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Sample records for antimicrobial host defense

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

    PubMed

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

    2013-12-01

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

  2. Antimicrobial peptides in echinoderm host defense.

    PubMed

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

    2015-03-01

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

  3. Epithelial antimicrobial peptides in host defense against infection

    PubMed Central

    Bals, Robert

    2000-01-01

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

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

    PubMed Central

    Zhang, Guolong; Sunkara, Lakshmi T.

    2014-01-01

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

  5. The Roles of Antimicrobial Peptides in Innate Host Defense

    PubMed Central

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

    2009-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

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

    2015-11-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

    Goyal, Ravinder K; Mattoo, Autar K

    2014-11-01

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

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

    PubMed

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

    2010-11-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

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

    2015-03-01

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

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

    PubMed Central

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

    2015-01-01

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

  14. Hepcidin and Host Defense against Infectious Diseases

    PubMed Central

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

    2015-01-01

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

  15. Hepcidin and Host Defense against Infectious Diseases.

    PubMed

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

    2015-08-01

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

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

    PubMed

    Wang, Guoshun; Nauseef, William M

    2015-08-01

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

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

    PubMed Central

    Wang, Guoshun; Nauseef, William M.

    2015-01-01

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

  18. Natural History of Innate Host Defense Peptides.

    PubMed

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

    2009-12-01

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

  19. Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense

    PubMed Central

    Prasad, Joni M.; Gorkun, Oleg V.; Raghu, Harini; Thornton, Sherry; Mullins, Eric S.; Palumbo, Joseph S.; Ko, Ya-Ping; Höök, Magnus; David, Tovo; Coughlin, Shaun R.; Degen, Jay L.

    2015-01-01

    Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin-dependent processes in vivo, FibAEK mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aα chain thrombin cleavage site. Homozygous FibAEK mice developed to term and exhibited postnatal survival superior to that of fibrinogen-deficient mice. Unlike fibrinogen-deficient mice, platelet-rich plasma from FibAEK mice supported normal platelet aggregation in vitro, highlighting that fibrinogenAEK retains the functional capacity to support interactions with platelets. Thrombin failed to release fibrinopeptide-A from fibrinogenAEK and failed to induce polymer formation with FibAEK plasma or purified fibrinogenAEK in 37°C mixtures regardless of incubation time. FibAEK mice displayed both an absence of fibrin polymer formation following liver injury, as assessed by electron microscopy, and a failure to generate stable occlusive thrombi following FeCl3 injury of carotid arteries. FibAEK mice exhibited a profound impediment in Staphylococcus aureus clearance following intraperitoneal infection similar to fibrinogen-deficient mice, yet FibAEK mice displayed a significant infection dose-dependent survival advantage over fibrinogen-deficient mice following peritonitis challenge. Collectively, these findings establish for the first time that fibrin polymer is the molecular form critical for antimicrobial mechanisms while simultaneously highlighting biologically meaningful contributions and functions of the soluble molecule. PMID:26228483

  20. Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense.

    PubMed

    Prasad, Joni M; Gorkun, Oleg V; Raghu, Harini; Thornton, Sherry; Mullins, Eric S; Palumbo, Joseph S; Ko, Ya-Ping; Höök, Magnus; David, Tovo; Coughlin, Shaun R; Degen, Jay L; Flick, Matthew J

    2015-10-22

    Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin-dependent processes in vivo, Fib(AEK) mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aα chain thrombin cleavage site. Homozygous Fib(AEK) mice developed to term and exhibited postnatal survival superior to that of fibrinogen-deficient mice. Unlike fibrinogen-deficient mice, platelet-rich plasma from Fib(AEK) mice supported normal platelet aggregation in vitro, highlighting that fibrinogen(AEK) retains the functional capacity to support interactions with platelets. Thrombin failed to release fibrinopeptide-A from fibrinogen(AEK) and failed to induce polymer formation with Fib(AEK) plasma or purified fibrinogen(AEK) in 37°C mixtures regardless of incubation time. Fib(AEK) mice displayed both an absence of fibrin polymer formation following liver injury, as assessed by electron microscopy, and a failure to generate stable occlusive thrombi following FeCl3 injury of carotid arteries. Fib(AEK) mice exhibited a profound impediment in Staphylococcus aureus clearance following intraperitoneal infection similar to fibrinogen-deficient mice, yet Fib(AEK) mice displayed a significant infection dose-dependent survival advantage over fibrinogen-deficient mice following peritonitis challenge. Collectively, these findings establish for the first time that fibrin polymer is the molecular form critical for antimicrobial mechanisms while simultaneously highlighting biologically meaningful contributions and functions of the soluble molecule. PMID:26228483

