.

    2016-01-01

    The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries on two nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1•8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the NFκB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type -I and –III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in PRR signaling, regulating the IIR. PMID:26756522

  9. Innate and Adaptive Immunity in Calcific Aortic Valve Disease

    PubMed Central

    Mathieu, Patrick; Bouchareb, Rihab

    2015-01-01

    Calcific aortic valve disease (CAVD) is the most common heart valve disorder. CAVD is a chronic process characterized by a pathologic mineralization of valve leaflets. Ectopic mineralization of the aortic valve involves complex relationships with immunity. Studies have highlighted that both innate and adaptive immunity play a role in the development of CAVD. In this regard, accumulating evidence indicates that fibrocalcific remodelling of the aortic valve is associated with activation of the NF-κB pathway. The expression of TNF-α and IL-6 is increased in human mineralized aortic valves and promotes an osteogenic program as well as the mineralization of valve interstitial cells (VICs), the main cellular component of the aortic valve. Different factors, including oxidized lipid species, activate the innate immune response through the Toll-like receptors. Moreover, VICs express 5-lipoxygenase and therefore produce leukotrienes, which may amplify the inflammatory response in the aortic valve. More recently, studies have emphasized that an adaptive immune response is triggered during CAVD. Herein, we are reviewing the link between the immune response and the development of CAVD and we have tried, whenever possible, to keep a translational approach. PMID:26065007

  10. Crosstalk between Vitamin D Metabolism, VDR Signalling, and Innate Immunity

    PubMed Central

    2016-01-01

    The primary function of vitamin D is to regulate calcium homeostasis, which is essential for bone formation and resorption. Although diet is a source of vitamin D, most foods are naturally lacking vitamin D. Vitamin D is also manufactured in the skin through a photolysis process, leading to a process called the “sunshine vitamin.” The active form of vitamin D, 1,25-dihydroxyvitamin D (calcitriol), is biosynthesised in the kidney through the hydroxylation of 25-hydroxycholecalciferol by the CYP27B1 enzyme. It has been found that several immune cells express the vitamin D receptor (VDR) and CYP27B1; of the latter, synthesis is determined by several immune-specific signals. The realisation that vitamin D employs several molecular mechanisms to regulate innate immune responses is more recent. Furthermore, evidence collected from intervention studies indicates that vitamin D supplements may boost clinical responses to infections. This review considers the current knowledge of how immune signals regulate vitamin D metabolism and how innate immune system function is modulated by ligand-bound VDR. PMID:27403416

  11. Innate and Adaptive Immunity in Calcific Aortic Valve Disease.

    PubMed

    Mathieu, Patrick; Bouchareb, Rihab; Boulanger, Marie-Chloé

    2015-01-01

    Calcific aortic valve disease (CAVD) is the most common heart valve disorder. CAVD is a chronic process characterized by a pathologic mineralization of valve leaflets. Ectopic mineralization of the aortic valve involves complex relationships with immunity. Studies have highlighted that both innate and adaptive immunity play a role in the development of CAVD. In this regard, accumulating evidence indicates that fibrocalcific remodelling of the aortic valve is associated with activation of the NF-κB pathway. The expression of TNF-α and IL-6 is increased in human mineralized aortic valves and promotes an osteogenic program as well as the mineralization of valve interstitial cells (VICs), the main cellular component of the aortic valve. Different factors, including oxidized lipid species, activate the innate immune response through the Toll-like receptors. Moreover, VICs express 5-lipoxygenase and therefore produce leukotrienes, which may amplify the inflammatory response in the aortic valve. More recently, studies have emphasized that an adaptive immune response is triggered during CAVD. Herein, we are reviewing the link between the immune response and the development of CAVD and we have tried, whenever possible, to keep a translational approach.

  12. Wheat amylase trypsin inhibitors as nutritional activators of innate immunity.

    PubMed

    Schuppan, Detlef; Zevallos, Victor

    2015-01-01

    While the central role of an adaptive, T cell-mediated immune response to certain gluten peptides in celiac disease is well established, the innate immune response to wheat proteins remains less well defined. We identified wheat amylase trypsin inhibitors (ATIs), but not gluten, as major stimulators of innate immune cells (dendritic cells>macrophages>monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2 toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17 proteins with molecular weights of around 15 kDa and a variable primary but conserved secondary structure characterized by 5 intrachain disulfide bonds and alpha helices. They mostly form di- and tetramers that appear to equally activate TLR4. Relevant biological activity is confined to ATIs in gluten-containing cereals, while gluten-free cereals display no or minimal activities. ATIs represent up to 4% of total wheat protein and are highly resistant to intestinal proteases. In line with their dose-dependent function as co-stimulatory molecules in adaptive immunity of celiac disease, they appear to play a role in promoting other immune-mediated diseases within and outside the GI tract. Thus, ATIs may be prime candidates of severe forms of non-celiac gluten (wheat) sensitivity. © 2015 S. Karger AG, Basel.

  13. Mosquito phenoloxidase and defensin colocalize in melanization innate immune responses.

    PubMed

    Hillyer, Julián F; Christensen, Bruce M

    2005-06-01

    Mosquitoes mount strong humoral and cellular immune responses against foreign organisms. Two components of the mosquito immune response that have received much attention are the phenoloxidase cascade that leads to melanization and antimicrobial peptides. The purpose of the current study was to use immunocytochemistry and transmission electron microscopy to identify the location of the melanization rate-limiting enzyme phenoloxidase and the antimicrobial peptide defensin in innate immune reactions against Escherichia coli and Micrococcus luteus by the mosquito Aedes aegypti. Our results show that both phenoloxidase and defensin are present at the sites of melanin biosynthesis in immune reactions against bacteria. Furthermore, both proteins are often present inside the same melanotic capsules. When hemocytes were analyzed, phenoloxidase was present in the cytosol of oenocytoids, but no significant amounts of defensin were detected inside any hemocytes. In summary, these data show that phenoloxidase and defensin colocalize in melanization reactions against bacteria and argue for further studies into the potential role of defensin in phenoloxidase-based melanization innate immune responses in mosquitoes.

  14. BCG-induced protection: effects on innate immune memory.

    PubMed

    Netea, Mihai G; van Crevel, Reinout

    2014-12-01

    The Bacille Calmette-Guerin (BCG) vaccine is the only vaccine proved to be effective against tuberculosis and it remains the most commonly used vaccine worldwide. In addition to its effects on mycobacterial diseases, an increasing body of epidemiological evidence accumulated since its introduction in 1921 shows that BCG also exerts beneficial non-specific effects ranging from protection against non-mycobacterial diseases, decreased incidence of allergic diseases, and treatment of certain malignancies. The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through epigenetic mechanisms, a process termed 'trained immunity'. The process of trained immunity may also play a role in the beneficial effects of BCG against tuberculosis and Mycobacterium tuberculosis infection, and this could have important consequences for our quest for improving vaccination strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines.

    PubMed

    Levy, Ofer; Netea, Mihai G

    2014-01-01

    Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named "trained immunity." Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases.

  16. Cancer immunoediting by the innate immune system in the absence of adaptive immunity.

    PubMed

    O'Sullivan, Timothy; Saddawi-Konefka, Robert; Vermi, William; Koebel, Catherine M; Arthur, Cora; White, J Michael; Uppaluri, Ravi; Andrews, Daniel M; Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J; Schreiber, Robert D; Bui, Jack D

    2012-09-24

    Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2(-/-), and RAG2(-/-)x γc(-/-) mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2(-/-)x γc(-/-) mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting.

  17. Cancer immunoediting by the innate immune system in the absence of adaptive immunity

    PubMed Central

    O’Sullivan, Timothy; Saddawi-Konefka, Robert; Vermi, William; Koebel, Catherine M.; Arthur, Cora; White, J. Michael; Uppaluri, Ravi; Andrews, Daniel M.; Ngiow, Shin Foong; Teng, Michele W.L.; Smyth, Mark J.; Schreiber, Robert D.

    2012-01-01

    Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3′methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2−/−, and RAG2−/−x γc−/− mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2−/−x γc−/− mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting. PMID:22927549

  18. Immune Receptors and Co-receptors in Antiviral Innate Immunity in Plants

    PubMed Central

    Gouveia, Bianca C.; Calil, Iara P.; Machado, João Paulo B.; Santos, Anésia A.; Fontes, Elizabeth P. B.

    2017-01-01

    Plants respond to pathogens using an innate immune system that is broadly divided into PTI (pathogen-associated molecular pattern- or PAMP-triggered immunity) and ETI (effector-triggered immunity). PTI is activated upon perception of PAMPs, conserved motifs derived from pathogens, by surface membrane-anchored pattern recognition receptors (PRRs). To overcome this first line of defense, pathogens release into plant cells effectors that inhibit PTI and activate effector-triggered susceptibility (ETS). Counteracting this virulence strategy, plant cells synthesize intracellular resistance (R) proteins, which specifically recognize pathogen effectors or avirulence (Avr) factors and activate ETI. These coevolving pathogen virulence strategies and plant resistance mechanisms illustrate evolutionary arms race between pathogen and host, which is integrated into the zigzag model of plant innate immunity. Although antiviral immune concepts have been initially excluded from the zigzag model, recent studies have provided several lines of evidence substantiating the notion that plants deploy the innate immune system to fight viruses in a manner similar to that used for non-viral pathogens. First, most R proteins against viruses so far characterized share structural similarity with antibacterial and antifungal R gene products and elicit typical ETI-based immune responses. Second, virus-derived PAMPs may activate PTI-like responses through immune co-receptors of plant PTI. Finally, and even more compelling, a viral Avr factor that triggers ETI in resistant genotypes has recently been shown to act as a suppressor of PTI, integrating plant viruses into the co-evolutionary model of host-pathogen interactions, the zigzag model. In this review, we summarize these important progresses, focusing on the potential significance of antiviral immune receptors and co-receptors in plant antiviral innate immunity. In light of the innate immune system, we also discuss a newly uncovered layer of

  19. Mechanisms and pathways of innate immune activation and regulation in health and cancer

    PubMed Central

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2015-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer. PMID:25625930

  20. Mechanisms and pathways of innate immune activation and regulation in health and cancer.

    PubMed

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2014-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.

  1. Role of TNF superfamily ligands in innate immunity.

    PubMed

    Vujanovic, Nikola L

    2011-08-01

    Natural killer (NK) cells and dendritic cells (DCs) are essential effector cells of the innate immune system that rapidly recognize and eliminate microbial pathogens and abnormal cells, and induce and regulate adaptive immune functions. While NK cells express perforin and granzymes in the lysosomal granules and transmembrane tumor necrosis factor superfamily ligands (tmTNFSFL) on the plasma membrane, DCs express only tmTNFSFL on the plasma membrane. Perforin and granzymes are cytolytic molecules, which NK cells use to mediate a secretory/necrotic killing mechanism against rare leukemia cell targets. TNFSFL are pleiotropic transmembrane molecules, which can mediate a variety of important functions such as apoptosis, development of peripheral lymphoid tissues, inflammation and regulation of immune functions. Using tmTNFSFL, NK cells and DCs mediate a cell contact-dependent non-secretory apoptotic cytotoxic mechanism against virtually all types of cancer cells, and cross talk that leads to polarization and reciprocal stimulation and amplification of Th1 type cytokines secreted by NK cells and DCs. In this paper, we review and discuss the supporting evidence of the non-secretory, tmTNFSFL-mediated innate mechanisms of NK cells and DCs, their roles in anticancer immune defense and potential of their modulation and use in prevention and treatment of cancer.

  2. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling.

    PubMed

    Petnicki-Ocwieja, Tanja; Kern, Aurelie

    2014-01-01

    Lyme disease is a long-term infection whose most severe pathology is characterized by inflammatory arthritis of the lower bearing joints, carditis, and neuropathy. The inflammatory cascades are initiated through the early recognition of invading Borrelia burgdorferi spirochetes by cells of the innate immune response, such as neutrophils and macrophage. B. burgdorferi does not have an intracellular niche and thus much research has focused on immune pathways activated by pathogen recognition molecules at the cell surface, such as the Toll-like receptors (TLRs). However, in recent years, studies have shown that internalization of the bacterium by host cells is an important component of the defense machinery in response to B. burgdorferi. Upon internalization, B. burgdorferi is trafficked through an endo/lysosomal pathway resulting in the activation of a number of intracellular pathogen recognition receptors including TLRs and Nod-like receptors (NLRs). Here we will review the innate immune molecules that participate in both cell surface and intracellular immune activation by B. burgdorferi.

  3. Responses of innate immune cells to group A Streptococcus

    PubMed Central

    Fieber, Christina; Kovarik, Pavel

    2014-01-01

    Group A Streptococcus (GAS), also called Streptococcus pyogenes, is a Gram-positive beta-hemolytic human pathogen which causes a wide range of mostly self-limiting but also several life-threatening diseases. Innate immune responses are fundamental for defense against GAS, yet their activation by pattern recognition receptors (PRRs) and GAS-derived pathogen-associated molecular patterns (PAMPs) is incompletely understood. In recent years, the use of animal models together with the powerful tools of human molecular genetics began shedding light onto the molecular mechanisms of innate immune defense against GAS. The signaling adaptor MyD88 was found to play a key role in launching the immune response against GAS in both humans and mice, suggesting that PRRs of the Toll-like receptor (TLR) family are involved in sensing this pathogen. The specific TLRs and their ligands have yet to be identified. Following GAS recognition, induction of cytokines such as TNF and type I interferons (IFNs), leukocyte recruitment, phagocytosis, and the formation of neutrophil extracellular traps (NETs) have been recognized as key events in host defense. A comprehensive knowledge of these mechanisms is needed in order to understand their frequent failure against GAS immune evasion strategies. PMID:25325020

  4. Innate immunity probed by lipopolysaccharides affinity strategy and proteomics.

    PubMed

    Giangrande, Chiara; Colarusso, Lucia; Lanzetta, Rosa; Molinaro, Antonio; Pucci, Piero; Amoresano, Angela

    2013-01-01

    Lipopolysaccharides (LPSs) are ubiquitous and vital components of the cell surface of Gram-negative bacteria that have been shown to play a relevant role in the induction of the immune-system response. In animal and plant cells, innate immune defenses toward microorganisms are triggered by the perception of pathogen associated molecular patterns. These are conserved and generally indispensable microbial structures such as LPSs that are fundamental in the Gram-negative immunity recognition. This paper reports the development of an integrated strategy based on lipopolysaccharide affinity methodology that represents a new starting point to elucidate the molecular mechanisms elicited by bacterial LPS and involved in the different steps of innate immunity response. Biotin-tagged LPS was immobilized on streptavidin column and used as a bait in an affinity capture procedure to identify protein partners from human serum specifically interacting with this effector. The complex proteins/lipopolysaccharide was isolated and the protein partners were fractionated by gel electrophoresis and identified by mass spectrometry. This procedure proved to be very effective in specifically binding proteins functionally correlated with the biological role of LPS. Proteins specifically bound to LPS essentially gathered within two functional groups, regulation of the complement system (factor H, C4b, C4BP, and alpha 2 macroglobulin) and inhibition of LPS-induced inflammation (HRG and Apolipoproteins). The reported strategy might have important applications in the elucidation of biological mechanisms involved in the LPSs-mediated molecular recognition and anti-infection responses.

  5. How metabolism generates signals during innate immunity and inflammation.

    PubMed

    McGettrick, Anne F; O'Neill, Luke A J

    2013-08-09

    The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1β appears to play a central role in these disorders. There is also evidence that metabolites such as NAD(+) (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1α) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1β. These observations cast new light on the role of metabolism during host defense and inflammation.

  6. Nucleosides Accelerate Inflammatory Osteolysis, Acting as Distinct Innate Immune Activators

    PubMed Central

    Pan, George; Zheng, Rui; Yang, Pingar; Li, Yao; Clancy, John P.; Liu, Jianzhong; Feng, Xu; Garber, David A; Spearman, Paul; McDonald, Jay M

    2015-01-01

    The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption activity in the presence of receptor activator for nuclear factor κB ligand (RANKL) in vitro. The studies described here further demonstrate that selected nucleosides and nucleoside analogues accelerate bone destruction in mice immunized with collagen II alone (CII) but also further enhance bone erosion in mice immunized by collagen II plus complete Freund's adjuvant (CII + CFA). Abundant osteoclasts are accumulated in destructive joints. These data indicate that nucleosides act as innate immune activators distinct from CFA, synergistically accelerating osteoclast formation and inflammatory osteolysis. The potential roles of the surface triggering receptor expressed on myeloid cells (TREM) and the intracellular inflammasome in nucleoside-enhanced osteoclastogenesis have been studied. These observations provide new insight into the pathogenesis and underlying mechanism of bone destruction in inflammatory autoimmune osteoarthritis. PMID:21472777

  7. Responses of innate immune cells to group A Streptococcus.

    PubMed

    Fieber, Christina; Kovarik, Pavel

    2014-01-01

    Group A Streptococcus (GAS), also called Streptococcus pyogenes, is a Gram-positive beta-hemolytic human pathogen which causes a wide range of mostly self-limiting but also several life-threatening diseases. Innate immune responses are fundamental for defense against GAS, yet their activation by pattern recognition receptors (PRRs) and GAS-derived pathogen-associated molecular patterns (PAMPs) is incompletely understood. In recent years, the use of animal models together with the powerful tools of human molecular genetics began shedding light onto the molecular mechanisms of innate immune defense against GAS. The signaling adaptor MyD88 was found to play a key role in launching the immune response against GAS in both humans and mice, suggesting that PRRs of the Toll-like receptor (TLR) family are involved in sensing this pathogen. The specific TLRs and their ligands have yet to be identified. Following GAS recognition, induction of cytokines such as TNF and type I interferons (IFNs), leukocyte recruitment, phagocytosis, and the formation of neutrophil extracellular traps (NETs) have been recognized as key events in host defense. A comprehensive knowledge of these mechanisms is needed in order to understand their frequent failure against GAS immune evasion strategies.

  8. Innate immune encounters of the (Type) 4th kind: Brucella.

    PubMed

    de Jong, Maarten F; Rolán, Hortensia G; Tsolis, Renée M

    2010-09-01

    In humans, pathogenic Brucella species cause a febrile illness known as brucellosis. A key pathogenic trait of this group of organisms is their ability to survive in immune cells and persist in tissues of the reticuloendothelial system, a process that requires the function of a Type IV secretion system. In contrast to other well-studied Gram-negative bacteria, Brucella spp. do not cause inflammation at the site of invasion, but have a latency period of 2-4 weeks before the onset of symptoms. This review discusses several mechanisms that allow Brucella spp. both to evade detection by pattern recognition receptors of the innate immune system and suppress their signalling. In contrast to these stealth features, the VirB Type IV secretion system, which mediates survival within phagocytic cells, stimulates innate immune responses in vivo. The responses stimulated by this virulence factor are sufficient to check bacterial growth, but not to elicit sterilizing immunity. The result is a stand-off between host and pathogen that results in persistent infection.

  9. Reversal of hepatitis B virus-induced systemic immune tolerance by intrinsic innate immune stimulation.

    PubMed

    Han, Qiuju; Lan, Peixiang; Zhang, Jian; Zhang, Cai; Tian, Zhigang

    2013-08-01

    Systemic immune tolerance induced by chronic hepatitis B virus (HBV) infection is a significant question, but the mechanism of which remains unclear. In this mini-review, we summarize the impaired innate and adaptive immune responses involved in immune tolerance in chronic HBV infection. Furthermore, we delineate a novel dual functional small RNA to inhibit HBV replication and stimulate innate immunity against HBV, which proposed a promising immunotherapeutic intervention to interrupt HBV-induced immunotolerance. A mouse model of HBV persistence was established and used to observe the immune tolerant to HBV vaccination, the cell-intrinsic immune tolerance of which might be reversed by chemically synthesized dual functional small RNA (3p-hepatitis B Virus X gene [HBx]-small interfering RNA) in vitro experiments and by biologically constructed dual functional vector (single-stranded RNA-HBx- short hairpin RNA) in vivo experiment using HBV-carrier mice.

  10. Studies of innate immune systems against human cells.

    PubMed

    Sakai, Rieko; Kitano, Etsuko; Maeda, Akira; Lo, Pei-Chi; Eguchi, Hiroshi; Watanabe, Masahito; Nagashima, Hiroshi; Okuyama, Hiroomi; Miyagawa, Shuji

    2017-02-01

    Pigs are frequently used as animal models for experiments in the surgical field, including allo- and xeno-transplantation. Regeneration studies, including studies dealing with human- and monkey-induced pluripotent stem cells (iPSC), have gradually progressed, with pigs sometimes being used as the scaffold. However, the immunological response of pigs against humans, especially innate immunities, remain unclear. This study reports on a comprehensive study of pig innate immunity against humans. Hemolytic complement activity of pig serum was measured using a microtitration technique. The pig natural anti-human antibody (Ab) was examined using human peripheral blood mononuclear cells (PBMC). The reaction of pig natural killer (NK) cells and monocytes/macrophages against human cells was also assessed. Most of the pig complement titers were measured based on methods used in human complement assays. The alternative pathway for pig complement reacts with human cells, indicating that pig complement can react with human cells. Pig serum contains relatively high levels of natural antibodies, IgM and IgG, to human PBMC. Furthermore, the killing of NK cells- and monocyte/macrophage-mediated human cells was clearly confirmed. The collective findings indicate that the pig innate immunological systems, not only serum but also cellular factors, are able to recognize and injure human cells. Copyright © 2016. Published by Elsevier B.V.