  1. Host defenses trigger salmonella's arsenal.

    PubMed

    Keestra, A Marijke; Bäumler, Andreas J

    2011-03-17

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

  2. Heterogeneity of mprF sequences in methicillin-resistant Staphylococcus aureus clinical isolates: role in cross-resistance between daptomycin and host defense antimicrobial peptides.

    PubMed

    Bayer, Arnold S; Mishra, Nagendra N; Sakoulas, George; Nonejuie, Poochit; Nast, Cynthia C; Pogliano, Joseph; Chen, Kuan-Tsen; Ellison, Steven N; Yeaman, Michael R; Yang, Soo-Jin

    2014-12-01

    Over the past several years, single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been proposed to be associated with a gain-of-function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) in Staphylococcus aureus. We investigated the frequencies of SNPs within the mprF ORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistant S. aureus (MRSA) isolates of the clonal complex 5 genotype were used. In addition to mprF SNPs and DAP-HDP cross-resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i) mprF expression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of ≤ 1 μg/ml) exhibited mprF SNPs, occasionally with high-level mprF sequence variation from the genotype reference strain. However, none of these SNPs were localized to well-chronicled mprF hot spot locations associated with DAP-R in S. aureus. In contrast, all 8 DAP-R isolates demonstrated SNPs within such known mprF hot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhanced mprF expression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array of mprF SNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrent mprF dysregulation, were associated with the DAP-R phenotype. PMID:25288091

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

    PubMed

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

    2015-01-01

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

  4. The Three Bacterial Lines of Defense against Antimicrobial Agents

    PubMed Central

    Zhou, Gang; Shi, Qing-Shan; Huang, Xiao-Mo; Xie, Xiao-Bao

    2015-01-01

    Antimicrobial agents target a range of extra- and/or intracellular loci from cytoplasmic wall to membrane, intracellular enzymes and genetic materials. Meanwhile, many resistance mechanisms employed by bacteria to counter antimicrobial agents have been found and reported in the past decades. Based on their spatially distinct sites of action and distribution of location, antimicrobial resistance mechanisms of bacteria were categorized into three groups, coined the three lines of bacterial defense in this review. The first line of defense is biofilms, which can be formed by most bacteria to overcome the action of antimicrobial agents. In addition, some other bacteria employ the second line of defense, the cell wall, cell membrane, and encased efflux pumps. When antimicrobial agents permeate the first two lines of defense and finally reach the cytoplasm, many bacteria will make use of the third line of defense, including alterations of intracellular materials and gene regulation to protect themselves from harm by bactericides. The presented three lines of defense theory will help us to understand the bacterial resistance mechanisms against antimicrobial agents and design efficient strategies to overcome these resistances. PMID:26370986

  5. Role of Antimicrobial Peptides in Amphibian Defense Against Trematode Infection

    PubMed Central

    Calhoun, Dana M.; Woodhams, Doug; Howard, Cierra; LaFonte, Bryan E.; Gregory, Jacklyn R.; Johnson, Pieter T. J.