  11. Innate and Adaptive Immune Response to Fungal Products and Allergens.

    PubMed

    Williams, P Brock; Barnes, Charles S; Portnoy, Jay M

    2016-01-01

    Exposure to fungi and their products is practically ubiquitous, yet most of this is of little consequence to most healthy individuals. This is because there are a number of elaborate mechanisms to deal with these exposures. Most of these mechanisms are designed to recognize and neutralize such exposures. However, in understanding these mechanisms it has become clear that many of them overlap with our ability to respond to disruptions in tissue function caused by trauma or deterioration. These responses involve the innate and adaptive immune systems usually through the activation of nuclear factor kappa B and the production of cytokines that are considered inflammatory accompanied by other factors that can moderate these reactivities. Depending on different genetic backgrounds and the extent of activation of these mechanisms, various pathologies with resulting symptoms can ensue. Complicating this is the fact that these mechanisms can bias toward type 2 innate and adaptive immune responses. Thus, to understand what we refer to as allergens from fungal sources, we must first understand how they influence these innate mechanisms. In doing so it has become clear that many of the proteins that are described as fungal allergens are essentially homologues of our own proteins that signal or cause tissue disruptions. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  12. Requirements for innate immune pathways in environmentally induced autoimmunity

    PubMed Central

    2013-01-01

    There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity. PMID:23557436

  13. Candesartan Ameliorates Impaired Fear Extinction Induced by Innate Immune Activation

    PubMed Central

    Quiñones, María M.; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T.

    2015-01-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 hrs after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. PMID:26520214

  14. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    PubMed

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD.

  15. Natural killer cells in the innate immunity network of atherosclerosis.

    PubMed

    Bonaccorsi, Irene; De Pasquale, Claudia; Campana, Stefania; Barberi, Chiara; Cavaliere, Riccardo; Benedetto, Filippo; Ferlazzo, Guido

    2015-11-01

    Natural killer (NK) cells are innate lymphocytes which have recently been proposed to play an immunoregulatory role in the pathogenesis and progression of atherosclerosis. Although several studies have evaluated the frequency and the functions of NK cells both in human and in experimental animal models of atherosclerosis, it is yet not clear whether NK cells might behave as protective or pro-atherogenic effectors. Here, we review current knowledge regarding the role of NK cells in atherosclerosis and discuss the potential interactions that might occur in atherosclerotic lesions between NK cells and antigen presenting cells, such as macrophages and dendritic cells. A clearer depiction of the innate immune cell network operating in atherosclerosis might pave the way to novel interesting approaches for the prevention and treatment of this disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Links between the innate immune system and sleep.

    PubMed

    Majde, Jeannine A; Krueger, James M

    2005-12-01

    Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non-rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non-rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep. It is now recognized that both infection-associated sleep and spontaneous sleep are regulated, in part, by immune mediators called cytokines. This review provides brief tutorials on the elements of the innate immune system that detect infection, how sleep is characterized in the laboratory, issues regarding the interpretation of sleep effects on immune function, the interaction of sleep with circadian rhythms and stress, and some of the microbial products, cytokines, and neuropeptides associated with sleep regulation. We also summarize our current understanding of the role of sleep in host defense and asthma exacerbation.

  17. [Natural killer cells: adaptation and memory in innate immunity].

    PubMed

    Narni-Mancinelli, Emilie; Ugolini, Sophie; Vivier, Eric

    2013-04-01

    Natural killer (NK) cells are lymphocytes of the innate immune system that can kill tumor and infected cells. NK cells also secrete cytokines that participate in the shaping of the adaptive immune response. During the past few years, several studies have shown that the threshold of NK cell responsiveness is more adaptable than originally thought. NK cell reactivity is tuned by the environment and depends on the time of exposure of NK cells to their microenvironment. The impact of the NK cell response on immunity also depends on the intensity and the nature of the tumor or infections assaults. We review here how the local context impacts on NK cell responsiveness and shapes the outcome of NK cell activation. © 2013 médecine/sciences – Inserm / SRMS.

  18. Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans

    PubMed Central

    Pashov, Anastas; Monzavi-Karbassi, Bejatolah; Raghava, Gajendra P. S.; Kieber-Emmons, Thomas

    2010-01-01

    Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies. PMID:20617150

  19. To con protection: TIR-domain containing proteins (Tcp) and innate immune evasion.

    PubMed

    Patterson, Nicholas J; Werling, Dirk

    2013-09-15

    The innate immune system provides the host's first line of defence against invading pathogens. Key to the stimulation of the innate immune response is pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), which recognize microbial-associated molecular patterns (MAMPs). Binding of MAMPs to TLRs triggers a signalling cascade resulting in the production of pro-inflammatory mediators. Central to this TLR signalling pathway are heterotypic protein-protein interactions mediated through Toll/interleukin-1 receptor (TIR) domains found in both the cytoplasmic regions of TLRs and several key adaptor proteins. Interestingly, TIR-domain containing proteins (Tcps) do not seem to be unique to the mammalian TLR system, but occurs in abundance in many biological forms. Recent evidence suggests that pathogenic bacteria have developed a range of ingenuous strategies to evade the host immune mechanisms involving Tcps. There is increasing evidence to suggest that these pathogen-encoded Tcps interfere directly with the TLR signalling pathway and thus inhibit the activation of NF-κB, with different modes of action and roles in virulence. Here, we review the current state of knowledge on the possible roles and mechanisms of action of bacterial encoded Tcp. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Bacterial TIR-containing proteins and host innate immune system evasion.

    PubMed

    Rana, Rohini R; Zhang, Minghao; Spear, Abigail M; Atkins, Helen S; Byrne, Bernadette

    2013-02-01

    The innate immune system provides the first line of host defence against invading pathogens. Key to upregulation of the innate immune response are Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and trigger a signaling pathway culminating in the production of inflammatory mediators. Central to this TLR signaling pathway are heterotypic protein-protein interactions mediated through Toll/interleukin-1 receptor (TIR) domains found in both the cytoplasmic regions of TLRs and adaptor proteins. Pathogenic bacteria have developed a range of ingenuous strategies to evade the host immune mechanisms. Recent work has identified a potentially novel evasion mechanism involving bacterial TIR domain proteins. Such domains have been identified in a wide range of pathogenic bacteria, and there is evidence to suggest that they interfere directly with the TLR signaling pathway and thus inhibit the activation of NF-κB. The individual TIR domains from the pathogenic bacteria Salmonella enterica serovar Enteritidis, Brucella sp, uropathogenic E. coli and Yersinia pestis have been analyzed in detail. The individual bacterial TIR domains from these pathogenic bacteria seem to differ in their modes of action and their roles in virulence. Here, we review the current state of knowledge on the possible roles and mechanisms of action of the bacterial TIR domains.

  1. Functions of innate immune cells and commensal bacteria in gut homeostasis.

    PubMed

    Kayama, Hisako; Takeda, Kiyoshi

    2016-02-01

    The intestinal immune system remains unresponsive to beneficial microbes and dietary antigens while activating pro-inflammatory responses against pathogens for host defence. In intestinal mucosa, abnormal activation of innate immunity, which directs adaptive immune responses, causes the onset and/or progression of inflammatory bowel diseases. Thus, innate immunity is finely regulated in the gut. Multiple innate immune cell subsets have been identified in both murine and human intestinal lamina propria. Some innate immune cells play a key role in the maintenance of gut homeostasis by preventing inappropriate adaptive immune responses while others are associated with the pathogenesis of intestinal inflammation through development of Th1 and Th17 cells. In addition, intestinal microbiota and their metabolites contribute to the regulation of innate/adaptive immune responses. Accordingly, perturbation of microbiota composition can trigger intestinal inflammation by driving inappropriate immune responses.

  2. Feliform carnivores have a distinguished constitutive innate immune response.

    PubMed

    Heinrich, Sonja K; Wachter, Bettina; Aschenborn, Ortwin H K; Thalwitzer, Susanne; Melzheimer, Jörg; Hofer, Heribert; Czirják, Gábor Á

    2016-05-15

    Determining the immunological phenotype of endangered and threatened populations is important to identify those vulnerable to novel pathogens. Among mammals, members of the order Carnivora are particularly threatened by diseases. We therefore examined the constitutive innate immune system, the first line of protection against invading microbes, of six free-ranging carnivore species; the black-backed jackal (Canis mesomelas), the brown hyena (Hyena brunnea), the caracal (Caracal caracal), the cheetah (Acinonyx jubatus), the leopard (Panthera pardus) and the lion (Panthera leo) using a bacterial killing assay. The differences in immune responses amongst the six species were independent of their foraging behaviour, body mass or social organisation but reflected their phylogenetic relatedness. The bacterial killing capacity of black-backed jackals, a member of the suborder Caniformia, followed the pattern established for a wide variety of vertebrates. In contrast, the five representatives of the suborder Feliformia demonstrated a killing capacity at least an order of magnitude higher than any species reported previously, with a particularly high capacity in caracals and cheetahs. Our results suggest that the immunocompetence of threatened felids such as the cheetah has been underestimated and its assessment ought to consider both innate and adaptive components of the immune system.

  3. Determining the Function of Long Noncoding RNA in Innate Immunity.

    PubMed

    Carpenter, Susan

    2016-01-01

    The advent of deep sequencing technologies has provided us with an unprecedented view of the human genome. Over 85 % of the genome is actively transcribed, yet we do not know the function of the vast majority of these RNA transcripts. Long noncoding RNAs (lncRNA) represent the largest group of RNA genes transcribed in the cell and currently there is limited experimental data supporting the functions of a very small proportion of these transcripts. lncRNA are expressed in a highly cell type specific manner and our interests involve understanding the role they play in innate immune signaling networks. In this chapter I will outline the approach we took to attempt to uncover the role for lncRNA in innate immune cells. Two of the main techniques required to study lncRNA are RNA-seq and loss of function analysis. This allows us to first identify all lncRNA in a cell type of choice and then try to determine the functional significance of these transcripts. This approach has been successful for us to date in identifying lincRNA-Cox2 as a highly inflammatory inducible lncRNA that is responsible for activation and repression of distinct immune genes.

  4. Joint Replacement Surgery and the Innate Immune System

    PubMed Central

    Goodman, Stuart; Konttinen, Yrjö T.; Takagi, Michiaki

    2015-01-01

    Total joint replacement is a highly successful, cost-effective surgical procedure that relieves pain and improves function for patients with end-stage arthritis. The most commonly used materials for modern joint replacements include metal alloys such as cobalt chrome and titanium alloys, polymers including polymethylmethacrylate and polyethylene, and ceramics. Implantation of a joint prosthesis incites an acute inflammatory reaction that is regulated by the innate immune system, a preprogrammed non-antigen specific biological response composed of cells, proteins, and other factors. This “frontline” immune mechanism was originally designed to combat invading microorganisms, but now responds to both pathogen-associated molecular patterns or PAMPS (by-products from microorganisms), and damage associated molecular patterns or DAMPS (molecular by-products from cells), via pattern recognition receptors (PRRs). In this way, potentially injurious stimuli that might disrupt the normal homeostatic regulatory mechanisms of the organism are efficiently dealt with, ensuring the survival of the host. Initial surgical implantation of the joint replacement, as well as ongoing generation of wear debris and byproducts during usage of the joint, activates the innate immune system. Understanding and potentially modulating these events may lead to improved function and increased longevity of joint replacements in the future. PMID:25747028

  5. Role of innate immunity in the development of hepatocellular carcinoma

    PubMed Central

    Aravalli, Rajagopal N

    2013-01-01

    Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. It is caused by a variety of risk factors, most common ones being infection with hepatitis viruses, alcohol, and obesity. HCC often develops in the background of underlying cirrhosis, and even though a number of interventional treatment methods are currently in use, recurrence is fairly common among patients who have had a resection. Therefore, whole liver transplantation remains the most practical treatment option for HCC. Due to the growing incidence of HCC, intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer. In recent years, it has become clear that innate immunity plays a critical role in the development of a number of liver diseases, including HCC. In particular, the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of pro-inflammatory cytokines and chemokines, and could cause acute inflammation in the liver. In this review, the current knowledge on the role of innate immune responses in the development and progression of HCC is examined, and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed. PMID:24282342

  6. Plasmodium activates the innate immune response of Anopheles gambiae mosquitoes.

    PubMed Central

    Richman, A M; Dimopoulos, G; Seeley, D; Kafatos, F C

    1997-01-01

    Innate immune-related gene expression in the major disease vector mosquito Anopheles gambiae has been analyzed following infection by the malaria parasite, Plasmodium berghei. Substantially increased levels of mRNAs encoding the antibacterial peptide defensin and a putative Gram-negative bacteria-binding protein (GNBP) are observed 20-30 h after ingestion of an infected blood-meal, at a time which indicates that this induction is a response to parasite invasion of the midgut epithelium. The induction is dependent upon the ingestion of infective, sexual-stage parasites, and is not due to opportunistic co-penetration of resident gut micro-organisms into the hemocoel. The response is activated following infection both locally (in the midgut) and systemically (in remaining tissues, presumably fat body and/or hemocytes). The observation that Plasmodium can trigger a molecularly defined immune response in the vector constitutes an important advance in our understanding of parasite-vector interactions that are potentially involved in malaria transmission, and extends knowledge of the innate immune system of insects to encompass responses to protozoan parasites. PMID:9321391

  7. Insect antiviral innate immunity: pathways, effectors, and connections

    PubMed Central

    Kingsolver, Megan B.; Huang, Zhijing; Hardy, Richard W.

    2014-01-01

    Insects are infected by a wide array of viruses some of which are insect-restricted and pathogenic, and some of which are transmitted by biting insects to vertebrates. The medical and economic importance of these viruses heightens the need to understand the interaction between the infecting pathogen and the insect immune system in order to develop transmission interventions. The interaction of the virus with the insect host innate immune system plays a critical role in the outcome of infection. The major mechanism of antiviral defense is the siRNA pathway that responds through the detection of virus-derived dsRNA to suppress virus replication. However, other innate antimicrobial pathways such as Imd, Toll, Jak-STAT, and the autophagy pathway have also been shown to play important roles in antiviral immunity. In this review we provide an overview of the current understanding of the main insect antiviral pathways and examine recent findings that further our understanding of the roles of these pathways in facilitating a systemic and specific response to infecting viruses. PMID:24120681

  8. Insect antiviral innate immunity: pathways, effectors, and connections.

    PubMed

    Kingsolver, Megan B; Huang, Zhijing; Hardy, Richard W

    2013-12-13

    Insects are infected by a wide array of viruses some of which are insect restricted and pathogenic, and some of which are transmitted by biting insects to vertebrates. The medical and economic importance of these viruses heightens the need to understand the interaction between the infecting pathogen and the insect immune system in order to develop transmission interventions. The interaction of the virus with the insect host innate immune system plays a critical role in the outcome of infection. The major mechanism of antiviral defense is the small, interfering RNA pathway that responds through the detection of virus-derived double-stranded RNA to suppress virus replication. However, other innate antimicrobial pathways such as Imd, Toll, and Jak-STAT and the autophagy pathway have also been shown to play important roles in antiviral immunity. In this review, we provide an overview of the current understanding of the main insect antiviral pathways and examine recent findings that further our understanding of the roles of these pathways in facilitating a systemic and specific response to infecting viruses.

  9. Feliform carnivores have a distinguished constitutive innate immune response

    PubMed Central

    Heinrich, Sonja K.; Wachter, Bettina; Aschenborn, Ortwin H. K.; Thalwitzer, Susanne; Melzheimer, Jörg; Hofer, Heribert; Czirják, Gábor Á.

    2016-01-01

    ABSTRACT Determining the immunological phenotype of endangered and threatened populations is important to identify those vulnerable to novel pathogens. Among mammals, members of the order Carnivora are particularly threatened by diseases. We therefore examined the constitutive innate immune system, the first line of protection against invading microbes, of six free-ranging carnivore species; the black-backed jackal (Canis mesomelas), the brown hyena (Hyena brunnea), the caracal (Caracal caracal), the cheetah (Acinonyx jubatus), the leopard (Panthera pardus) and the lion (Panthera leo) using a bacterial killing assay. The differences in immune responses amongst the six species were independent of their foraging behaviour, body mass or social organisation but reflected their phylogenetic relatedness. The bacterial killing capacity of black-backed jackals, a member of the suborder Caniformia, followed the pattern established for a wide variety of vertebrates. In contrast, the five representatives of the suborder Feliformia demonstrated a killing capacity at least an order of magnitude higher than any species reported previously, with a particularly high capacity in caracals and cheetahs. Our results suggest that the immunocompetence of threatened felids such as the cheetah has been underestimated and its assessment ought to consider both innate and adaptive components of the immune system. PMID:27044323

  10. Evolution of adaptive immunity from transposable elements combined with innate immune systems.

    PubMed

    Koonin, Eugene V; Krupovic, Mart

    2015-03-01

    Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems.

  11. Yersinia type III effectors perturb host innate immune responses

    PubMed Central

    Pha, Khavong; Navarro, Lorena

    2016-01-01

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

  12. Epithelial innate immune response to Acinetobacter baumannii challenge.

    PubMed

    Feng, Zhimin; Jia, Xun; Adams, Mark D; Ghosh, Santosh K; Bonomo, Robert A; Weinberg, Aaron

    2014-11-01

    Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human β-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection.

  13. Complement: a unique innate immune sensor for danger signals.

    PubMed

    Gasque, Philippe

    2004-11-01

    The complement (C) inflammatory cascade is part of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. It has three critical physiologic activities: (i) defending against microbial infections by triggering the generation of a membranolytic complex (C5b9 complex) at the surface of the pathogen and C fragments (named opsonins, i.e., C1q, C3b and iC3b) which interact with C cell surface receptors (CR1, CR3 and CR4) to promote phagocytosis. Soluble C anaphylatoxins (C4a, C3a and C5a) greatly control the local pro-inflammatory response through the chemotaxis and activation of leukocytes; (ii) bridging innate and adaptive immunity (essentially through C receptor type 2, CR2, expressed by B cells) and (iii) disposing of immune complexes and the products of the inflammatory injury (i.e., other danger signals, e.g., toxic cell debris and apoptotic corpses) to ensure the protection and healing of the host. The regulatory mechanisms of C are finely balanced so that, on the one hand, the deposition of C is focused on the surface of invading microorganisms and, on the other hand, the deposition of C on normal cells is limited by several key C inhibitors (e.g., CD46, CD55 and CD59). Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology should facilitate the design of effective therapeutic strategies to fight selectively against intruders.

  14. Epithelial Innate Immune Response to Acinetobacter baumannii Challenge

    PubMed Central

    Feng, Zhimin; Jia, Xun; Adams, Mark D.; Ghosh, Santosh K.; Bonomo, Robert A.

    2014-01-01

    Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human β-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection. PMID:25114113

  15. The Role of Innate Immunity and Aeroallergens in Chronic Rhinosinusitis.

    PubMed

    London, Nyall R; Tharakan, Anuj; Ramanathan, Murugappan

    2016-01-01

    Allergy has been inferred to contribute to the pathophysiology of chronic rhinosinusitis (CRS) although this role is controversial and the mechanism is debated. Furthermore, the role of aeroallergens in CRS is poorly defined and has been postulated to contribute to CRS through direct penetration in the sinuses or downstream systemic consequences. Common aeroallergens implicated in chronic rhinosinusitis include air pollution/second hand smoke, dust mite and pollen [1,2,3]. One emerging potential mechanism whereby aeroallergens contribute to CRS is through sinonasal epithelial barrier disruption (fig. 1). Characterization of cytokine disruption of sinonasal epithelial cell barrier has been described including interleukin (IL)-4 and IL-13, as well as aeroallergens such as house dust mite and cigarette smoke. Recent results have demonstrated severe barrier disruption in response to direct application of either particulate matter (PM) or house dust mite (HDM) to sinonasal epithelial cells. Sinonasal epithelial barrier disruption may contribute to CRS by enabling the perpetual and chronic exposure of inflammatory allergens and stimuli. The sinonasal epithelial barrier plays a significant role in innate immune host defense. Mechanisms of innate immune defense include pattern recognition receptors (PRRs), secreted endogenous antimicrobials and inflammatory cytokines that aid in repair mechanisms including IL-33. Here we discuss recent evidence implicating aeroallergens and dysregulated host innate immune responses in the development of CRS.

    1Fig. 1. Aeroallergens and inflammatory stimuli disrupt sinonasal epithelial barrier function. These agents act to destabilize the barrier through stimulating endocytosis and destruction of cell junction proteins via oxidative stress and MyD88-dependent mechanisms. Furthermore

  16. Condition, innate immunity and disease mortality of inbred crows.

    PubMed

    Townsend, Andrea K; Clark, Anne B; McGowan, Kevin J; Miller, Andrew D; Buckles, Elizabeth L

    2010-09-22

    Cooperatively breeding American crows (Corvus brachyrhynchos) suffer a severe disease-mediated survival cost from inbreeding, but the proximate mechanisms linking inbreeding to disease are unknown. Here, we examine indices of nestling body condition and innate immunocompetence in relationship to inbreeding and disease mortality. Using an estimate of microsatellite heterozygosity that predicts inbreeding in this population, we show that inbred crows were in relatively poor condition as nestlings, and that body condition index measured in the first 2-33 days after hatching, in addition to inbreeding index, predicted disease probability in the first 34 months of life. Inbred nestlings also mounted a weaker response along one axis of innate immunity: the proportion of bacteria killed in a microbiocidal assay increased as heterozygosity index increased. Relatively poor body condition and low innate immunocompetence are two mechanisms that might predispose inbred crows to ultimate disease mortality. A better understanding of condition-mediated inbreeding depression can guide efforts to minimize disease costs of inbreeding in small populations.

  17. Condition, innate immunity and disease mortality of inbred crows

    PubMed Central

    Townsend, Andrea K.; Clark, Anne B.; McGowan, Kevin J.; Miller, Andrew D.; Buckles, Elizabeth L.

    2010-01-01

    Cooperatively breeding American crows (Corvus brachyrhynchos) suffer a severe disease-mediated survival cost from inbreeding, but the proximate mechanisms linking inbreeding to disease are unknown. Here, we examine indices of nestling body condition and innate immunocompetence in relationship to inbreeding and disease mortality. Using an estimate of microsatellite heterozygosity that predicts inbreeding in this population, we show that inbred crows were in relatively poor condition as nestlings, and that body condition index measured in the first 2–33 days after hatching, in addition to inbreeding index, predicted disease probability in the first 34 months of life. Inbred nestlings also mounted a weaker response along one axis of innate immunity: the proportion of bacteria killed in a microbiocidal assay increased as heterozygosity index increased. Relatively poor body condition and low innate immunocompetence are two mechanisms that might predispose inbred crows to ultimate disease mortality. A better understanding of condition-mediated inbreeding depression can guide efforts to minimize disease costs of inbreeding in small populations. PMID:20444716

  18. Innate Immune Memory: Activation of Macrophage Killing Ability by Developmental Duties.

    PubMed

    Schneider, David; Tate, Ann Thomas

    2016-06-20

    Innate immune systems in many taxa exhibit hallmarks of memory in response to previous microbial exposure. A new study demonstrates that innate immune memory in Drosophila embryonic macrophages can also be induced by the successful engulfment of apoptotic cells, highlighting the importance of early exposure events for developing responsive immune systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

    PubMed Central

    He, Hongzhen; Stone, James R; Perkins, David L

    2003-01-01

    The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation. PMID:12757613

  20. Innate and Adaptive Immune Response to Apoptotic Cells

    PubMed Central

    Peng, YuFeng; Martin, David A; Kenkel, Justin; Zhang, Kang; Ogden, Carol Anne; Elkon, Keith B.

    2007-01-01

    The immune system is constantly exposed to dying cells, most of which arise during central tolerance and from effete circulating immune cells. Under homeostatic conditions, phagocytes (predominantly macrophages and dendritic cells) belonging to the innate immune system, rapidly ingest cells and their debris. Apoptotic cell removal requires recognition of altered self on the apoptotic membrane, a process which is facilitated by natural antibodies and serum opsonins. Recognition, may be site and context specific. Uptake and ingestion of apoptotic cells promotes an immunosuppressive environment that avoids inflammatory responses to self antigens. However, it does not preclude a T cell response and it is likely that constant exposure to self antigen, particularly by immature dendritic cells, leads to T cell tolerance. Tolerance occurs by several different mechanisms including anergy and deletion (for CD8+ T cells) and induction of T regulatory cells (for CD4+ T cells). Failed apoptotic cell clearance promotes immune responses to self antigens, especially when the cellular contents are leaked from the cell (necrosis). Inflammatory responses may be induced by nucleic acid stimulation of toll like receptors and other immune sensors, specific intracellular proteins and non protein (uric acid) stimulation of inflammasomes. PMID:17888627

  1. Modular Activating Receptors in Innate and Adaptive Immunity.

    PubMed

    Berry, Richard; Call, Matthew E

    2017-03-14

    Triggering of cell-mediated immunity is largely dependent on the recognition of foreign or abnormal molecules by a myriad of cell surface-bound receptors. Many activating immune receptors do not possess any intrinsic signaling capacity but instead form noncovalent complexes with one or more dimeric signaling modules that communicate with a common set of kinases to initiate intracellular information-transfer pathways. This modular architecture, where the ligand binding and signaling functions are detached from one another, is a common theme that is widely employed throughout the innate and adaptive arms of immune systems. The evolutionary advantages of this highly adaptable platform for molecular recognition are visible in the variety of ligand-receptor interactions that can be linked to common signaling pathways, the diversification of receptor modules in response to pathogen challenges, and the amplification of cellular responses through incorporation of multiple signaling motifs. Here we provide an overview of the major classes of modular activating immune receptors and outline the current state of knowledge regarding how these receptors assemble, recognize their ligands, and ultimately trigger intracellular signal transduction pathways that activate immune cell effector functions.

  2. Evasion of Innate and Adaptive Immunity by Mycobacterium tuberculosis.

    PubMed

    Goldberg, Michael F; Saini, Neeraj K; Porcelli, Steven A

    2014-10-01

    Through thousands of years of reciprocal coevolution, Mycobacterium tuberculosis has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of M. tuberculosis to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable M. tuberculosis and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which M. tuberculosis evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis.

  3. Innate and Adaptive Cellular Immune Responses to Mycobacterium tuberculosis Infection.

    PubMed

    Mayer-Barber, Katrin D; Barber, Daniel L

    2015-07-17

    Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the coordinated efforts of innate and adaptive immune cells. Diverse pulmonary myeloid cell populations respond to Mtb with unique contributions to both host-protective and potentially detrimental inflammation. Although multiple cell types of the adaptive immune system respond to Mtb infection, CD4 T cells are the principal antigen-specific cells responsible for containment of Mtb infection, but they can also be major contributors to disease during Mtb infection in several different settings. Here, we will discuss the role of different myeloid populations as well as the dual nature of CD4 T cells in Mtb infection with a primary focus on data generated using in vivo cellular immunological studies in experimental animal models and in humans when available. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  4. Long non-coding RNAs in innate and adaptive immunity

    PubMed Central

    Aune, Thomas M.; Spurlock, Charles F.

    2015-01-01

    Long noncoding RNAs (lncRNAs) represent a newly discovered class of regulatory molecules that impact a variety of biological processes in cells and organ systems. In humans, it is estimated that there may be more than twice as many lncRNA genes than protein-coding genes. However, only a handful of lncRNAs have been analyzed in detail. In this review, we describe expression and functions of lncRNAs that have been demonstrated to impact innate and adaptive immunity. These emerging paradigms illustrate remarkably diverse mechanisms that lncRNAs utilize to impact the transcriptional programs of immune cells required to fight against pathogens and maintain normal health and homeostasis. PMID:26166759

  5. [ROLE OF INNATE IMMUNITY FACTORS IN PERIODONTITIS PATHOGENESIS].

    PubMed

    Gankovskaya, L V; Khelminskaya, N M; Molchanova, E A; Svitich, O A

    2016-01-01

    Chronic generalized periodontitis (CGP) is a disease of periodontium tissues supporting tooth induced by bacteria, that is characterized by the presence of processes of inflammation with destruction of bone tissue. The knowledge of molecular mechanisms of CGP pathogenesis facilitates creation of the most effective methods of therapy of this disease. Bacterial infection is a primary factor in periodontitis etiology, however is not sufficient for its start and subsequent development. It is known, that bacterial factors induce alocal inflammationreaction and.activate the system of innate immunity through activation of Toll-like receptors (TLR), located on the surface of resident cells and leukocytes. Activation of these cells results in production of pro-inflammatory cytokines and recruitment of phagocytes and lymphocytes into the inflammation zone. In review we examined the known data regarding factors of immune protection of periodontium including cell populations and cytokines, as well as mechanisms of tissue destruction, that support the tooth. Perspectives of therapy are also discussed

  6. Rapid innate control of antigen abrogates adaptive immunity

    PubMed Central

    Pembroke, Thomas P I; Gallimore, Awen M; Godkin, Andrew

    2013-01-01

    Natural killer (NK) cells provide an immediate first line of defence against viral infections. Memory responses, maintained by CD4+ T cells, require exposure to viral antigen and provide long-term protection against future infections. It is known that NK cells can promote the development of the adaptive response through cytokine production and cross-talk with antigen-presenting cells. In this paper however, we summarize a series of recent publications, in mouse models and for the first time in man, with the unifying message that rapid viral antigen control by the innate immune system limits antigen exposure to CD4+ cells thereby abrogating the development of a memory response. We discuss the significant implication of these studies on viral treatment strategies and immunization models. PMID:23198899

  7. Innate immune sensing of HIV-1 by dendritic cells.

    PubMed

    Luban, Jeremy

    2012-10-18

    HIV-1-specific antibodies and CD8(+) cytotoxic T cells are detected in most HIV-1-infected people, yet HIV-1 infection is not eradicated. Contributing to the failure to mount a sterilizing immune response may be the inability of antigen-presenting dendritic cells (DCs) to sense HIV-1 during acute infection, and thus the inability to effectively prime naive, HIV-1-specific T cells. Recent findings related to DC-expressed innate immune factors including SAMHD1, TREX1, and TRIM5 provide a molecular basis for understanding why DCs fail to adequately sense invasion by this deadly pathogen and suggest experimental approaches to improve T cell priming to HIV-1 in prophylactic vaccination protocols. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Leukocyte antimicrobial peptides: multifunctional effector molecules of innate immunity.

    PubMed

    Risso, A

    2000-12-01

    Antimicrobial peptides are effector molecules of innate immunity that provide a first line of defense against pathogens. In mammals, they are stored in granules of leukocytes and are present in those sites that are exposed to microbial invasion, such as mucosal surfaces and skin. In the last decade, biochemical investigations and recombinant DNA technology have allowed the identification and characterization of several antimicrobial peptides from various animal and vegetal species. Most of the mammalian peptides have been grouped in two broad families: defensins and cathelicidin-derived peptides. Functional studies have shown that the toxicity mechanisms for many peptides consist of a rapid permeabilization of the target cell membrane. In addition to their microbicidal activity, some members of both families are multifunctional molecules, playing a modulating role in the inflammation and the antigen-driven immune response.

  9. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response.

    PubMed

    de Brito, Cyro Alves; Goldoni, Adriana Letícia; Sato, Maria Notomi

    2009-09-01

    The neonatal phase is a transitory period characterized by an absence of memory cells, favoring a slow adaptive response prone to tolerance effects and the development of Th2-type responses. However, when appropriately stimulated, neonates may achieve an immune response comparable with adult counterparts. One strategy to stimulate the immunological response of neonates or children in early infancy has been to explore natural or synthetic ligands of cell receptors to stimulate innate immunity. The use of adjuvants for activating different cell receptors may be the key to enhancing neonatal adaptive immunity. This review highlights recent advances in the emerging field of molecular adjuvants of innate immune response and their implications for the development of immunotherapies, with particular focus on the neonatal period.

  10. Innate and adaptive immune responses against Staphylococcus aureus skin infections.

    PubMed

    Krishna, Sheila; Miller, Lloyd S

    2012-03-01

    Staphylococcus aureus is an important human pathogen that is responsible for the vast majority of bacterial skin and soft tissue infections in humans. S. aureus can also become more invasive and cause life-threatening infections such as bacteremia, pneumonia, abscesses of various organs, meningitis, osteomyelitis, endocarditis, and sepsis. These infections represent a major public health threat due to the enormous numbers of these infections and the widespread emergence of methicillin-resistant S. aureus (MRSA) strains. MSRA is endemic in hospitals worldwide and is rapidly spreading throughout the normal human population in the community. The increasing frequency of MRSA infections has complicated treatment as these strains are more virulent and are increasingly becoming resistant to multiple different classes of antibiotics. The important role of the immune response against S. aureus infections cannot be overemphasized as humans with certain genetic and acquired immunodeficiency disorders are at an increased risk for infection. Understanding the cutaneous immune responses against S. aureus is essential as most of these infections occur or originate from a site of infection or colonization of the skin and mucosa. This review will summarize the innate immune responses against S. aureus skin infections, including antimicrobial peptides that have direct antimicrobial activity against S. aureus as well as pattern recognition receptors and proinflammatory cytokines that promote neutrophil abscess formation in the skin, which is required for bacterial clearance. Finally, we will discuss the recent discoveries involving IL-17-mediated responses, which provide a key link between cutaneous innate and adaptive immune responses against S. aureus skin infections.

  11. [Protagonists of innate immunity during in Salmonella infections].

    PubMed

    Salez, Laurent; Malo, Danielle

    2004-12-01

    Salmonella are facultative intracellular Gram-negative bacteria that are found ubiquitously in nature and have the ability to infect a wide range of hosts including humans, domesticated, wild mammals, and birds. The principal clinical manifestations associated with Salmonella infection in humans are enteric fever (typhoid and paratyphoid) and a self-limiting gastroenteritis (salmonellosis). Additionally, silent carriage of this bacterium is frequent and contributes to disease dissemination. Typhoid fever still represents a major public health problem in many developing countries. On the other hand, industrialized countries experience an increased incidence of nontyphoidal Salmonella infections with most cases tracing back to food contamination. Studies using mouse model of infection with a highly virulent Salmonella typhimurium serotype have provided important insight into the complexity of the innate immune response to infection. The players are numerous but emphasis was placed on the genes that were discovered using genetic approaches and in vivo assay with live pathogen and include positional cloning of mouse mutations and manipulation of genes in the context of whole animal either by transgenesis or knockout technologies. Some of the critical genes include those known to play a role in the detection of the bacteria (Cd14, Lbp, Tlr4 and Tlr5) and in microbicidal activity (Slc11a1, Nos2, NADPH oxidase and cryptdins). These discoveries have already initiated the search for the contribution of particular genetic pathways in the innate immune response of humans to infection with Salmonella and other intracellular microorganisms.

  12. Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response

    PubMed Central

    West, A. Phillip; Khoury-Hanold, William; Staron, Matthew; Tal, Michal C.; Pineda, Cristiana M.; Lang, Sabine M.; Bestwick, Megan; Duguay, Brett A.; Raimundo, Nuno; MacDuff, Donna A.; Kaech, Susan M.; Smiley, James R.; Means, Robert E.; Iwasaki, Akiko; Shadel, Gerald S.

    2014-01-01

    Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids1. The abundant mtDNA-binding protein, transcription factor A mitochondrial (TFAM), regulates nucleoid architecture, abundance, and segregation2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation (OXPHOS), triggering calcium-dependent stress signaling and adaptive metabolic responses3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and aging, remain ill-defined4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signaling to enhance the expression of a subset of interferon-stimulated genes (ISG). Mechanistically, we have found that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS and promotes STING-IRF3-dependent signaling to elevate ISG expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which potentiates antiviral signaling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling, and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully license antiviral innate immunity. PMID:25642965

  13. Ipr1 gene mediates innate immunity to tuberculosis

    PubMed Central

    Pan, Hui; Yan, Bo-Shiun; Rojas, Mauricio; Shebzukhov, Yuriy V.; Zhou, Hongwei; Kobzik, Lester; Higgins, Darren; Daly, Mark; Bloom, Barry R.; Kramnik, Igor

    2005-01-01

    An estimated 8 million people are infected each year with the pathogen, Mycobacterium tuberculosis, and over 2 million die annually1. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to play a significant role in humans and animals 2,3, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis1)4. Here we demonstrate in sst1 congenic mouse strains that this locus mediates innate immunity, and identify a candidate gene, Intracellular Pathogen Resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages upon activation and infection, but is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits multiplication not only of MTB but also Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data suggest that the Ipr1 gene product may play a novel role in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis. PMID:15815631

  14. GATA-3 function in innate and adaptive immunity.

    PubMed

    Tindemans, Irma; Serafini, Nicolas; Di Santo, James P; Hendriks, Rudi W

    2014-08-21

    The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor.

  15. Innate immune inflammatory response in the acutely ischemic myocardium.

    PubMed

    Deftereos, Spyridon; Angelidis, Christos; Bouras, Georgios; Raisakis, Konstantinos; Gerckens, Ulrich; Cleman, Michael W; Giannopoulos, Georgios

    2014-01-01

    The "holy grail" of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous 'danger' signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing.

  16. Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy.

    PubMed

    Jha, Babal K; Dong, Beihua; Nguyen, Carvell T; Polyakova, Irina; Silverman, Robert H

    2013-09-01

    The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-α, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals.

  17. Innate immunity and genetic determinants of urinary tract infection susceptibility

    PubMed Central

    Godaly, Gabriela; Ambite, Ines; Svanborg, Catharina

    2015-01-01

    Purpose of review Urinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knock-out mice and clinical studies. Recent findings The susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI-prone patients. Summary It is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated. PMID:25539411

  18. Etiology of myasthenia gravis: innate immunity signature in pathological thymus.

    PubMed

    Cavalcante, Paola; Cufi, Perrine; Mantegazza, Renato; Berrih-Aknin, Sonia; Bernasconi, Pia; Le Panse, Rozen

    2013-07-01

    Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction (NMJ), whose clinical hallmark is muscle weakness and early fatigability. The main target of autoimmunity in MG is the acetylcholine receptor (AChR) located in the NMJ. It is now widely accepted that the thymus is probably the prime site of autoimmunity development and maintenance in AChR-positive MG patients; however, the exact mechanisms triggering and perpetuating the intra-thymic autoimmune response to AChR are still unknown. As with many autoimmune diseases, MG has a multifactorial etiology, resulting from complex interactions between genetic and environmental factors, as fully described in this review. Among environmental factors, viral infections could play a central role in autoimmunity, mainly through the induction of dysregulated Toll-like receptor (TLR)-mediated innate immune responses, which can lead to inflammation and adaptive autoimmune response. Growing evidence of chronic inflammation, TLR activation, and persistent viral infections in the thymus of MG patients, strongly supports the hypothesis that, in the context of a genetic susceptible background, the intrathymic innate immune responses to pathogen infections might contribute to MG etiology.

  19. Influenza-induced innate immunity: regulators of viral replication, respiratory tract pathology & adaptive immunity

    PubMed Central

    Oslund, Karen L; Baumgarth, Nicole

    2011-01-01

    Influenza virus infections usually cause mild to moderately severe respiratory disease, however some infections, like those involving the avian H5N1 virus, can cause massive viral pneumonia, systemic disease and death. The innate immune response of respiratory tract resident cells is the first line of defense and limits virus replication. Enhanced cytokine and chemokine production following infection, however, appears to underlie much of the pathology that develops after infection with highly pathogenic strains. A so-called `cytokine storm' can damage the lung tissue and cause systemic disease, despite the control of viral replication. By summarizing current knowledge of the innate responses mounted to influenza infection, this review highlights the importance of the respiratory tract epithelial cells as regulators of innate and adaptive immunity to influenza virus. PMID:21909336

  20. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity.

    PubMed

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

    2016-02-01

    Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro-IL-1β and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer, and autoimmunity.

  1. AIM2 inflammasome in infection, cancer and autoimmunity: role in DNA sensing, inflammation and innate immunity

    PubMed Central

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

    2016-01-01

    Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multi-protein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer and autoimmunity. PMID:26626159

  2. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

    PubMed Central

    Sternberg, Esther M.

    2006-01-01

    The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system. PMID:16557263

  3. Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

    PubMed

    Israel, Laura; Wang, Ying; Bulek, Katarzyna; Della Mina, Erika; Zhang, Zhao; Pedergnana, Vincent; Chrabieh, Maya; Lemmens, Nicole A; Sancho-Shimizu, Vanessa; Descatoire, Marc; Lasseau, Théo; Israelsson, Elisabeth; Lorenzo, Lazaro; Yun, Ling; Belkadi, Aziz; Moran, Andrew; Weisman, Leonard E; Vandenesch, François; Batteux, Frederic; Weller, Sandra; Levin, Michael; Herberg, Jethro; Abhyankar, Avinash; Prando, Carolina; Itan, Yuval; van Wamel, Willem J B; Picard, Capucine; Abel, Laurent; Chaussabel, Damien; Li, Xiaoxia; Beutler, Bruce; Arkwright, Peter D; Casanova, Jean-Laurent; Puel, Anne

    2017-02-23

    The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

  4. NLR proteins: integral members of innate immunity and mediators of inflammatory diseases

    PubMed Central

    Wilmanski, Jeanette M.; Petnicki-Ocwieja, Tanja; Kobayashi, Koichi S.