    2016-01-01

    Antimicrobial peptides (AMPs) contribute to the immune defenses of many vertebrates, including amphibians. As larvae, amphibians are often exposed to the infectious stages of trematode parasites, many of which must penetrate the host’s skin, potentially interacting with host AMPs. We tested the effects of the natural AMPs repertoires on both the survival of trematode infectious stages as well as their ability to infect larval amphibians. All five trematode species exhibited decreased survival of cercariae in response to higher concentrations of adult bullfrog AMPs, but no effect when exposed to AMPs from larval bullfrogs. Similarly, the use of norepinephrine to remove AMPs from larval bullfrogs, Pacific chorus frogs, and gray treefrogs had only weak (gray treefrogs) or non-significant (other tested species) effects on infection success by Ribeiroia ondatrae. We nonetheless observed strong differences in parasite infection as a function of both host stage (first- versus second-year bullfrogs) and host species (Pacific chorus frogs versus gray treefrogs) that were apparently unrelated to AMPs. Taken together, our results suggest that AMPs do not play a significant role in defending larval amphibians against trematode cercariae, but that they could be one mechanism helping to prevent infection of post-metamorphic amphibians, particularly for highly aquatic species. PMID:26911920

  6. Host Antimicrobial Peptides in Bacterial Homeostasis and Pathogenesis of Disease

    PubMed Central

    Heimlich, Derek R.; Harrison, Alistair; Mason, Kevin M.

    2014-01-01

    Innate immune responses function as a first line of host defense against the development of bacterial infection, and in some cases to preserve the sterility of privileged sites in the human host. Bacteria that enter these sites must counter host responses for colonization. From the host’s perspective, the innate immune system works expeditiously to minimize the bacterial threat before colonization and subsequent dysbiosis. The multifactorial nature of disease further challenges predictions of how each independent variable influences bacterial pathogenesis. From bacterial colonization to infection and through disease, the microenvironments of the host are in constant flux as bacterial and host factors contribute to changes at the host-pathogen interface, with the host attempting to eradicate bacteria and the bacteria fighting to maintain residency. A key component of this innate host response towards bacterial infection is the production of antimicrobial peptides (AMPs). As an early component of the host response, AMPs modulate bacterial load and prevent establishment of infection. Under quiescent conditions, some AMPs are constitutively expressed by the epithelium. Bacterial infection can subsequently induce production of other AMPs in an effort to maintain sterility, or to restrict colonization. As demonstrated in various studies, the absence of a single AMP can influence pathogenesis, highlighting the importance of AMP concentration in maintaining homeostasis. Yet, AMPs can increase bacterial virulence through the co-opting of the peptides or alteration of bacterial virulence gene expression. Further, bacterial factors used to subvert AMPs can modify host microenvironments and alter colonization of the residential flora that principally maintain homeostasis. Thus, the dynamic interplay between host defense peptides and bacterial factors produced to quell peptide activity play a critical role in the progression and outcome of disease. PMID:26029470

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2005-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Becknell, Brian; Spencer, John David

    2016-01-01

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

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

    PubMed

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

    2015-10-01

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

  12. Evolution of Host Defense against Multiple Enemy Populations.

    PubMed

    Toor, Jaspreet; Best, Alex

    2016-03-01

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

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

    PubMed Central

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

    2015-01-01

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

  14. Oncolytic Activities of Host Defense Peptides

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2013-08-21

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

  16. Dietary antioxidants: immunity and host defense.

    PubMed

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

    2011-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

    Ko, Ya-Ping; Flick, Matthew J

    2016-06-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed Central

    Cohen, Lianne B.; Troemel, Emily R.

    2014-01-01

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

  3. 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.…

  4. 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

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

    PubMed

    Davies, Nicholas B; Welbergen, Justin A

    2009-06-01

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

  6. CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense.

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides.

    PubMed

    Bayer, Arnold S; Mishra, Nagendra N; Chen, Liang; Kreiswirth, Barry N; Rubio, Aileen; Yang, Soo-Jin

    2015-08-01

    MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance in Staphylococcus aureus. (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin-susceptible (DAP(s))/daptomycin-resistant (DAP(r)) clinical methicillin-resistant S. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putative mprF gain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact of mprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of the mprF SNPs identified in our DAP(r) strains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location of mprF SNPs in DAP(r) strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAP(r) strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAP(r) strains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance in S. aureus. PMID:26055370

  9. Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides

    PubMed Central

    Bayer, Arnold S.; Mishra, Nagendra N.; Chen, Liang; Kreiswirth, Barry N.; Rubio, Aileen