    2012-01-01

    The innate immune system is the first line of defense against microorganisms and is conserved in both plants and animals. The NLR protein family is a recent addition to the members of innate immunity effector molecules. These proteins are characterized by a central oligomerization domain termed NACHT (or NBD/NOD) and a protein interaction domain, LRRs (Leucine rich repeats) at the C-terminus. It has been shown that NLR proteins are localized to the cytoplasm and recognize microbial products. To date, it is known that Nod1 and Nod2 detect bacterial cell wall components, whereas IPAF and NAIP detect bacterial flagellin and NALP1 has been shown to detect anthrax lethal toxin. NLR proteins comprise a diverse protein family (over 20 in humans), indicating that NLRs have evolved to acquire specificity to various pathogenic microorganisms, thereby controlling host-pathogen interactions. Activation of NLR proteins results in inflammatory responses mediated either by NF-κB, MAPK or Caspase-1 activation, accompanied by subsequent secretion of pro-inflammatory cytokines. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interaction and inflammatory responses. Therefore, understanding NLR signaling is important for the therapeutic intervention of various infectious and inflammatory diseases. PMID:17875812

  5. Role of the HIN Domain in Regulation of Innate Immune Responses

    PubMed Central

    Shaw, Neil

    2014-01-01

    The oligonucleotide/oligosaccharide binding (OB) fold is employed by proteins to bind nucleic acids during replication, transcription, and translation. Recently, a variation of the OB fold consisting of a tandem pair of OB folds named the HIN (hematopoietic expression, interferon-inducible nature, and nuclear localization) domain was shown to play essential roles in the regulation of innate immune responses originating from binding of nucleic acids in the cytoplasm or the nucleus of the cell. Although the two OB folds of the HIN domain are linked via a long linker region, conserved hydrophobic contacts between the two OB folds hold them together firmly, resulting in a single compact domain. This overall topology of the HIN domain seems to be highly conserved, and proteins containing the HIN domain have been grouped in the PYHIN family. Structures of the recently solved HIN domains reveal that these domains exhibit either absent in melanoma2 (Aim2) HIN-like or p202 HINa-like modes of DNA binding. These two modes of DNA binding seem to result in different responses and as a consequence confer distinct roles on the proteins. This review summarizes our current understanding of the structure and function of the HIN domains in context with the innate immune responses. PMID:24164899

  6. Early innate immune response of immune proteins in juvenile channel catfish Ictalurus punctatus

    USDA-ARS?s Scientific Manuscript database

    Channel catfish (Ictalurus punctatus) are raised for aquaculture in the Southeast U.S. and are susceptible to bacterial and viral infections acquired from their pond environment. Innate immune proteins mannose-binding lectin (MBL) and lysozyme were studied during two consecutive years in channel cat...

  7. Disorders of innate immunity in human ageing and effects of nutraceutical administration.

    PubMed

    Magrone, Thea; Jirillo, Emilio

    2014-01-01

    Immune decline with ageing accounts for the increased risk of infections, inflammatory chronic disease, autoimmunity and cancer in humans. Both innate and adaptive immune functions are compromised in aged people and, therefore, attempts to correct these dysfunctions represent a major goal of modern medicine. In this review, special emphasis will be placed on the aged innate immunity with special reference to polymorphonuclear cell, monocyte/ macrophage, dendritic cell and natural killer cell functions. As potential modifiers of the impaired innate immunity, some principal nutraceuticals will be illustrated, such as micronutrients, pre-probiotics and polyphenols. In elderly, clinical trials with the above products are scanty, however, some encouraging effects on the recovery of innate immune cells have been reported. In addition, our own results obtained with symbiotics and polyphenols extracted from red wine or fermented grape marc suggest the potential ability of these substances to modulate the innate immune response in ageing, thus reducing the inflammaging which characterizes immune senescence.

  8. Innate immune memory: towards a better understanding of host defense mechanisms.

    PubMed

    Quintin, Jessica; Cheng, Shih-Chin; van der Meer, Jos W M; Netea, Mihai G

    2014-08-01

    Innate immunity is classically defined as unable to build up immunological memory. Recently however, the assumption of the lack of immunological memory within innate immune responses has been reconsidered. Plants and invertebrates lacking adaptive immune system can be protected against secondary infections. It has been shown that mammals can build cross-protection to secondary infections independently of T-lymphocytes and B-lymphocytes. Moreover, recent studies have demonstrated that innate immune cells such as NK cells and monocytes can display adaptive characteristics, a novel concept for which the term trained immunity has been proposed. Several mechanisms are involved in mediating innate immune memory, among which epigenetic histone modifications and modulation of recognition receptors on the surface of innate immune cells are likely to play a central role. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Long-term activation of the innate immune system in atherosclerosis.

    PubMed

    Christ, Anette; Bekkering, Siroon; Latz, Eicke; Riksen, Niels P

    2016-08-01

    Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of 'trained' innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation.

  10. Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response.

    PubMed

    Zaiss, Anne K; Vilaysane, Akosua; Cotter, Matthew J; Clark, Sharon A; Meijndert, H Christopher; Colarusso, Pina; Yates, Robin M; Petrilli, Virginie; Tschopp, Jurg; Muruve, Daniel A

    2009-06-01

    Adenovirus is a nonenveloped dsDNA virus that activates intracellular innate immune pathways. In vivo, adenovirus-immunized mice displayed an enhanced innate immune response and diminished virus-mediated gene delivery following challenge with the adenovirus vector AdLacZ suggesting that antiviral Abs modulate viral interactions with innate immune cells. Under naive serum conditions in vitro, adenovirus binding and internalization in macrophages and the subsequent activation of innate immune mechanisms were inefficient. In contrast to the neutralizing effect observed in nonhematopoietic cells, adenovirus infection in the presence of antiviral Abs significantly increased FcR-dependent viral internalization in macrophages. In direct correlation with the increased viral internalization, antiviral Abs amplified the innate immune response to adenovirus as determined by the expression of NF-kappaB-dependent genes, type I IFNs, and caspase-dependent IL-1beta maturation. Immune serum amplified TLR9-independent type I IFN expression and enhanced NLRP3-dependent IL-1beta maturation in response to adenovirus, confirming that antiviral Abs specifically amplify intracellular innate pathways. In the presence of Abs, confocal microscopy demonstrated increased targeting of adenovirus to LAMP1-positive phagolysosomes in macrophages but not epithelial cells. These data show that antiviral Abs subvert natural viral tropism and target the adenovirus to phagolysosomes and the intracellular innate immune system in macrophages. Furthermore, these results illustrate a cross-talk where the adaptive immune system positively regulates the innate immune system and the antiviral state.

  11. Arthropod Innate Immune Systems and Vector-Borne Diseases.

    PubMed

    Baxter, Richard H G; Contet, Alicia; Krueger, Kathryn

    2017-02-21

    Arthropods, especially ticks and mosquitoes, are the vectors for a number of parasitic and viral human diseases, including malaria, sleeping sickness, Dengue, and Zika, yet arthropods show tremendous individual variation in their capacity to transmit disease. A key factor in this capacity is the group of genetically encoded immune factors that counteract infection by the pathogen. Arthropod-specific pattern recognition receptors and protease cascades detect and respond to infection. Proteins such as antimicrobial peptides, thioester-containing proteins, and transglutaminases effect responses such as lysis, phagocytosis, melanization, and agglutination. Effector responses are initiated by damage signals such as reactive oxygen species signaling from epithelial cells and recognized by cell surface receptors on hemocytes. Antiviral immunity is primarily mediated by siRNA pathways but coupled with interferon-like signaling, antimicrobial peptides, and thioester-containing proteins. Molecular mechanisms of immunity are closely linked to related traits of longevity and fertility, and arthropods have the capacity for innate immunological memory. Advances in understanding vector immunity can be leveraged to develop novel control strategies for reducing the rate of transmission of both ancient and emerging threats to global health.

  12. Interferon-inducible GTPases in cell autonomous and innate immunity.

    PubMed

    Meunier, Etienne; Broz, Petr

    2016-02-01

    Detection and clearance of invading pathogens requires a coordinated response of the adaptive and innate immune system. Host cell, however, also features different mechanisms that restrict pathogen replication in a cell-intrinsic manner, collectively referred to as cell-autonomous immunity. In immune cells, the ability to unleash those mechanisms strongly depends on the activation state of the cell, which is controlled by cytokines or the detection of pathogen-associated molecular patterns by pattern-recognition receptors. The interferon (IFN) class of cytokines is one of the strongest inducers of antimicrobial effector mechanisms and acts against viral, bacterial and parasitic intracellular pathogens. This has been linked to the upregulation of several hundreds of IFN-stimulated genes, among them the so-called IFN-inducible GTPases. Two subfamilies of IFN-inducible GTPases, the immunity-related GTPases (IRGs) and the guanylate-binding proteins (GBPs), have gained attention due to their exceptional ability to specifically target intracellular vacuolar pathogens and restrict their replication by destroying their vacuolar compartment. Their repertoire has recently been expanded to the regulation of inflammasome complexes, which are cytosolic multi-protein complexes that control an inflammatory cell death called pyroptosis and the release of cytokines like interleukin-1β and interleukin-18. Here we discuss recent advances in understanding the function, the targeting and regulation of IRG and GBP proteins during microbial infections.

  13. Regulation of DAF-16-mediated Innate Immunity in Caenorhabditis elegans.

    PubMed

    Singh, Varsha; Aballay, Alejandro

    2009-12-18

    Activation of the innate immune system results in a rapid microbicidal response against microorganisms, which needs to be fine-tuned because uncontrolled immune responses can lead to infection and cancer, as well as conditions such as Crohn disease, atherosclerosis, and Alzheimer disease. Here we report that excessive activity of the conserved FOXO transcription factor DAF-16 enhances susceptibility to bacterial infections in Caenorhabditis elegans. We found that increased temperature activates not only DAF-16 nuclear import but also a control mechanism involved in DAF-16 nuclear export. The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. Furthermore, we show that increased expression of the water channel Aquoporin-1 is responsible for the deleterious consequences of excessive DAF-16-mediated immune response. These studies reveal a stress-inducible mechanism involved in the regulation of DAF-16 and indicate that uncontrolled DAF-16 activity and water homeostasis are a cause of the deleterious effects of excessive immune responses.

  14. Shades of grey--the blurring view of innate and adaptive immunity.

    PubMed

    Lanier, Lewis L

    2013-02-01

    This special issue of Nature Reviews Immunology focuses on the types of lymphocyte that blur the traditional boundaries between the innate and adaptive immune systems. The development and functional properties of 'innate-like' B and T cells and natural killer (NK) cells are reviewed and the emerging understanding of newly discovered innate lymphoid cells (ILCs) is considered.

  15. Intrinsic and Extrinsic Regulation of Innate Immune Receptors

    PubMed Central

    Jeong, Eunshil

    2011-01-01

    Pattern recognition receptors (PRRs) in innate immune cells play a pivotal role in the first line of host defense system. PRRs recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to initiate and regulate innate and adaptive immune responses. PRRs include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), which have their own features in ligand recognition and cellular location. Activated PRRs deliver signals to adaptor molecules (MyD88, TRIF, MAL/TIRAP, TRAM, IPS-1) which act as important messengers to activate downstream kinases (IKK complex, MAPKs, TBK1, RIP-1) and transcription factors (NF-κB, AP-1, IRF3), which produce effecter molecules including cytokines, chemokines, inflammatory enzymes, and type I interferones. Since excessive PRR activation is closely linked to the development of chronic inflammatory diseases, the role of intrinsic and extrinsic regulators in the prevention of over- or unnecessary activation of PRRs has been widely studied. Intracellular regulators include MyD88s, SOCS1, TOLLIP, A20, and CYLD. Extrinsic regulators have also been identified with their molecular targets in PRR signaling pathways. TLR dimerization has been suggested as an inhibitory target for small molecules such as curcumin, cinnamaldehyde, and sulforaphane. TBK1 kinase can be a target for certain flavonoids such as EGCG, luteolin, quercetin, chrysin, and eriodictyol to regulate TRIF-dependent TLR pathways. This review focuses on the features of PRR signaling pathways and the therapeutic targets of intrinsic and extrinsic regulators in order to provide beneficial strategies for controlling the activity of PRRs and the related inflammatory diseases and immune disorders. PMID:21488180

  16. Innate Immune Response to Rift Valley Fever Virus in Goats

    PubMed Central

    Nfon, Charles K.; Marszal, Peter; Zhang, Shunzhen; Weingartl, Hana M.

    2012-01-01

    Rift Valley fever (RVF), a re-emerging mosquito-borne disease of ruminants and man, was endemic in Africa but spread to Saudi Arabia and Yemen, meaning it could spread even further. Little is known about innate and cell-mediated immunity to RVF virus (RVFV) in ruminants, which is knowledge required for adequate vaccine trials. We therefore studied these aspects in experimentally infected goats. We also compared RVFV grown in an insect cell-line and that grown in a mammalian cell-line for differences in the course of infection. Goats developed viremia one day post infection (DPI), which lasted three to four days and some goats had transient fever coinciding with peak viremia. Up to 4% of peripheral blood mononuclear cells (PBMCs) were positive for RVFV. Monocytes and dendritic cells in PBMCs declined possibly from being directly infected with virus as suggested by in vitro exposure. Infected goats produced serum IFN-γ, IL-12 and other proinflammatory cytokines but not IFN-α. Despite the lack of IFN-α, innate immunity via the IL-12 to IFN-γ circuit possibly contributed to early protection against RVFV since neutralising antibodies were detected after viremia had cleared. The course of infection with insect cell-derived RVFV (IN-RVFV) appeared to be different from mammalian cell-derived RVFV (MAM-RVFV), with the former attaining peak viremia faster, inducing fever and profoundly affecting specific immune cell subpopulations. This indicated possible differences in infections of ruminants acquired from mosquito bites relative to those due to contact with infectious material from other animals. These differences need to be considered when testing RVF vaccines in laboratory settings. PMID:22545170

  17. Detection of innate immune response modulating impurities in therapeutic proteins.

    PubMed

    Haile, Lydia Asrat; Puig, Montserrat; Kelley-Baker, Logan; Verthelyi, Daniela

    2015-01-01

    Therapeutic proteins can contain multiple impurities, some of which are variants of the product, while others are derived from the cell substrate and the manufacturing process. Such impurities, even when present at trace levels, have the potential to activate innate immune cells in peripheral blood or embedded in tissues causing expression of cytokines and chemokines, increasing antigen uptake, facilitating processing and presentation by antigen presenting cells, and fostering product immunogenicity. Currently, while products are tested for host cell protein content, assays to control innate immune response modulating impurities (IIRMIs) in products are focused mainly on endotoxin and nucleic acids, however, depending on the cell substrate and the manufacturing process, numerous other IIRMI could be present. In these studies we assess two approaches that allow for the detection of a broader subset of IIRMIs. In the first, we use commercial cell lines transfected with Toll like receptors (TLR) to detect receptor-specific agonists. This method is sensitive to trace levels of IIRMI and provides information of the type of IIRMIs present but is limited by the availability of stably transfected cell lines and requires pre-existing knowledge of the IIRMIs likely to be present in the product. Alternatively, the use of a combination of macrophage cell lines of human and mouse origin allows for the detection of a broader spectrum of impurities, but does not identify the source of the activation. Importantly, for either system the lower limit of detection (LLOD) of impurities was similar to that of PBMC and it was not modified by the therapeutic protein tested, even in settings where the product had inherent immune modulatory properties. Together these data indicate that a cell-based assay approach could be used to screen products for the presence of IIRMIs and inform immunogenicity risk assessments, particularly in the context of comparability exercises.

  18. Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

    PubMed Central

    Chang, C-H; Chen, Y-C; Yu, Y-H; Tao, M-H; Leung, P S C; Ansari, A A; Gershwin, M E; Chuang, Y-H

    2014-01-01

    Although primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA–BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA–BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA–BSA/PBS or 2-OA–BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways. PMID:24547942

  19. Plant phosphatidylinositol-specific phospholipase C at the center of plant innate immunity.

    PubMed

    Abd-El-Haliem, Ahmed M; Joosten, Matthieu H A J

    2017-03-01

    Understanding plant resistance to pathogenic microbes requires detailed information on the molecular mechanisms controlling the execution of plant innate immune responses. A growing body of evidence places phosphoinositide-specific phospholipase C (PI-PLC) enzymes immediately downstream of activated immune receptors, well upstream of the initiation of early defense responses. An increase of the cytoplasmic levels of free Ca(2+) , lowering of the intercellular pH and the oxidative burst are a few examples of such responses and these are regulated by PI-PLCs. Consequently, PI-PLC activation represents an early primary signaling switch between elicitation and response involving the controlled hydrolysis of essential signaling phospholipids, thereby simultaneously generating lipid and non-lipid second messenger molecules required for a swift cellular defense response. Here, we elaborate on the signals generated by PI-PLCs and their respective downstream effects, while providing an inventory of different types of evidence describing the involvement of PI-PLCs in various aspects of plant immunity. We project the discussed information into a model describing the cellular events occurring after the activation of plant immune receptors. With this review we aim to provide new insights supporting future research on plant PI-PLCs and the development of plants with improved resistance. © 2017 Institute of Botany, Chinese Academy of Sciences.

  20. Overcoming the hurdles of tumor immunity by targeting regulatory pathways in innate and adaptive immune cells.

    PubMed

    Zwirner, Norberto W; Croci, Diego O; Domaica, Carolina I; Rabinovich, Gabriel A

    2010-01-01

    The improved understanding of the biochemical nature of tumor antigens and the identification of cellular and molecular mechanisms leading to activation of innate and adaptive immune cells have been of paramount importance in the progress of tumor immunology. Studies on the intricate network of interactions between tumor and immune cells have revealed novel regulatory signals, including cell surface inhibitory receptors and costimulatory molecules, intracellular regulatory pathways, immunosuppressive cytokines and proapoptotic mediators, which may operate in concert to orchestrate tumor-immune escape. This emerging portfolio of inhibitory checkpoints can influence the physiology of innate immune cells including dendritic cells, macrophages and natural killer (NK) cells, as well as different subsets of T cells to fine tune their effector function. The synergistic combination of strategies aimed at overcoming regulatory signals and/or stimulating effector pathways, may offer therapeutic advantage as adjuvants of conventional anticancer therapies. Based on this premise, we will discuss here how the control of the effector functions of innate and adaptive immune cells and the manipulation of regulatory pathways, either alone or in combination, could be exploited for therapeutic purposes in cancer patients.

  1. The innate immune response to adjuvants dictates the adaptive immune response to autoantigens.

    PubMed

    Staykova, Maria A; Liñares, David; Fordham, Susan A; Paridaen, Judith T; Willenborg, David O

    2008-06-01

    To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant. In BN and PVG rats, there were numerous inflammatory lesions with prominent involvement of microglia and, to a lesser extent, perivascular macrophages. These data suggest that different levels of activation of the innate immune system by different adjuvants determine whether EAE will or will not develop. Accordingly, the widely accepted scale of susceptibility to EAE development (Lewis > PVG > BN) should be revised because it does not take into account the important contribution of the composition of the adjuvant to the quality and quantity of the innate immune response and, consequently, to the generation and extent of the pathogenic T-cell-mediated, that is, adaptive, autoimmune disease.

  2. Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways

    PubMed Central

    Li, Kai; Qu, Shuai; Chen, Xi; Wu, Qiong; Shi, Ming

    2017-01-01

    Malignant cancers employ diverse and intricate immune evasion strategies, which lead to inadequately effective responses of many clinical cancer therapies. However, emerging data suggest that activation of the tolerant innate immune system in cancer patients is able, at least partially, to counteract tumor-induced immunosuppression, which indicates triggering of the innate immune response as a novel immunotherapeutic strategy may result in improved therapeutic outcomes for cancer patients. The promising innate immune targets include Toll-like Receptors (TLRs), RIG-I-like Receptors (RLRs), and Stimulator of Interferon Genes (STING). This review discusses the antitumor properties of TLRs, RLRs, and STING-mediated innate immune pathways, as well as the promising innate immune targets for potential application in cancer immunotherapy. PMID:28216575

  3. Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways.

    PubMed

    Li, Kai; Qu, Shuai; Chen, Xi; Wu, Qiong; Shi, Ming

    2017-02-14

    Malignant cancers employ diverse and intricate immune evasion strategies, which lead to inadequately effective responses of many clinical cancer therapies. However, emerging data suggest that activation of the tolerant innate immune system in cancer patients is able, at least partially, to counteract tumor-induced immunosuppression, which indicates triggering of the innate immune response as a novel immunotherapeutic strategy may result in improved therapeutic outcomes for cancer patients. The promising innate immune targets include Toll-like Receptors (TLRs), RIG-I-like Receptors (RLRs), and Stimulator of Interferon Genes (STING). This review discusses the antitumor properties of TLRs, RLRs, and STING-mediated innate immune pathways, as well as the promising innate immune targets for potential application in cancer immunotherapy.

  4. Oxidative stress, innate immunity, and age-related macular degeneration

    PubMed Central

    Shaw, Peter X.; Stiles, Travis; Douglas, Christopher; Ho, Daisy; Fan, Wei; Du, Hongjun; Xiao, Xu

    2016-01-01

    Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer’s disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have

  5. Oxidative stress, innate immunity, and age-related macular degeneration.

    PubMed

    Shaw, Peter X; Stiles, Travis; Douglas, Christopher; Ho, Daisy; Fan, Wei; Du, Hongjun; Xiao, Xu

    Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer's disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have

  6. Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity?

    PubMed

    Sun, Joseph C; Lanier, Lewis L

    2009-08-01

    Since their discovery three decades ago, NK cells have been classified as cells of the innate immune system. NK cells were shown to respond rapidly and non-specifically to infection, and were thought to act as a functional "bridge" to sustain the early innate immune response until the later adaptive immune responses could be mounted. In light of new findings showing how NK cells possess nearly all of the features of adaptive immunity including memory, we propose the placement of NK cells as an "evolutionary bridge" between innate and adaptive immunity.

  7. Innate immunity against Legionella pneumophila during pulmonary infections in mice.

    PubMed

    Park, Bonggoo; Park, Gayoung; Kim, Jiyoung; Lim, Seon Ah; Lee, Kyung-Mi

    2017-02-01

    Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns that are absent in host cells. During pulmonary legionella infections, various inflammatory cells such as macrophages, neutrophils, natural killer (NK) cells, large mononuclear cells, B cells, and CD4+ and CD8+ T cells are recruited into infected lungs, and predominantly occupy interstitial areas to control legionella. During pulmonary legionella infections, the interplay between distinct cytokines and chemokines also modulates innate host responses to clear legionella from the lungs. Recognition by NK cell receptors triggers effector functions including secretion of cytokines and chemokines, and leads to lysis of target cells. Crosstalk between NK cells and dendritic cells, monocytes, and macrophages provides a major first-line defense against legionella infection, whereas activation of T and B cells resolves the infection and mounts legionella-specific memory in the host.

  8. Dissecting Phaseolus vulgaris Innate Immune System against Colletotrichum lindemuthianum Infection

    PubMed Central

    Chowdhury, Bablu; Caldas, Danielle Gregório Gomes; Tsai, Siu Mui; Camargo, Luis Eduardo Aranha; Melotto, Maeli

    2012-01-01

    the molecular components of the bean innate immune system regulated upon pathogen attack. PMID:22912818

  9. Dissecting Phaseolus vulgaris innate immune system against Colletotrichum lindemuthianum infection.

    PubMed

    Oblessuc, Paula Rodrigues; Borges, Aline; Chowdhury, Bablu; Caldas, Danielle Gregório Gomes; Tsai, Siu Mui; Camargo, Luis Eduardo Aranha; Melotto, Maeli

    2012-01-01

    The genus Colletotrichum is one of the most economically important plant pathogens, causing anthracnose on a wide range of crops including common beans (Phaseolus vulgaris L.). Crop yield can be dramatically decreased depending on the plant cultivar used and the environmental conditions. This study aimed to identify potential genetic components of the bean immune system to provide environmentally friendly control measures against this fungus. As the common bean is not amenable to reverse genetics to explore functionality and its genome is not fully curated, we used putative Arabidopsis orthologs of bean expressed sequence tag (EST) to perform bioinformatic analysis and experimental validation of gene expression to identify common bean genes regulated during the incompatible interaction with C. lindemuthianum. Similar to model pathosystems, Gene Ontology (GO) analysis indicated that hormone biosynthesis and signaling in common beans seem to be modulated by fungus infection. For instance, cytokinin and ethylene responses were up-regulated and jasmonic acid, gibberellin, and abscisic acid responses were down-regulated, indicating that these hormones may play a central role in this pathosystem. Importantly, we have identified putative bean gene orthologs of Arabidopsis genes involved in the plant immune system. Based on experimental validation of gene expression, we propose that hypersensitive reaction as part of effector-triggered immunity may operate, at least in part, by down-regulating genes, such as FLS2-like and MKK5-like, putative orthologs of the Arabidopsis genes involved in pathogen perception and downstream signaling. We have identified specific bean genes and uncovered metabolic processes and pathways that may be involved in the immune response against pathogens. Our transcriptome database is a rich resource for mining novel defense-related genes, which enabled us to develop a model of the molecular components of the bean innate immune system regulated upon

  10. Functional properties of flagellin as a stimulator of innate immunity

    PubMed Central

    Lu, Yuan; Swartz, James R.

    2016-01-01

    We report the development of a well-defined flagellin-based nanoparticle stimulator and also provide a new mechanism of action model explaining how flagellin-triggered innate immunity has evolved to favor localized rather than potentially debilitating systemic immune stimulation. Cell-free protein synthesis (CFPS) was used to facilitate mutational analysis and precisely orientated display of flagellin on Hepatitis B core (HBc) protein virus-like particles (VLPs). The need for product stability and an understanding of mechanism of action motivated investigations indicating that the D0 domain of flagellin is sensitive to amino acid sequence independent hydrolysis – apparently due to the need for structural flexibility during natural flagellin polymerization. When D0-stabilized flagellin was attached to HBc VLPs with the D0 domain facing outward, flagellin’s tendency to polymerize caused the VLPs to precipitate. However, attaching the D0 domain to the VLP surface produced a stable nanoparticle adjuvant. Surprisingly, attaching only 2 flagellins per VLP provided the same 1 pM potency as did VLPs with about 33 attached flagellins suggesting that the TLR5 receptor is highly effective in delivering its intracellular signal. These observations suggest that flagellin’s protease sensitivity, tendency to aggregate, and very high affinity for TLR5 receptors limit its systemic distribution to favor localized immune stimulation. PMID:26755208

  11. Intestinal epithelial cells and their role in innate mucosal immunity.

    PubMed

    Maldonado-Contreras, A L; McCormick, Beth A

    2011-01-01

    The mucosal surfaces of the respiratory, gastrointestinal and urogenital tracts are covered by a layer of epithelial cells that are responsible for sensing and promoting a host immune response in order to establish the limits not only for commensal microorganisms but also for foreign organisms or particles. This is a remarkable task as the human body represents a composite of about 10 trillion human-self cells plus non-self cells from autochthonous or indigenous microbes that outnumber human cells 10:1. Hence, the homeostasis of epithelial cells that line mucosal surfaces relies on a fine-tuned immune system that patrols the boundaries between human and microbial cells. In the case of the intestine, the epithelial layer is composed of at least six epithelial cell lineages that act as a physiological barrier in addition to aiding digestion and the absorption of nutrients, water and electrolytes. In this review, we highlight the immense role of the intestinal epithelium in coordinating the mucosal innate immune response.

  12. Danger, diversity and priming in innate antiviral immunity.

    PubMed

    Collins, Susan E; Mossman, Karen L

    2014-10-01

    The prototypic response to viral infection involves the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), leading to the activation of transcription factors such as IRF3 and NFkB and production of type 1 IFN. While this response can lead to the induction of hundreds of IFN-stimulated genes (ISGs) and recruitment and activation of immune cells, such a comprehensive response is likely inappropriate for routine low level virus exposure. Moreover, viruses have evolved a plethora of immune evasion strategies to subvert antiviral signalling. There is emerging evidence that cells have developed very sensitive methods of detecting not only specific viral PAMPS, but also more general danger or stress signals associated with viral entry and replication. Such stress-induced cellular responses likely serve to prime cells to respond to further PAMP stimulation or allow for a rapid and localized intracellular response independent of IFN production and its potential immune sequelae. This review discusses diversity in innate antiviral players and pathways, the role of "danger" sensing, and how alternative pathways, such as the IFN-independent pathway, may serve to prime cells for further pathogen attack.

  13. Baculovirus Capsid Display Potentiates OVA Cytotoxic and Innate Immune Responses

    PubMed Central

    Molinari, Paula; Crespo, María I.; Gravisaco, María J.

    2011-01-01

    Baculoviruses (BV) are DNA viruses that are pathogenic for insects. Although BV infect a range of mammalian cell types, they do not replicate in these cells. Indeed, the potential effects of these insect viruses on the immune responses of mammals are only just beginning to be studied. We show in this paper that a recombinant Autographa californica multiple nuclear polyhedrosis virus carrying a fragment of ovalbumin (OVA) on the VP39 capsid protein (BV-OVA) has the capacity to act as an adjuvant and vector of antigens in mice, thereby promoting specific CD4 and cytotoxic T cell responses against OVA. BV also induced in vivo maturation of dendritic cells and the production of inflammatory cytokines, thus promoting innate and adaptive immune responses. The OVA-specific response induced by BV-OVA was strong enough to reject a challenge with OVA-expressing melanoma cells (MO5 cells) and effectively prolonged survival of MO5 bearing mice. All these findings, together with the absence of pre-existing immunity to BV in humans and the lack of viral gene expression in mammalian cells, make BV a candidate for vaccination. PMID:21918683

  14. Innate Immunity and Inflammation in NAFLD/NASH.

    PubMed

    Arrese, Marco; Cabrera, Daniel; Kalergis, Alexis M; Feldstein, Ariel E

    2016-05-01

    Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.

  15. Pentraxins in the activation and regulation of innate immunity.

    PubMed

    Daigo, Kenji; Inforzato, Antonio; Barajon, Isabella; Garlanda, Cecilia; Bottazzi, Barbara; Meri, Seppo; Mantovani, Alberto

    2016-11-01

    Humoral fluid phase pattern recognition molecules (PRMs) are a key component of the activation and regulation of innate immunity. Humoral PRMs are diverse. We focused on the long pentraxin PTX3 as a paradigmatic example of fluid phase PRMs. PTX3 acts as a functional ancestor of antibodies and plays a non-redundant role in resistance against selected microbes in mouse and man and in the regulation of inflammation. This molecule interacts with complement components, thus modulating complement activation. In particular, PTX3 regulates complement-driven macrophage-mediated tumor progression, acting as an extrinsic oncosuppressor in preclinical models and selected human tumors. Evidence collected over the years suggests that PTX3 is a biomarker and potential therapeutic agent in humans, and pave the way to translation of this molecule into the clinic. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. BACH transcription factors in innate and adaptive immunity.

    PubMed

    Igarashi, Kazuhiko; Kurosaki, Tomohiro; Roychoudhuri, Rahul

    2017-07-01

    BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family. Recent studies indicate widespread roles of BACH proteins in controlling the development and function of the innate and adaptive immune systems, including the differentiation of effector and memory cells of the B and T cell lineages, CD4(+) regulatory T cells and macrophages. Here, we emphasize similarities at a molecular level in the cell-type-specific activities of BACH factors, proposing that competitive interactions of BACH proteins with transcriptional activators of the bZIP family form a common mechanistic theme underlying their diverse actions. The findings contribute to a general understanding of how transcriptional repressors shape lineage commitment and cell-type-specific functions through repression of alternative lineage programmes.

  17. Modulation of innate immunity by Toxoplasma gondii virulence effectors

    PubMed Central

    Hunter, Christopher A.; Sibley, L. David

    2013-01-01

    Preface Toxoplasma gondii is a common parasite of animals and humans that can cause serious opportunistic infections. However, the majority of infections are asymptomatic possibly because the organism has co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward genetic approaches aimed at unraveling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite. PMID:23070557

  18. Extra- and intracellular innate immune recognition in endothelial cells.

    PubMed

    Opitz, Bastian; Hippenstiel, Stefan; Eitel, Julia; Suttorp, Norbert

    2007-08-01

    The innate immune system represents the principal sensor of infections in multicellular organisms and might also mediate responses to some endogenous molecules. In this context, endothelial cells are among the first cells coming into contact with microbial or endogenous (danger-associated) molecules or whole pathogens entering the bloodstream. Since many bacteria and viruses invade the endothelium, endothelial cells are equipped with both extracellular and cytosolic surveillance systems capable of sensing microbial components, and endogenous danger-associated molecules. The receptor molecules, called pattern recognition receptors (PRRs), are classified as transmembrane or cytosolic molecules. While the transmembrane PRRs recognize extracellular and membrane-enclosed foreign organisms, the cytosolic PRRs appear to sense intracellular infections. Here we focus on both PRR classes in general, and outline the current knowledge of extra- and intracellular pattern recognition in endothelial cells and its potential role in vascular diseases and sepsis.

  19. Metabolic reprogramming in macrophages and dendritic cells in innate immunity

    PubMed Central

    Kelly, Beth; O'Neill, Luke AJ

    2015-01-01

    Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity. PMID:26045163

  20. INNATE IMMUNITY AND THE FAILING HEART: THE CYTOKINE HYPOTHESIS REVISITED

    PubMed Central

    Mann, Douglas L.

    2015-01-01

    Elevated levels of inflammatory mediators have been identified in patients with heart failure, including heart failure with reduced and preserved ejection fraction, as well as acute decompensated heart failure. Moreover, experimental studies have shown repeatedly that activation of inflammation in the heart provokes left ventricular (LV) remodeling and LV dysfunction. Nonetheless, phase III clinical trials that have attempted to antagonize inflammatory mediators have been negative with respect to the primary end points of the trials, and in some patients, resulted in worsening heart failure and/or death. The following review will discuss how recent developments in the field of innate immunity have advanced our understanding of the role of inflammation in the pathogenesis of heart failure and will discuss the negative outcomes of the existing clinical trials in light of this new information. PMID:25814686

  1. Glucosinolate metabolites required for an Arabidopsis innate immune response.

    PubMed

    Clay, Nicole K; Adio, Adewale M; Denoux, Carine; Jander, Georg; Ausubel, Frederick M

    2009-01-02

    The perception of pathogen or microbe-associated molecular pattern molecules by plants triggers a basal defense response analogous to animal innate immunity and is defined partly by the deposition of the glucan polymer callose at the cell wall at the site of pathogen contact. Transcriptional and metabolic profiling in Arabidopsis mutants, coupled with the monitoring of pathogen-triggered callose deposition, have identified major roles in pathogen response for the plant hormone ethylene and the secondary metabolite 4-methoxy-indol-3-ylmethylglucosinolate. Two genes, PEN2 and PEN3, are also necessary for resistance to pathogens and are required for both callose deposition and glucosinolate activation, suggesting that the pathogen-triggered callose response is required for resistance to microbial pathogens. Our study shows that well-studied plant metabolites, previously identified as important in avoiding damage by herbivores, are also required as a component of the plant defense response against microbial pathogens.

  2. Viral evasion of DNA-stimulated innate immune responses

    PubMed Central

    Christensen, Maria H; Paludan, Søren R

    2017-01-01

    Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP–AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway. PMID:26972769

  3. Natural variation in innate immunity of a pioneer species.

    PubMed

    Holub, Eric B

    2007-08-01

    By 2010, we will have detailed knowledge about the genome of Arabidopsis thaliana from a Linnean-like effort by an international research community to identify nearly all of the genes in the species and to classify the products that these genes encode according to a primary function in a generic plant cell. To know the wild species, however, we will require knowledge of which genes provide the raw material for phenotypic variation and natural selection, and consequently affect the adaptability of individual plants and local populations across their geographic range, and ultimately survival of the species. Natural variation in innate immunity will be at the forefront of this exciting research frontier as a model for the molecular ecology of plant-microbe interactions.

  4. IL-37 is a fundamental inhibitor of innate immunity.

    PubMed

    Nold, Marcel F; Nold-Petry, Claudia A; Zepp, Jarod A; Palmer, Brent E; Bufler, Philip; Dinarello, Charles A

    2010-11-01

    The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines were unaffected. Mice with transgenic expression of IL-37 were protected from lipopolysaccharide-induced shock, and showed markedly improved lung and kidney function and reduced liver damage after treatment with lipopolysaccharide. Transgenic mice had lower concentrations of circulating and tissue cytokines (72-95% less) than wild-type mice and showed less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice showed less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.

  5. Interleukin 37 is a fundamental inhibitor of innate immunity

    PubMed Central

    Nold, Marcel F; Nold-Petry, Claudia A; Zepp, Jarod A; Palmer, Brent E; Bufler, Philip; Dinarello, Charles A

    2012-01-01

    The function of interleukin 37 (formerly IL-1 family member 7) remains elusive. Expression of IL-37 in macrophages or epithelial cells imparted near complete suppression of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines remained unchanged under similar conditions. IL-37-transgenic mice were protected from lipopolysaccharide-induced shock, exhibiting markedly improved lung and kidney function and reduced liver damage. IL-37-transgenic mice had less circulating and tissue cytokines (72-95% lower) than wild-type mice and exhibited less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice exhibited less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses. PMID:20935647

  6. Manipulation of the innate immune response by human papillomaviruses.

    PubMed

    Hong, Shiyuan; Laimins, Laimonis A

    2017-03-02

    The innate immune response constitutes the first line of defense against infections by pathogens. Successful pathogens such as human papillomaviruses (HPVs) have evolved mechanisms that target several points in these pathways including sensing of viral genomes, blocking the synthesis of interferons and inhibiting the action of JAK/STAT transcription factors. Disruption of these inhibitory mechanisms contributes to the ability of HPVs to establish persistent infections, which is the major etiological factor in the development of anogenital cancers. Interestingly, HPVs also positively activate several members of these pathways such as STAT-5 that are important for their differentiation-dependent life cycle. STAT-5 activation induces the ATM and ATR DNA damage response pathways that play critical roles in HPV genome amplification. Targeting of these pathways by pharmaceuticals can provide novel opportunities to inhibit infections by these important human pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Exploring the Innate Immune System: Using Complement-Medicated Cell Lysis in the Classroom

    ERIC Educational Resources Information Center

    Fuller, Kevin G.

    2008-01-01

    The protein complement pathway comprises an important part of the innate immunity. The use of serum to demonstrate complement-mediated destruction across a series of bacterial dilutions allows an instructor to introduce a number of important biological concepts such as bacterial growth, activation cascades, and adaptive versus innate immunity.

  8. Exploring the Innate Immune System: Using Complement-Medicated Cell Lysis in the Classroom

    ERIC Educational Resources Information Center

    Fuller, Kevin G.

    2008-01-01

    The protein complement pathway comprises an important part of the innate immunity. The use of serum to demonstrate complement-mediated destruction across a series of bacterial dilutions allows an instructor to introduce a number of important biological concepts such as bacterial growth, activation cascades, and adaptive versus innate immunity.

  9. Metabolic signals and innate immune activation in obesity and exercise.

    PubMed

    Ringseis, Robert; Eder, Klaus; Mooren, Frank C; Krüger, Karsten

    2015-01-01

    The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities. Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.

  10. The tumor suppressor ARF regulates innate immune responses in mice.

    PubMed

    Través, Paqui G; López-Fontal, Raquel; Luque, Alfonso; Hortelano, Sonsoles

    2011-12-15

    The innate immune system is the first line of defense against invading organisms, and TLRs are the main sensors of microbial components, initiating signaling pathways that induce the production of proinflammatory cytokines and type I IFNs. An antiviral action for the tumor suppressor alternative reading frame (ARF) has been reported; however, the precise role of ARF in innate immunity is unknown. In this study, we show that ARF plays an important role in regulation of inflammatory responses. In peritoneal macrophages and bone marrow-derived macrophages from ARF-deficient animals, the induction of proinflammatory cytokines and chemokines by TLR ligands was severely impaired. The altered responses of ARF(-/-) cells to TLR ligands result from aberrant activation of intracellular signaling molecules including MAPKs, IκBα degradation, and NF-κB activation. Additionally, animals lacking ARF were resistant to LPS-induced endotoxic shock. This impaired activation of inflammation in ARF(-/-) mice was not restricted to TLRs, as it was also shown in response to non-TLR signaling pathways. Thus, ARF(-/-) mice were also unable to trigger a proper inflammatory response in experimental peritonitis or in 12-O-tetradecanoylphorbol-13-acetate-induced edema. Overexpression of ARF, but not its downstream target p53, rescued the ARF-deficient phenotype, increasing TLR4 levels and restoring inflammatory reaction. An increase in the E2F1 protein levels observed in ARF(-/-) macrophages at basal condition and after LPS stimulation may be involved in the impaired response in this system, as E2F1 has been described as an inflammatory suppressor. These results indicate that tumor suppressor ARF is a new regulator of inflammatory cell signaling.

  11. Autophagy, inflammation and innate immunity in inflammatory myopathies.

    PubMed

    Cappelletti, Cristina; Galbardi, Barbara; Kapetis, Dimos; Vattemi, Gaetano; Guglielmi, Valeria; Tonin, Paola; Salerno, Franco; Morandi, Lucia; Tomelleri, Giuliano; Mantegazza, Renato; Bernasconi, Pia

    2014-01-01

    Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.

  12. Diversification of innate immune genes: lessons from the purple sea urchin.

    PubMed

    Smith, L Courtney

    2010-01-01

    Pathogen diversification can alter infection virulence, which in turn drives the evolution of host immune diversification, resulting in countermeasures for survival in this arms race. Somatic recombination of the immunoglobulin gene family members is a very effective mechanism to diversify antibodies and T-cell receptors that function in the adaptive immune system. Although mechanisms to diversify innate immune genes are not clearly understood, a seemingly unlikely source for insight into innate immune diversification may be derived from the purple sea urchin, which has recently had its genome sequenced and annotated. Although there are many differences, some characteristics of the sea urchin make for a useful tool to understand the human immune system. The sea urchin is phylogenetically related to humans although, as a group, sea urchins are evolutionarily much older than mammals. Humans require both adaptive and innate immune responses to survive immune challenges, whereas sea urchins only require innate immune functions. Genes that function in immunity tend to be members of families, and the sea urchin has several innate immune gene families. One of these is the Sp185/333 gene family with about 50 clustered members that encode a diverse array of putative immune response proteins. Understanding gene diversification in the Sp185/333 family in the sea urchin may illuminate new mechanisms of diversification that could apply to gene families that function in innate immunity in humans, such as the killer immunoglobulin-like receptor genes.

  13. Recognition of pathogens and activation of immune responses in Drosophila and horseshoe crab innate immunity.

    PubMed

    Kurata, Shoichiro; Ariki, Shigeru; Kawabata, Shun-ichiro

    2006-01-01

    In innate immunity, pattern recognition receptors discriminate between self- and infectious non-self-matter. Mammalian homologs of the Drosophila Toll protein, which are collectively referred to as Toll-like receptors (TLRs), recognize pathogen-associated molecular patterns (PAMPs), including lipopolysaccharides (LPS) and lipoproteins, whereas the Drosophila Toll protein does not act as a PAMP receptor, but rather binds to Spätzle, an endogenous peptide. In Drosophila, innate immune surveillance is mediated by members of the peptidoglycan recognition protein (PGRP) family, which recognize diverse bacteria-derived peptidoglycans and initiate appropriate immune reactions including the release of antimicrobial peptides and the activation of the prophenoloxidase cascade, the latter effecting localized wound healing, melanization, and microbial phagocytosis. In the horseshoe crab, LPS induces hemocyte exocytotic degranulation, resulting in the secretion of various defense molecules, such as coagulation factors, antimicrobial peptides, and lectins. Recent studies have demonstrated that the zymogen form of the serine protease factor C, a major granular component of hemocyte, also exists on the hemocyte surface and functions as a biosensor for LPS. The proteolytic activity of activated factor C initiates hemocyte exocytosis via a G protein mediated signal transduction pathway. Furthermore, it has become clear that an endogenous mechanism for the feedback amplification of the innate immune response exists and is dependent upon a granular component of the horseshoe crab hemocyte.

  14. The role of innate immune signals in immunity to Brucella abortus.

    PubMed

    Gomes, Marco Túlio R; Campos, Priscila C; de Almeida, Leonardo A; Oliveira, Fernanda S; Costa, Miriam Maria S; Marim, Fernanda M; Pereira, Guilherme S M; Oliveira, Sergio C

    2012-01-01

    Innate immunity serves as the first line of defense against infectious agents such as intracellular bacteria. The innate immune platform includes Toll-like receptors (TLRs), retinoid acid-inducible gene-I-like receptors and other cytosolic nucleic acid sensors, nucleotide-binding and oligomerization domain-like receptors, adaptors, kinases and other signaling molecules that are required to elicit effective responses against different pathogens. Our research group has been using the Gram-negative bacteria Brucella abortus as a model of pathogen. We have demonstrated that B. abortus triggers MAPK and NF-κB signaling pathways in macrophages in a MyD88 and IRAK-4-dependent manner. Furthermore, we claimed that so far TLR9 is the most important single TLR during Brucella infection. The identification of host receptors that recognize pathogen-derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. Besides TLRs, herein we describe recent advances in NOD1, NOD2, and type I IFN receptors in innate immune pathways during B. abortus infection.

  15. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines.

    PubMed

    Blok, Bastiaan A; Arts, Rob J W; van Crevel, Reinout; Benn, Christine Stabell; Netea, Mihai G

    2015-09-01

    An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccination models independently of lymphocytes. This process is regulated through epigenetic reprogramming of innate immune cells and has been termed "trained immunity." It has been hypothesized that induction of trained immunity is responsible for the protective, nonspecific effects induced by vaccines, such as BCG, measles vaccination, and other whole-microorganism vaccines. In this review, we will present the mechanisms of trained immunity responsible for the long-lasting effects of vaccines on the innate immune system.

  16. Epithelial NEMO links innate immunity to chronic intestinal inflammation.

    PubMed

    Nenci, Arianna; Becker, Christoph; Wullaert, Andy; Gareus, Ralph; van Loo, Geert; Danese, Silvio; Huth, Marion; Nikolaev, Alexei; Neufert, Clemens; Madison, Blair; Gumucio, Deborah; Neurath, Markus F; Pasparakis, Manolis

    2007-03-29

    Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis-acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-kappaB, a master regulator of pro-inflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappaB through conditional ablation of NEMO (also called IkappaB kinase-gamma (IKKgamma)) or both IKK1 (IKKalpha) and IKK2 (IKKbeta)-IKK subunits essential for NF-kappaB activation-spontaneously caused severe chronic intestinal inflammation in mice. NF-kappaB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-kappaB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract

  17. Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

    SciTech Connect

    McDermott, Jason E.; Vartanian, Keri B.; Mitchell, Hugh D.; Stevens, S.L.; Sanfilippo, Antonio P.; Stenzel-Poore, Mary

    2012-06-20

    The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

  18. Tim-3: an activation marker and activation limiter of innate immune cells.

    PubMed

    Han, Gencheng; Chen, Guojiang; Shen, Beifen; Li, Yan

    2013-12-10

    Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss (1) how Tim-3 is expressed and regulated on different innate immune cells; (2) how it affects the activity of different innate immune cells; and (3) how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.

  19. Immune Evasion Strategies of Ranaviruses and Innate Immune Responses to These Emerging Pathogens

    PubMed Central

    Grayfer, Leon; Andino, Francisco De Jesús; Chen, Guangchun; Chinchar, Gregory V.; Robert, Jacques

    2012-01-01

    Ranaviruses (RV, Iridoviridae) are large double-stranded DNA viruses that infect fish, amphibians and reptiles. For ecological and commercial reasons, considerable attention has been drawn to the increasing prevalence of ranaviral infections of wild populations and in aquacultural settings. Importantly, RVs appear to be capable of crossing species barriers of numerous poikilotherms, suggesting that these pathogens possess a broad host range and potent immune evasion mechanisms. Indeed, while some of the 95–100 predicted ranavirus genes encode putative evasion proteins (e.g., vIFα, vCARD), roughly two-thirds of them do not share significant sequence identity with known viral or eukaryotic genes. Accordingly, the investigation of ranaviral virulence and immune evasion strategies is promising for elucidating potential antiviral targets. In this regard, recombination-based technologies are being employed to knock out gene candidates in the best-characterized RV member, Frog Virus (FV3). Concurrently, by using animal infection models with extensively characterized immune systems, such as the African clawed frog, Xenopus laevis, it is becoming evident that components of innate immunity are at the forefront of virus-host interactions. For example, cells of the macrophage lineage represent important combatants of RV infections while themselves serving as targets for viral infection, maintenance and possibly dissemination. This review focuses on the recent advances in the understanding of the RV immune evasion strategies with emphasis on the roles of the innate immune system in ranaviral infections. PMID:22852041

  20. Trade-offs between acquired and innate immune defenses in humans

    PubMed Central

    McDade, Thomas W.; Georgiev, Alexander V.; Kuzawa, Christopher W.

    2016-01-01

    Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID:26739325

  1. Crosstalk between innate and adaptive immunity in hepatitis B virus infection.

    PubMed

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-12-28

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.

  2. Crosstalk between innate and adaptive immunity in hepatitis B virus infection

    PubMed Central

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-01-01

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection. PMID:26730277

  3. Pathogenesis of innate immunity and adaptive immunity in the mouse model of experimental autoimmune uveitis.

    PubMed

    Bi, Hong-Sheng; Liu, Zheng-Feng; Cui, Yan

    2015-05-01

    Experimental autoimmune uveitis, a well-established model for human uveitis, is similar to human uveitis in many pathological features. Studies concerning the mechanisms of experimental autoimmune uveitis would cast a light on the pathogenesis of human uveitis as well as the search for more effective therapeutic agents. The cellular components of innate immunity include natural killer cells, gamma delta T lymphocytes, antigen-presenting dendritic cells, phagocytic macrophages, and granulocytes. It is believed that T cells are central in the generation of human uveitis. It has already become clear that CD4(+) effecter cells that predominantly produce interleukin-17 (the so-called Th17 cells) may play an important role in uveitis. In addition, the occurrence and recurrence of uveitis depends on a complex interplay between the elements of innate and adaptive immunity.

  4. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity

    PubMed Central

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  5. Modeling Innate Immune Response to Early Mycobacterium Infection

    PubMed Central

    Carvalho, Rafael V.; Kleijn, Jetty; Meijer, Annemarie H.

    2012-01-01

    In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection. PMID:23365620

  6. Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

    PubMed Central

    Audsley, Michelle D; Moseley, Gregory W

    2013-01-01

    The paramyxoviruses are a family of > 30 viruses that variously infect humans, other mammals and fish to cause diverse outcomes, ranging from asymptomatic to lethal disease, with the zoonotic paramyxoviruses Nipah and Hendra showing up to 70% case-fatality rate in humans. The capacity to evade host immunity is central to viral infection, and paramyxoviruses have evolved multiple strategies to overcome the host interferon (IFN)-mediated innate immune response through the activity of their IFN-antagonist proteins. Although paramyxovirus IFN antagonists generally target common factors of the IFN system, including melanoma differentiation associated factor 5, retinoic acid-inducible gene-I, signal transducers and activators of transcription (STAT)1 and STAT2, and IFN regulatory factor 3, the mechanisms of antagonism show remarkable diversity between different genera and even individual members of the same genus; the reasons for this diversity, however, are not currently understood. Here, we review the IFN antagonism strategies of paramyxoviruses, highlighting mechanistic differences observed between individual species and genera. We also discuss potential sources of this diversity, including biological differences in the host and/or tissue specificity of different paramyxoviruses, and potential effects of experimental approaches that have largely relied on in vitro systems. Importantly, recent studies using recombinant virus systems and animal infection models are beginning to clarify the importance of certain mechanisms of IFN antagonism to in vivo infections, providing important indications not only of their critical importance to virulence, but also of their potential targeting for new therapeutic/vaccine approaches. PMID:24175230

  7. Chromosome Conformation Capture for Research on Innate Antiviral Immunity.

    PubMed

    Kim, Yoon Jung; Kim, Tae Hoon

    2017-01-01

    Chromosome conformation capture (3C) technology has revolutionized our knowledge on chromatin folding and nuclear organization. This cis-loop detection approach can be used to identify candidate regulatory elements interacting with target gene of interest. This chapter introduces the application of 3C technique to investigate a dynamic alteration in the chromosome folding structure or genomic architecture resulting from interaction changes between the enhancer and its target gene. Innate antiviral immunity is one of the well-known gene induction systems, involving rapid first-line response to virus or pathogen to trigger gene expression changes in order to protect cells and to limit further infection. Thus, the 3C technique can be a powerful tool for exploring how enhancers control expression of immunity genes during virus infection. 3C assay consists of four major steps: Cross-linking with formaldehyde, restriction enzyme digestion, ligation of cross-linked DNA fragments, and quantitative data analysis. Here, we discuss in detail the design, application, and data analysis of a 3C experiment.

  8. Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity.

    PubMed

    Gao, Yuanqing; Vidal-Itriago, Andrés; Kalsbeek, Martin J; Layritz, Clarita; García-Cáceres, Cristina; Tom, Robby Zachariah; Eichmann, Thomas O; Vaz, Frédéric M; Houtkooper, Riekelt H; van der Wel, Nicole; Verhoeven, Arthur J; Yan, Jie; Kalsbeek, Andries; Eckel, Robert H; Hofmann, Susanna M; Yi, Chun-Xia

    2017-09-26

    Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Air Pollution Particulate Matter Alters Antimycobacterial Respiratory Epithelium Innate Immunity

    PubMed Central

    Rivas-Santiago, César E.; Sarkar, Srijata; Cantarella, Pasquale; Osornio-Vargas, Álvaro; Quintana-Belmares, Raúl; Meng, Qingyu; Kirn, Thomas J.; Ohman Strickland, Pamela; Chow, Judith C.; Watson, John G.; Torres, Martha

    2015-01-01

    Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses against Mycobacterium tuberculosis has been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 μm (PM2.5) and 10 μm (PM10) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM2.5 or PM10 deregulated the ability of the A549 cells to express the antimicrobial peptides human β-defensin 2 (HBD-2) and HBD-3 upon infection with M. tuberculosis and increased intracellular M. tuberculosis growth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhanced M. tuberculosis growth represent mechanisms by which exposure to air pollution PM may increase the risk of M. tuberculosis infection and the development of TB. PMID:25847963

  10. Innate and adaptive immune responses to cell death

    PubMed Central

    Rock, Kenneth L.; Lai, Jiann-Jyh; Kono, Hajime

    2011-01-01

    Summary The immune system plays an essential role in protecting the host against infections and to accomplish this task has evolved mechanisms to recognize microbes and destroy them. In addition, it monitors the health of cells and responds to ones that have been injured and die, even if this occurs under sterile conditions. This process is initiated when dying cells expose intracellular molecules that can be recognized by cells of the innate immune system. As a consequence of this recognition, dendritic cells are activated in ways that help to promote T-cell responses to antigens associated with the dying cells. In addition, macrophages are stimulated to produce the cytokine interleukin-1 that then acts on radioresistant parenchymal cells in the host in ways that drive a robust inflammatory response. In addition to dead cells, a number of other sterile particles and altered physiological states can similarly stimulate an inflammatory response and do so through common pathways involving the inflammasome and interleukin-1. These pathways underlie the pathogenesis of a number of diseases. PMID:21884177

  11. Suppression of innate inflammation and immunity by interleukin-37.

    PubMed

    Dinarello, Charles A; Nold-Petry, Claudia; Nold, Marcel; Fujita, Mayumi; Li, Suzhao; Kim, Soohyun; Bufler, Philip

    2016-05-01

    IL-37 is unique in the IL-1 family in that unlike other members of the family, IL-37 broadly suppresses innate immunity. IL-37 can be elevated in humans with inflammatory and autoimmune diseases where it likely functions to limit inflammation. Transgenic mice expressing human IL-37 (IL37-tg) exhibit less severe inflammation in models of endotoxin shock, colitis, myocardial infarction, lung, and spinal cord injury. IL37-tg mice have reduced antigen-specific responses and dendritic cells (DCs) from these mice exhibit characteristics of tolerogenic DCs. Compared to aging wild-type (WT) mice, aging IL37-tg mice are protected against B-cell leukemogenesis and heart failure. Treatment of WT mice with recombinant human IL-37 has been shown to be protective in several models of inflammation and injury. IL-37 binds to the IL-18 receptor but then recruits the orphan IL-1R8 (formerly TIR8 or SIGIRR) in order to function as an inhibitor. Here, we review the discovery of IL-37, its production, release, and mechanisms by which IL-37 reduces inflammation and suppresses immune responses. The data reviewed here suggest a therapeutic potential for IL-37. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Air pollution particulate matter alters antimycobacterial respiratory epithelium innate immunity.

    PubMed

    Rivas-Santiago, César E; Sarkar, Srijata; Cantarella, Pasquale; Osornio-Vargas, Álvaro; Quintana-Belmares, Raúl; Meng, Qingyu; Kirn, Thomas J; Ohman Strickland, Pamela; Chow, Judith C; Watson, John G; Torres, Martha; Schwander, Stephan

    2015-06-01

    Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses against Mycobacterium tuberculosis has been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 μm (PM2.5) and 10 μm (PM10) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM2.5 or PM10 deregulated the ability of the A549 cells to express the antimicrobial peptides human β-defensin 2 (HBD-2) and HBD-3 upon infection with M. tuberculosis and increased intracellular M. tuberculosis growth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhanced M. tuberculosis growth represent mechanisms by which exposure to air pollution PM may increase the risk of M. tuberculosis infection and the development of TB.

  13. Regulation of antiviral innate immune signaling by stress-induced RNA granules.

    PubMed

    Yoneyama, Mitsutoshi; Jogi, Michihiko; Onomoto, Koji

    2016-03-01

    Activation of antiviral innate immunity is triggered by cellular pattern recognition receptors. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) detect viral non-self RNA in cytoplasm of virus-infected cells and play a critical role in the clearance of the invaded viruses through production of antiviral cytokines. Among the three known RLRs, RIG-I and melanoma differentiation-associated gene 5 recognize distinct non-self signatures of viral RNA and activate antiviral signaling. Recent reports have clearly described the molecular machinery underlying the activation of RLRs and interactions with the downstream adaptor, mitochondrial antiviral signaling protein (MAVS). RLRs and MAVS are thought to form large multimeric filaments around cytoplasmic organelles depending on the presence of Lys63-linked ubiquitin chains. Furthermore, RLRs have been shown to localize to stress-induced ribonucleoprotein aggregate known as stress granules and utilize them as a platform for recognition/activation of signaling. In this review, we will focus on the current understanding of RLR-mediated signal activation and the interactions with stress-induced RNA granules. © The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society.

  14. Regulation of antiviral innate immune signaling by stress-induced RNA granules

    PubMed Central

    Yoneyama, Mitsutoshi; Jogi, Michihiko; Onomoto, Koji

    2016-01-01

    Activation of antiviral innate immunity is triggered by cellular pattern recognition receptors. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) detect viral non-self RNA in cytoplasm of virus-infected cells and play a critical role in the clearance of the invaded viruses through production of antiviral cytokines. Among the three known RLRs, RIG-I and melanoma differentiation-associated gene 5 recognize distinct non-self signatures of viral RNA and activate antiviral signaling. Recent reports have clearly described the molecular machinery underlying the activation of RLRs and interactions with the downstream adaptor, mitochondrial antiviral signaling protein (MAVS). RLRs and MAVS are thought to form large multimeric filaments around cytoplasmic organelles depending on the presence of Lys63-linked ubiquitin chains. Furthermore, RLRs have been shown to localize to stress-induced ribonucleoprotein aggregate known as stress granules and utilize them as a platform for recognition/activation of signaling. In this review, we will focus on the current understanding of RLR-mediated signal activation and the interactions with stress-induced RNA granules. PMID:26748340

  15. Interrogation of Cellular Innate Immunity by Diamond-Nanoneedle-Assisted Intracellular Molecular Fishing.

    PubMed

    Wang, Zixun; Yang, Yang; Xu, Zhen; Wang, Ying; Zhang, Wenjun; Shi, Peng

    2015-10-14

    Understanding intracellular signaling cascades and network is one of the core topics in modern biology. Novel tools based on nanotechnologies have enabled probing and analyzing intracellular signaling with unprecedented sensitivity and specificity. In this study, we developed a minimally invasive method for in situ probing specific signaling components of cellular innate immunity in living cells. The technique was based on diamond-nanoneedle arrays functionalized with aptamer-based molecular sensors, which were inserted into cytoplasmic domain using a centrifugation controlled process to capture molecular targets. Simultaneously, these diamond-nanoneedles also facilitated the delivery of double-strand DNAs (dsDNA90) into cells to activate the pathway involving the stimulator of interferon genes (STING). We showed that the nanoneedle-based biosensors can be successfully utilized to isolate transcriptional factor, NF-κB, from intracellular regions without damaging the cells, upon STING activation. By using a reversible protocol and repeated probing in living cells, we were able to examine the singling dynamics of NF-κB, which was quickly translocated from cytoplasm to nucleus region within ∼40 min of intracellular introduction of dsDNA90 for both A549 and neuron cells. These results demonstrated a novel and versatile tool for targeted in situ dissection of intracellular signaling, providing the potential to resolve new sights into various cellular processes.

  16. Analysis of evolutionarily conserved innate immune components in coral links immunity and symbiosis.

    PubMed

    Kvennefors, E Charlotte E; Leggat, William; Kerr, Caroline C; Ainsworth, Tracy D; Hoegh-Guldberg, Ove; Barnes, Andrew C

    2010-11-01

    Reef-building corals are representatives of one of the earliest diverging metazoan lineages and are experiencing increases in bleaching events (breakdown of the coral-Symbiodinium symbiosis) and disease outbreaks. The present study investigates the roles of two pattern recognition proteins, the mannose binding lectin Millectin and a complement factor C3-like protein (C3-Am), in the coral Acropora millepora. The results indicate that the innate immune functions of these molecules are conserved and arose early in evolution. C3-Am is expressed in response to injury, and may function as an opsonin. In contrast, Millectin expression is up-regulated in response to lipopolysaccharide and peptidoglycan. These observations, coupled with localization of Millectin in nematocysts in epidermal tissue, and reported binding of pathogens, are consistent with a key role for the lectin in innate immunity. Furthermore, Millectin was consistently detected binding to the symbiont Symbiodinium in vivo, indicating that the Millectin function of recognition and binding of non-self-entities may have been co-opted from an ancient innate immune system into a role in symbiosis.

  17. Genetic and evolutionary patterns of innate immune genes in the Pacific oyster Crassostrea gigas.

    PubMed

    Song, Kai; Li, Yingxiang; Huang, Baoyu; Li, Li; Zhang, Guofan

    2017-12-01

    The invertebrate innate immune system functions in immune defence and the stress response. However, knowledge of the genetic and evolutionary patterns of innate immune genes in Mollusca is limited, especially for oysters. Such information would help clarify how oysters adapt to pathogen-rich environments. Here, we characterized the genetic and evolutionary patterns of the innate immune genes in Crassostrea gigas, using population diversity analysis and evolution rates comparison. Innate immune genes have higher median nucleotide diversity than non-immune genes. Nucleotide diversity varied with functional regions and different immune-related gene families. Evolutionary analysis of two Crassostrea species showed that the innate immune genes are less conserved and have higher rates of evolution in C. gigas. We also noted a positive association between nucleotide diversity and selective pressures for genes having orthologues. Our findings will help determine the evolutionary patterns of innate immune genes and the association of these genes with mollusc immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Cortisol Biosynthesis in the Human Ocular Surface Innate Immune Response

    PubMed Central

    Walker, Elizabeth A.; Bujalska, Iwona J.; Alsalem, Jawaher; Williams, Geraint P.; Sreekantam, Sreekanth; Taylor, Angela E.; Tallouzi, Mohammad; Southworth, H. Susan; Murray, Philip I.; Wallace, Graham R.; Rauz, Saaeha

    2014-01-01

    Innate immune responses have a critical role in regulating sight-threatening ocular surface (OcS) inflammation. While glucocorticoids (GCs) are frequently used to limit tissue damage, the role of intracrine GC (cortisol) bioavailability via 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in OcS defense, remains unresolved. We found that primary human corneal epithelial cells (PHCEC), fibroblasts (PHKF) and allogeneic macrophages (M1, GM-CSF; M2, M-CSF) were capable of generating cortisol (M1>PHKF>M2>PHCEC) but in corneal cells, this was independent of Toll-like receptor (TLR) activation. While PolyI∶C induced maximal cytokine and chemokine production from both PHCEC (IFNγ, CCL2, CCL3, and (CCL4), IL6, CXCL10, CCL5, TNFα) and PHKF (CCL2, IL-6, CXCL10, CCL5), only PHKF cytokines were inhibited by GCs. Both Poly I∶C and LPS challenged-corneal cells induced M1 chemotaxis (greatest LPS-PHKF (250%), but down-regulated M1 11β-HSD1 activity (30 and 40% respectively). These data were supported by clinical studies demonstrating reduced human tear film cortisol∶cortisone ratios (a biomarker of local 11β-HSD1 activity) in pseudomonas keratitis (1∶2.9) versus healthy controls (1∶1.3; p<0.05). This contrasted with putative TLR3-mediated OcS disease (Stevens-Johnson Syndrome, Mucous membrane pemphigoid) where an increase in cortisol∶cortisone ratio was observed (113.8∶1; p<0.05). In summary, cortisol biosynthesis in human corneal cells is independent of TLR activation and is likely to afford immunoprotection under physiological conditions. Contribution to ocular mucosal innate responses is dependent on the aetiology of immunological challenge. PMID:24736562

  19. Therapies targeting innate immunity for fighting inflammation in atherosclerosis.

    PubMed

    Mendel, Itzhak; Yacov, Niva; Harats, Dror; Breitbart, Eyal

    2015-01-01

    Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.

  20. Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals.

    PubMed

    Silveira-Nunes, Gabriela; Speziali, Elaine; Teixeira-Carvalho, Andréa; Vitelli-Avelar, Danielle M; Sathler-Avelar, Renato; Figueiredo-Soares, Taciana; Silva, Maria Luiza; Peruhype-Magalhães, Vanessa; Chaves, Daniel Gonçalves; Brito-Melo, Gustavo Eustáquio; Cardoso, Glenda Meira; Soares, Eric Bassetti; Elói-Santos, Silvana Maria; Teixeira, Rosângela; Queiroz, Dulciene Magalhães; Corrêa-Oliveira, Rodrigo; Faria, Ana Maria Caetano; Martins-Filho, Olindo Assis

    2017-01-01

    Immunosenescence is associated with several changes in adaptive and innate immune cells. Altered cytokine production is among the most prominent of these changes. The impact of age-related alterations on cytokine global profiles produced by distinct populations of leukocytes from healthy Brazilian individuals was studied. We analysed frequencies of cytokine-producing lymphocytes and innate immune cells from individuals at several ages spanning a lifetime period (0-85 years). Healthy adult individuals presented a balanced profile suggestive of a mature immune system with equal contributions of both innate and adaptive immunity and of both categories of cytokines (inflammatory and regulatory). In healthy newborns and elderly, innate immune cells, especially neutrophils and NK-cells, contributed the most to a balanced profile of cytokines. Our results support the hypothesis that ageing is not associated with a progressive pro-inflammatory cytokine production by all leukocytes but rather with distinct fluctuations in the frequency of cytokine-producing cells throughout life.

  1. Evasion and Interactions of the Humoral Innate Immune Response in Pathogen Invasion, Autoimmune Disease, and Cancer

    PubMed Central

    Rettig, Trisha A.; Harbin, Julie N.; Harrington, Adelaide; Dohmen, Leonie; Fleming, Sherry D.

    2015-01-01

    The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how gram positive bacteria, viruses, cancer, and the autoimmune conditions Systemic Lupus Erythematosus and Anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development. PMID:26145788

  2. Microarray expression analysis of genes involved in innate immune memory in peritoneal macrophages.

    PubMed

    Yoshida, Keisuke; Renard-Guillet, Claire; Inoue, Kentaro; Shirahige, Katsuhiko; Okada-Hatakeyama, Mariko; Ishii, Shunsuke

    2016-03-01

    Immunological memory has been believed to be a feature of the adaptive immune system for long period, but recent reports suggest that the innate immune system also exhibits memory-like reaction. Although evidence of innate immune memory is accumulating, no in vivo experimental data has clearly implicated a molecular mechanism, or even a cell-type, for this phenomenon. In this study of data deposited into Gene Expression Omnibus (GEO) under GSE71111, we analyzed the expression profile of peritoneal macrophages isolated from mice pre-administrated with toll-like receptor (TLR) ligands, mimicking pathogen infection. In these macrophages, increased expression of a group of innate immunity-related genes was sustained over a long period of time, and these genes overlapped with ATF7-regulated genes. We conclude that ATF7 plays an important role in innate immune memory in macrophages.

  3. A systems biology approach to nutritional immunology - focus on innate immunity.

    PubMed

    Afacan, Nicole J; Fjell, Christopher D; Hancock, Robert E W

    2012-02-01

    Innate immunity and nutrient metabolism are complex biological systems that must work in concert to sustain and preserve life. The effector cells of the innate immune system rely on essential nutrients to generate energy, produce metabolic precursors for macromolecule biosynthesis and tune their responses to infectious agents. Thus disruptions to nutritional status have a substantial impact on immune competence and can result in increased susceptibility to infection in the case of nutrient deficiency, or chronic inflammation in the case of over-nutrition. The traditional, reductionist methods used in the study of nutritional immunology are incapable of exploring the extremely complex interactions between nutrient metabolism and innate immunity. Here, we review a relatively new analytical approach, systems biology, and highlight how it can be applied to nutritional immunology to provide a comprehensive view of the mechanisms behind nutritional regulation of the innate immune system.

  4. The Anopheles innate immune system in the defense against malaria infection

    PubMed Central

    Clayton, April M.; Dong, Yuemei; Dimopoulos, George

    2014-01-01

    The multifaceted innate immune system of insects is capable of fighting infection by a variety of pathogens including those causing human malaria. Malaria transmission by the Anopheles mosquito depends on the Plasmodium parasite’s successful completion of its lifecycle in the insect vector, a process that involves interactions with several tissues and cell types as well as with the mosquito’s innate immune system. This review will discuss our current understanding of the Anopheles mosquito’s innate immune responses against the malaria parasite Plasmodium and the influence of the insect’s intestinal microbiota on parasite infection. PMID:23988482

  5. Self-eating and self-defense: autophagy controls innate immunity and adaptive immunity.

    PubMed

    Liu, Guangwei; Bi, Yujing; Wang, Ruoning; Wang, Xianghui

    2013-04-01

    Autophagy (macroautophagy; "self-eating") is a degradation process, in which cytoplasmic content is engulfed and degraded by the lysosome. And, immunity is an important mechanism of the "self-defense" system. Autophagy has long been recognized as a stress response to nutrient deprivation. This will provide energy and anabolic building blocks to maintain cellular bioenergetic homeostasis. Thus, autophagy plays critical roles in regulating a wide variety of pathophysiological processes, including tumorigenesis, embryo development, tissue remodeling, and most recently, immunity. The latter shows that a self-eating (autophagy) process could regulate a self-defense (immune) system. In this review, we summarize the recent findings regarding the regulatory and mechanistic insights of the autophagy pathway in immunity.

  6. Sympathetic nervous system influence on the innate immune response.

    PubMed

    Maestroni, Georges J M

    2006-06-01

    Our studies focused on the sympathetic nervous system (SNS) influence on dendritic cells (DCs), which play a crucial role in the innate immune response. We found that DCs express a variety of adrenergic receptors (ARs) with alpha1-ARs playing a stimulatory and beta2-ARs an inhibitory effect on DCs migration. beta2-ARs in skin and bone marrow-derived DCs when stimulated by bacterial toll-like receptors (TLRs) agonists respond to norepinephrine (NE) by decreased interleukin-12 (IL-12) and increased IL-10 production which in turn downregulates inflammatory cytokine production and CCR7 expression and thus their migration ability leading to reduced T helper-1 (Th1) priming. We also found that contact sensitizers that may induce a predominant Th1 response, do so by inhibiting the local NE turnover in the skin. The SNS seems therefore to contribute in shaping the information conveyed by DCs to T cells and thus in inducing the appropriate adaptive immune response. In this sense, the SNS physiological influence may allow Th2 priming to fight infections sustained by extracellular pathogens and limit the risk for organ-specific autoimmune reactions associated with excessive Th1 priming and inhibition of T regulatory cell functions. More recently, we found that preconditioning of the skin by beta-adrenergic antagonist and the TLR2 agonist S. Aureus peptidoglycan (PGN) may instruct a Th1 adaptive response to a soluble protein antigen. On the contrary, when the TLR4 agonist E. Coli lipopolysaccharide was used, the presence of the beta-adrenergic antagonist was not effective. These effects were consonant with the pattern of TLRs expression shown by epidermal keratinocytes (EKs) but not by skin DCs. As beta-ARs signaling defects together with S. Aureus infections are thought to serve as initiation and/or persistence factors for numerous Th1-sustained autoimmune inflammatory skin diseases, we might have disclosed at least part of the relevant pathogenetic mechanism.

  7. RNAi Induces Innate Immunity through Multiple Cellular Signaling Pathways

    PubMed Central

    Wu, Jun; Pei, Rongjuan; Xu, Yang; Yang, Dongliang; Roggendorf, Michael; Lu, Mengji

    2013-01-01

    Background & Aims Our previous results showed that the knockdown of woodchuck hepatitis virus (WHV) by RNA interference (RNAi) led to upregulation of interferon stimulated genes (ISGs) in primary hepatocytes. In the present study, we tested the hypothesis that the cellular signaling pathways recognizing RNA molecules may be involved the ISG stimulation by RNAi. Methods Primary murine hepatocytes (PMHs) from wild type mice and WHV transgenic (Tg) mice were prepared and treated with defined siRNAs. The mRNA levels of target genes and ISGs were detected by real-time RT-PCR. The involvement of the signaling pathways including RIG-I/MDA5, PKR, and TLR3/7/8/9 was examined by specific inhibition and the analysis of their activation by Western blotting. Results In PMHs from WHV Tg mice, specific siRNAs targeting WHV, mouse β-actin, and GAPDH reduced the levels of targeted mRNAs and increased the mRNA expression of IFN-β, MxA, and IP-10. The enhanced ISG expression by siRNA transfection were abolished by siRNA-specific 2′-O-methyl antisense RNA and the inhibitors 2-AP and chloroquine blocking PKR and other TLR-mediated signaling pathways. Furthermore, Western blotting revealed that RNAi results in an increase in PKR phosphorylation and nuclear translocation of IRF3 and NF-êB, indicating the possible role of IRF3 in the RNAi-directed induction of ISGs. In contrast, silencing of RIG-I and MDA5 failed to block RNAi-mediated MxA induction. Conclusions RNAi is capable of enhancing innate immune responses through the PKR- and TLR-dependent signaling pathways in primary hepatocytes. The immune stimulation by RNAi may contribute to the antiviral activity of siRNAs in vivo. PMID:23700487

  8. Mechanisms linking metabolic stress with innate immunity in the endometrium.

    PubMed

    Sheldon, I Martin; Cronin, James G; Pospiech, Mateusz; Turner, Matthew L

    2017-09-06

    Bacterial infections of the uterus after parturition are ubiquitous in dairy cattle and often cause uterine disease, such as metritis or endometritis. However, the metabolic stress associated with milk production increases the risk of developing disease. Resolution of bacterial infections requires rapid and robust innate immune responses, which depend on host cell receptors recognizing pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) from gram-negative bacteria. Here, we argue that metabolic stress impairs the inflammatory response to pathogens. Glucose and glutamine are the major energy sources for cells, but their abundance is reduced in postpartum dairy cows. Furthermore, inflammatory responses exacerbate metabolic stress, with animals and tissues consuming more glucose when challenged with LPS. However, depriving endometrial tissue of glucose or glutamine impairs the secretion of IL-1β, IL-6, and IL-8 in response to pathogen-associated molecular patterns. Glycolysis and the intracellular sensor of energy, AMP-activated protein kinase, are important for the response to LPS because perturbing glycolysis or AMP-activated protein kinase activity reduces the secretion of IL-1β, IL-6, and IL-8 in the endometrium. The mevalonate pathway for cellular cholesterol synthesis may also be linked to immunity, as inhibition of the terminal enzyme in the pathway, squalene synthase, reduces inflammatory responses to pathogenic bacteria and LPS. In contrast, only modest effects on inflammation are found when modulating the sensor of cellular nutrient satiety, mammalian target of rapamycin, or the endocrine regulator of metabolism, insulin-like growth factor-1. We suggest that stressing cellular metabolism increases the risk of uterine disease by impairing endometrial defenses. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  9. A Role for Innate Immunity in the Development of Hypertension

    PubMed Central

    Gomolak, Jessica R.; Didion, Sean P.

    2014-01-01

    Clinically, Angiotensin II (Ang II) has been implicated in some forms of hypertension and linked to vascular injury. Experimentally, chronic Ang II infusion leads to an increase in blood pressure, resulting in impaired endothelial function and vascular hypertrophy. Ang II also upregulates the activity and expression of a number of inflammatory molecules, including nuclear factor kappa B (NFκB) and pro-inflammatory cytokines, such as interleukin-6 (IL-6). More recently, it has been reported that Ang II is associated with upregulation of toll-like receptor TLR expression, specifically TLR4. Classical TLR4 signaling is mediated in large part by the effector protein myeloid differentiation factor 88 (MyD88), with resultant activation of NFκB, a transcription factor that promotes expression of a number of inflammatory gene products, including IL-6. A role for IL-6 has been previously implicated in the vascular dysfunction associated with Ang II-dependent hypertension. It is not known whether the MyD88 signaling pathway represents a cellular mechanism by which Ang II promotes endothelial dysfunction via NFκB activation and increases in IL-6. Taken together, we propose to mechanistically elucidate the role of innate immune signaling in Ang II-dependent hypertension. We hypothesize MyD88-deficiency will prevent the activation and transcription of NFκB-related gene products, including IL-6, thereby limiting Ang II-dependent hypertension and vascular complications. PMID:25441337

  10. Infectious Disease: Connecting Innate Immunity to Biocidal Polymers

    PubMed Central

    Gabriel, Gregory J.; Som, Abhigyan; Madkour, Ahmad E.; Eren, Tarik; Tew, Gregory N.

    2007-01-01

    Infectious disease is a critically important global healthcare issue. In the U.S. alone there are 2 million new cases of hospital-acquired infections annually leading to 90,000 deaths and 5 billion dollars of added healthcare costs. Couple these numbers with the appearance of new antibiotic resistant bacterial strains and the increasing occurrences of community-type outbreaks, and clearly this is an important problem. Our review attempts to bridge the research areas of natural host defense peptides (HDPs), a component of the innate immune system, and biocidal cationic polymers. Recently discovered peptidomimetics and other synthetic mimics of HDPs, that can be short oligomers as well as polymeric macromolecules, provide a unique link between these two areas. An emerging class of these mimics are the facially amphiphilic polymers that aim to emulate the physicochemical properties of HDPs but take advantage of the synthetic ease of polymers. These mimics have been designed with antimicrobial activity and, importantly, selectivity that rivals natural HDPs. In addition to providing some perspective on HDPs, selective mimics, and biocidal polymers, focus is given to the arsenal of biophysical techniques available to study their mode of action and interactions with phospholipid membranes. The issue of lipid type is highlighted and the important role of negative curvature lipids is illustrated. Finally, materials applications (for instance, in the development of permanently antibacterial surfaces) are discussed as this is an important part of controlling the spread of infectious disease. PMID:18160969

  11. The suppression of innate immune response by human rhinovirus C.

    PubMed

    Pang, Li-Li; Yuan, Xin-Hui; Shao, Chang-Sheng; Li, Mao-Zhong; Wang, Ying; Wang, Hui-Min; Xie, Guang-Cheng; Xie, Zhi-Ping; Yuan, Yue; Zhou, Dong-Mei; Sun, Xiao-Man; Zhang, Qing; Xin, Yan; Li, Dan-di; Duan, Zhao-Jun

    2017-08-12

    Rhinovirus C (RV-C), a newly identified group of human rhinoviruses (RVs), is associated with exacerbation of severe asthma. The type I interferon (IFN) response induced by this virus and the mechanisms of evasion of IFN-mediated innate immunity for RV-C remain unclear. In this study, we constructed a full-length cDNA clone of RV-C (LZ651) from a clinical sample. IFN-β mRNA and protein levels were not elevated in differentiated Human bronchial epithelial (HBE) cells at the air-liquid interface infected with RV-C, except in the early stage of infection. The ability to attenuate IFN-β activation was ascribed to 3C(pro) of RV-C, and the 40-His site of 3C(pro) played an important role. Furthermore, RIG-I was degraded by 3C(pro) in a caspase-dependent manner and 3C(pro) cleaved MAVS at 148 Q/A, which inhibited IFN signaling. Taken together, our results demonstrate the mechanism by which RV-C circumvents the production of type I IFN in infected cells. Copyright © 2017. Published by Elsevier Inc.

  12. [Innate immunity: cutaneous expression of Toll-like receptors].

    PubMed

    Musette, Philippe; Auquit Auckbur, Isabelle; Begon, Edouard

    2006-02-01

    Toll receptors were first identified as an essential molecule for embryonic patterning in Drosophila and were subsequently shown to be a key in antibacterial and antifungal immunity in adult flies. Toll receptors have been conserved throughout evolution. In mammals, TLRs have been implicated in both inflammatory responses and innate host defense to pathogens. The 11 different TLRs recognize conserved molecular patterns of microbial pathogens termed pathogen-specific molecular patterns (PAMPs), that permit to confer responsiveness to a wide variety of pathogens. Endogenous ligands are also able to activate TLRs. All adult tissue is capable to express at least one of member of TLR family, but a largest repertoire of TLRs is found in tissues exposed to the external environment. The TLR activation induce the NF-kappaB translocation to the nucleus and cytokine secretion. Since the primary function of skin is to provide an effective barrier against outside agression, it is likely that keratinocytes may play a role in a rapid and efficient host defence system, and the fact that keratinocytes are capable of expressing a wide variety of TLRs is subsequently not surprising.

  13. gammadelta T cells link innate and adaptive immune responses.

    PubMed

    Holtmeier, Wolfgang; Kabelitz, Dieter

    2005-01-01

    While most T cells use a CD3-associated alpha/beta T cell receptor as antigen recognition structure, a second population of T cells expresses the alternative gamma/delta T cell receptor. gamma/delta T cells are a minor population in the peripheral blood but constitute a major population among intestinal intraepithelial lymphocytes. Most gamma/delta T cells recognize ligands which are fundamentally different from the short peptides that are seen by alpha/beta T cells in the context of MHC class I or class II molecules. Thus, human Vdelta2 T cells recognize small bacterial phosphoantigens, alkylamines and synthetic aminobisphosphonates, whereas Vdelta1 T cells recognize stress-inducible MHC-related molecules MICA/B as well as several other ligands. At the functional level, gamma/delta T cells rapidly produce a variety of cytokines and usually exert potent cytotoxic activity, also towards many tumor cells. In this article, we discuss the role of gamma/delta T cells as a bridge between the innate and the adaptive immune system, based on the interpretation that gamma/delta T cells use their T cell receptor as a pattern recognition receptor. Our increasing understanding of the ligand recognition and activation mechanisms of gamma/delta T cells also opens new perspectives for the development of gamma/delta T cell-based immunotherapies.

  14. Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation.

    PubMed

    Inglis, Fiona M; Lee, Kim M; Chiu, Kevin B; Purcell, Olivia M; Didier, Peter J; Russell-Lodrigue, Kasi; Weaver, Scott C; Roy, Chad J; MacLean, Andrew G

    2016-04-01

    Chikungunya, "that which bends up" in the Makonde dialect, is an emerging global health threat, with increasing incidence of neurological complications. Until 2013, Chikungunya infection had been largely restricted to East Africa and the Indian Ocean, with cases within the USA reported to be from foreign travel. However, in 2014, over 1 million suspected cases were reported in the Americas, and a recently infected human could serve as an unwitting reservoir for the virus resulting in an epidemic in the continental USA. Chikungunya infection is increasingly being associated with neurological sequelae. In this study, we sought to understand the role of astrocytes in the neuropathogenesis of Chikungunya infection. Even after virus has been cleared form the circulation, astrocytes were activated with regard to TLR2 expression. In addition, white matter astrocytes were hypertrophic, with increased arbor volume in gray matter astrocytes. Combined, these would alter the number and distribution of synapses that each astrocyte would be capable of forming. These results provide the first evidence that Chikungunya infection induces morphometric and innate immune activation of astrocytes in vivo. Perturbed glia-neuron signaling could be a major driving factor in the development of Chikungunya-associated neuropathology.

  15. Crosstalk between the circadian clock and innate immunity in Arabidopsis.

    PubMed

    Zhang, Chong; Xie, Qiguang; Anderson, Ryan G; Ng, Gina; Seitz, Nicholas C; Peterson, Thomas; McClung, C Robertson; McDowell, John M; Kong, Dongdong; Kwak, June M; Lu, Hua

    2013-01-01

    The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity.

  16. Transferred interbacterial antagonism genes augment eukaryotic innate immune function.

    PubMed

    Chou, Seemay; Daugherty, Matthew D; Peterson, S Brook; Biboy, Jacob; Yang, Youyun; Jutras, Brandon L; Fritz-Laylin, Lillian K; Ferrin, Michael A; Harding, Brittany N; Jacobs-Wagner, Christine; Yang, X Frank; Vollmer, Waldemar; Malik, Harmit S; Mougous, Joseph D

    2015-02-05

    Horizontal gene transfer allows organisms to rapidly acquire adaptive traits. Although documented instances of horizontal gene transfer from bacteria to eukaryotes remain rare, bacteria represent a rich source of new functions potentially available for co-option. One benefit that genes of bacterial origin could provide to eukaryotes is the capacity to produce antibacterials, which have evolved in prokaryotes as the result of eons of interbacterial competition. The type VI secretion amidase effector (Tae) proteins are potent bacteriocidal enzymes that degrade the cell wall when delivered into competing bacterial cells by the type VI secretion system. Here we show that tae genes have been transferred to eukaryotes on at least six occasions, and that the resulting domesticated amidase effector (dae) genes have been preserved for hundreds of millions of years through purifying selection. We show that the dae genes acquired eukaryotic secretion signals, are expressed within recipient organisms, and encode active antibacterial toxins that possess substrate specificity matching extant Tae proteins of the same lineage. Finally, we show that a dae gene in the deer tick Ixodes scapularis limits proliferation of Borrelia burgdorferi, the aetiologic agent of Lyme disease. Our work demonstrates that a family of horizontally acquired toxins honed to mediate interbacterial antagonism confers previously undescribed antibacterial capacity to eukaryotes. We speculate that the selective pressure imposed by competition between bacteria has produced a reservoir of genes encoding diverse antimicrobial functions that are tailored for co-option by eukaryotic innate immune systems.

  17. Control of the innate immune response by the mevalonate pathway

    PubMed Central

    Akula, Murali K.; Shi, Man; Jiang, Zhaozhao; Foster, Celia E.; Miao, David; Li, Annie S.; Zhang, Xiaoman; Gavin, Ruth M.; Forde, Sorcha D.; Germain, Gail; Carpenter, Susan; Rosadini, Charles V.; Gritsman, Kira; Chae, Jae Jin; Hampton, Randolph; Silverman, Neal; Gravallese, Ellen M.; Kagan, Jonathan C.; Fitzgerald, Katherine A.; Kastner, Daniel L.; Golenbock, Douglas T.; Bergo, Martin O.; Wang, Donghai

    2016-01-01

    Deficiency of mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate (GGPP), a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, protein post-translational modification catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) cause autoinflammatory Familial Mediterranean Fever (FMF) syndrome. Here, we show that protein geranylgeranylation enables Toll-like receptor (TLR)-induced phosphatidylinositol-3-OH kinase PI(3)K) activation by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages deficient for GGTase I or p110δ exhibited constitutive interleukin-1β release that was MEFV-dependent, but NLRP3-, AIM2- and NLRC4- inflammasome independent. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows for an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome. PMID:27270400

  18. Infectious Disease: Connecting Innate Immunity to Biocidal Polymers.

    PubMed

    Gabriel, Gregory J; Som, Abhigyan; Madkour, Ahmad E; Eren, Tarik; Tew, Gregory N

    2007-08-01

    Infectious disease is a critically important global healthcare issue. In the U.S. alone there are 2 million new cases of hospital-acquired infections annually leading to 90,000 deaths and 5 billion dollars of added healthcare costs. Couple these numbers with the appearance of new antibiotic resistant bacterial strains and the increasing occurrences of community-type outbreaks, and clearly this is an important problem. Our review attempts to bridge the research areas of natural host defense peptides (HDPs), a component of the innate immune system, and biocidal cationic polymers. Recently discovered peptidomimetics and other synthetic mimics of HDPs, that can be short oligomers as well as polymeric macromolecules, provide a unique link between these two areas. An emerging class of these mimics are the facially amphiphilic polymers that aim to emulate the physicochemical properties of HDPs but take advantage of the synthetic ease of polymers. These mimics have been designed with antimicrobial activity and, importantly, selectivity that rivals natural HDPs. In addition to providing some perspective on HDPs, selective mimics, and biocidal polymers, focus is given to the arsenal of biophysical techniques available to study their mode of action and interactions with phospholipid membranes. The issue of lipid type is highlighted and the important role of negative curvature lipids is illustrated. Finally, materials applications (for instance, in the development of permanently antibacterial surfaces) are discussed as this is an important part of controlling the spread of infectious disease.

  19. Initial Immunopathogenesis of Multiple Sclerosis: Innate Immune Response

    PubMed Central

    Hernández-Pedro, Norma Y.; de la Cruz, Verónica Pérez; Pineda, Benjamín; Sotelo, Julio

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The hallmark to MS is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, the formation of astrocytic scars, and the mononuclear cell infiltrates concentrated in perivascular spaces composed of T cells, B lymphocytes, plasma cells, and macrophages. Activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurological deficit. The immunological phenomena that lead to the activation of autoreactive T cells to myelin sheath components are the result of multiple and complex interactions between environment and genetic background conferring individual susceptibility. Within the CNS, an increase of TLR expression during MS is observed, even in the absence of any apparent microbial involvement. In the present review, we focus on the role of the innate immune system, the first line of defense of the organism, as promoter and mediator of cross reactions that generate molecular mimicry triggering the inflammatory response through an adaptive cytotoxic response in MS. PMID:24174969

  20. An engineered innate immune defense protects grapevines from Pierce disease

    PubMed Central

    Dandekar, Abhaya M.; Gouran, Hossein; Ibáñez, Ana María; Uratsu, Sandra L.; Agüero, Cecilia B.; McFarland, Sarah; Borhani, Yasmin; Feldstein, Paul A.; Bruening, George; Nascimento, Rafael; Goulart, Luiz R.; Pardington, Paige E.; Chaudhary, Anu; Norvell, Meghan; Civerolo, Edwin; Gupta, Goutam

    2012-01-01

    We postulated that a synergistic combination of two innate immune functions, pathogen surface recognition and lysis, in a protein chimera would lead to a robust class of engineered antimicrobial therapeutics for protection against pathogens. In support of our hypothesis, we have engineered such a chimera to protect against the Gram-negative Xylella fastidiosa (Xf), which causes diseases in multiple plants of economic importance. Here we report the design and delivery of this chimera to target the Xf subspecies fastidiosa (Xff), which causes Pierce disease in grapevines and poses a great threat to the wine-growing regions of California. One domain of this chimera is an elastase that recognizes and cleaves MopB, a conserved outer membrane protein of Xff. The second domain is a lytic peptide, cecropin B, which targets conserved lipid moieties and creates pores in the Xff outer membrane. A flexible linker joins the recognition and lysis domains, thereby ensuring correct folding of the individual domains and synergistic combination of their functions. The chimera transgene is fused with an amino-terminal signal sequence to facilitate delivery of the chimera to the plant xylem, the site of Xff colonization. We demonstrate that the protein chimera expressed in the xylem is able to directly target Xff, suppress its growth, and significantly decrease the leaf scorching and xylem clogging commonly associated with Pierce disease in grapevines. We believe that similar strategies involving protein chimeras can be developed to protect against many diseases caused by human and plant pathogens. PMID:22355130

  1. Innate Immune Cells Induce Hemorrhage in Tumors during Thrombocytopenia

    PubMed Central

    Ho-Tin-Noé, Benoit; Carbo, Carla; Demers, Mélanie; Cifuni, Stephen M.; Goerge, Tobias; Wagner, Denisa D.

    2009-01-01

    Platelets are crucial regulators of tumor vascular homeostasis and continuously prevent tumor hemorrhage through secretion of their granules. However, the reason for tumor bleeding in the absence of platelets remains unknown. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. Here, we investigated the role of the inflamed tumor microenvironment in the induction of tumor vessel injury in thrombocytopenic mice. Using s.c. injections of vascular endothelial growth factor or tumor necrosis factor-α combined with depletion of neutrophils, we demonstrate that enhancing the opening of endothelial cell junctions was not sufficient to cause bleeding in the absence of platelets; instead, induction of tissue hemorrhage in thrombocytopenia required recruitment of leukocytes. Immunohistology revealed that thrombocytopenia-induced tumor hemorrhage occurs at sites of macrophage and neutrophil accumulation. Mice deficient in β2 or β3 integrins, which have decreased neutrophil and/or macrophage infiltration in their tumor stroma, were protected from thrombocytopenia-induced tumor hemorrhage, indicating that, in the absence of platelets, stroma-infiltrating leukocytes induced tumor vessel injury. This injury was independent of reactive oxygen species generation and of complement activation, as suggested by the persistence of tumor hemorrhage in C3- and nicotinamide adenine dinucleotide phosphate oxidase-deficient thrombocytopenic mice. Our results show that platelets counteract tumor-associated inflammation and that the absence of this platelet function elicits vascular injuries by tumor-infiltrating innate immune cells. PMID:19729481

  2. Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity.

    PubMed

    Irwin, Michael R; Opp, Mark R

    2017-01-01

    Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder. This review and overview provides an integrated understanding of the reciprocal relationships between sleep and the innate immune system and considers the role of sleep in the nocturnal regulation of the inflammatory biology dynamics; the impact of insomnia complaints, extremes of sleep duration, and experimental sleep deprivation on genomic, cellular, and systemic markers of inflammation; and the influence of sleep complaints and insomnia on inflammaging and molecular processes of cellular aging. Clinical implications of this research include discussion of the contribution of sleep disturbance to depression and especially inflammation-related depressive symptoms. Reciprocal action of inflammatory mediators on the homeostatic regulation of sleep continuity and sleep macrostructure, and the potential of interventions that target insomnia to reverse inflammation, are also reviewed. Together, interactions between sleep and inflammatory biology mechanisms underscore the implications of sleep disturbance for inflammatory disease risk, and provide a map to guide the development of treatments that modulate inflammation, improve sleep, and promote sleep health.

  3. Crosstalk between the Circadian Clock and Innate Immunity in Arabidopsis

    PubMed Central

    Zhang, Chong; Xie, Qiguang; Anderson, Ryan G.; Ng, Gina; Seitz, Nicholas C.; Peterson, Thomas; McClung, C. Robertson; McDowell, John M.; Kong, Dongdong; Kwak, June M.; Lu, Hua

    2013-01-01

    The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity. PMID:23754942

  4. Massive expansion and functional divergence of innate immune genes in a protostome

    PubMed Central

    Zhang, Linlin; Li, Li; Guo, Ximing; Litman, Gary W.; Dishaw, Larry J.; Zhang, Guofan

    2015-01-01

    The molecules that mediate innate immunity are encoded by relatively few genes and exhibit broad specificity. Detailed annotation of the Pacific oyster (Crassostrea gigas) genome, a protostome invertebrate, reveals large-scale duplication and divergence of multigene families encoding molecules that effect innate immunity. Transcriptome analyses indicate dynamic and orchestrated specific expression of numerous innate immune genes in response to experimental challenge with pathogens, including bacteria, and a pathogenic virus. Variable expression of individual members of the multigene families encoding these genes also occurs during different types of abiotic stress (environmentally-equivalent conditions of temperature, salinity and desiccation). Multiple families of immune genes are responsive in concert to certain biotic and abiotic challenges. Individual members of expanded families of immune genes are differentially expressed under both biotic challenge and abiotic stress conditions. Members of the same families of innate immune molecules also are transcribed in developmental stage- and tissue-specific manners. An integrated, highly complex innate immune system that exhibits remarkable discriminatory properties and responses to different pathogens as well as environmental stress has arisen through the adaptive recruitment of tandem duplicated genes. The co-adaptive evolution of stress and innate immune responses appears to have an ancient origin in phylogeny. PMID:25732911

  5. Does baseline innate immunity change with age? A multi-year study in great tits.

    PubMed

    Vermeulen, Anke; Eens, Marcel; Van Dongen, Stefan; Müller, Wendt

    2017-03-16

    Throughout their life animals progressively accumulate mostly detrimental changes in cells, tissues and their functions, causing a decrease in individual performance and ultimately an increased risk of death. The latter may be amplified if it also leads to a deterioration of the immune system which forms the most important protection against the permanent threat of pathogens and infectious diseases. Here, we investigated how four baseline innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin and concentrations of nitric oxide) changed with age in free-living great tits (Parus major). We applied both cross-sectional and longitudinal approaches as birds were sampled for up to three years of their lives. Three out of the four selected innate immune parameters were affected by age. However, the shape of the response curves differed strongly among the innate immune parameters. Natural antibody levels increased during early life until mid-age to decrease thereafter when birds aged. Complement activity was highest in young birds, while levels slightly decreased with increasing age. Haptoglobin levels on the other hand, showed a linear, but highly variable increase with age, while nitric oxide concentrations were unaffected by age. The observed differences among the four studied innate immune traits not only indicate the importance of considering several immune traits at the same time, but also highlight the complexity of innate immunity. Unraveling the functional significance of the observed changes in innate immunity is thus a challenging next step.

  6. Transgenerational epigenetic effects on innate immunity in broilers: an underestimated field to be explored?

    PubMed

    Berghof, T V L; Parmentier, H K; Lammers, A

    2013-11-01

    Transgenerational epigenetics is becoming more and more important for understanding the variation of physiological responses of individuals to the environment and the inheritance of these responses based on all mechanisms other than the actual DNA nucleotide sequence. Transgenerational epigenetics is the phenomenon that the information of the environment of (usually) a female animal is translated into memory-like responses preparing the offspring. As a consequence, individuals of the next generation may show different phenotypic traits depending whether their mothers were kept under different environmental conditions. This may result in either positive or negative effects on the next-generation individuals, which is different from individuals from mothers that have been kept in a different environment. Transgenerational epigenetic effects have been proposed and indicated for specific immune (T cell and antibody) responses (especially in mammals, but also in birds) and innate immunity (nonvertebrates), but surprisingly very little is known of transgenerational effects on innate immunity in chickens. Given the short lifespan of the chicken and therefore the likely dependence of chicken on innate immune mechanisms, more attention should be given to this arm of immunity and mechanisms of inheritance including transgenerational effects that can be initiated in the breeder generation. In addition, it is becoming evident that innate immunity also underlies metabolic disorders in broilers. In the current paper, we will argue that although very little is known of transgenerational effects of innate immunity in poultry, more attention should be given to this type of study. We will illustrate examples of transgenerational epigenetics, and finally propose strategies that should reveal the presence of transgenerational epigenetic effects on innate immunity in chickens and strategies to modulate breeder birds such that these effects positively affect innate immunity of broilers

  7. c-di-GMP enhances protective innate immunity in a murine model of pertussis.

    PubMed

    Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A; Gerdts, Volker

    2014-01-01

    Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.

  8. Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.

    PubMed

    Ren, Junping; Liu, Guangliang; Go, Jonathan; Kolli, Deepthi; Zhang, Guanping; Bao, Xiaoyong

    2014-01-01

    Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS). Whether M2-2 regulates the innate immunity in human dendritic cells (DC), an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2) produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT), suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88), an essential adaptor for Toll-like receptors (TLRs), plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.

  9. Mechanisms for eco-immunity in a changing enviroment: how does the coral innate immune system contend with climate change?

    NASA Astrophysics Data System (ADS)

    Traylor-Knowles, N. G.

    2016-02-01

    Innate immunity plays a central role in maintaining homeostasis, and within the context of impending climate change scenarios, understanding how this system works is critical. However, the actual mechanisms involved in the evolution of the innate immune system are largely unknown. Cnidaria (including corals, sea anemones and jellyfish) are well suited for studying the fundamental functions of innate immunity because they share a common ancestor with bilaterians. This study will highlight the transcriptomic changes during a heat shock in the coral Acropora hyacinthus of American Samoa, examining the temporal changes, every half an hour for 5 hours. We hypothesize that genes involved in innate immunity, and extracellular matrix maintenance will be key components to the heat stress response. This presentation will highlight the novel role of the tumor necrosis factor receptor gene family as a responder to heat stress and present future directions for this developing field in coral reef research.

  10. Forkhead, a new cross regulator of metabolism and innate immunity downstream of TOR in Drosophila.

    PubMed

    Varma, Disha; Bülow, Margret H; Pesch, Yanina-Yasmin; Loch, Gerrit; Hoch, Michael

    2014-10-01

    Antimicrobial peptides (AMPs) are conserved cationic peptides which act both as defense molecules of the host immune system and as regulators of the commensal microbiome. Expression of AMPs is induced in response to infection by the Toll and Imd pathway. Under non-infected conditions, the transcription factor dFOXO directly regulates a set of AMP expression at low levels when nutrients are limited. Here we have analyzed whether target of rapamycin (TOR), another major regulator of growth and metabolism, also modulates AMP responses in Drosophila. We found that downregulation of TOR by feeding the drug rapamycin or by overexpressing the negative TOR regulators TSC1/TSC2, resulted in a specific induction of the AMPs Diptericin (Dpt) and Metchnikowin (Mtk). In contrast, overexpression of Rheb, which positively regulates TOR led to a repression of the two AMPs. Genetic and pharmacological experiments indicate that Dpt and Mtk activation is controlled by the transcription factor Forkhead (FKH), the founding member of the FoxO family. Shuttling of FKH from the cytoplasm to the nucleus is induced in the fat body and in the posterior midgut in response to T