    2015-01-01

    MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance in Staphylococcus aureus. (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin-susceptible (DAPs)/daptomycin-resistant (DAPr) clinical methicillin-resistant S. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putative mprF gain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact of mprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of the mprF SNPs identified in our DAPr strains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location of mprF SNPs in DAPr strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAPr strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAPr strains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance in S. aureus. PMID:26055370

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

    PubMed

    Charles, Tysheena P; Shellito, Judd E

    2016-04-01

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

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

    PubMed

    Okumura, Cheryl Y M; Nizet, Victor

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-29

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

  14. Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

    PubMed Central

    Gjini, Erida; Brito, Patricia H.

    2016-01-01

    Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. We use mathematical modelling of within-host infection dynamics to study the interplay between pathogen-dependent host immune responses and antibiotic treatment. We compare classical (fixed dose and duration) and adaptive (coupled to pathogen load) treatment regimes, exploring systematically infection outcomes such as time to clearance, immunopathology, host immunization, and selection of resistant bacteria. Our analysis and simulations uncover effective treatment strategies that promote synergy between the host immune system and the antimicrobial drug in clearing infection. Both in classical and adaptive treatment, we quantify how treatment timing and the strength of the immune response determine the success of moderate therapies. We explain key parameters and dimensions, where an adaptive regime differs from classical treatment, bringing new insight into the ongoing debate of resistance management. Emphasizing the sensitivity of treatment outcomes to the balance between external antibiotic intervention and endogenous natural defenses, our study calls for more empirical attention to host immunity processes. PMID:27078624

  15. Associations between host characteristics and antimicrobial resistance of Salmonella typhimurium.

    PubMed

    Ruddat, I; Tietze, E; Ziehm, D; Kreienbrock, L

    2014-10-01

    A collection of Salmonella Typhimurium isolates obtained from sporadic salmonellosis cases in humans from Lower Saxony, Germany between June 2008 and May 2010 was used to perform an exploratory risk-factor analysis on antimicrobial resistance (AMR) using comprehensive host information on sociodemographic attributes, medical history, food habits and animal contact. Multivariate resistance profiles of minimum inhibitory concentrations for 13 antimicrobial agents were analysed using a non-parametric approach with multifactorial models adjusted for phage types. Statistically significant associations were observed for consumption of antimicrobial agents, region type and three factors on egg-purchasing behaviour, indicating that besides antimicrobial use the proximity to other community members, health consciousness and other lifestyle-related attributes may play a role in the dissemination of resistances. Furthermore, a statistically significant increase in AMR from the first study year to the second year was observed. PMID:24300336

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

    PubMed Central

    Gupta, Kshitij; Subramanian, Hariharan; Ali, Hydar

    2016-01-01

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

  17. The role of antimicrobial peptides in animal defenses

    NASA Astrophysics Data System (ADS)

    Hancock, Robert E. W.; Scott, Monisha G.

    2000-08-01

    It is becoming clear that the cationic antimicrobial peptides are an important component of the innate defenses of all species of life. Such peptides can be constitutively expressed or induced by bacteria or their products. The best peptides have good activities vs. a broad range of bacterial strains, including antibiotic-resistant isolates. They kill very rapidly, do not easily select resistant mutants, are synergistic with conventional antibiotics, other peptides, and lysozyme, and are able to kill bacteria in animal models. It is known that bacterial infections, especially when treated with antibiotics, can lead to the release of bacterial products such as lipopolysaccharide (LPS) and lipoteichoic acid, resulting in potentially lethal sepsis. In contrast to antibiotics, the peptides actually prevent cytokine induction by bacterial products in tissue culture and human blood, and they block the onset of sepsis in mouse models of endotoxemia. Consistent with this, transcriptional gene array experiments using a macrophage cell line demonstrated that a model peptide, CEMA, blocks the expression of many genes whose transcription was induced by LPS. The peptides do this in part by blocking LPS interaction with the serum protein LBP. In addition, CEMA itself has a direct effect on macrophage gene expression. Because cationic antimicrobial peptides are induced by LPS and are able to dampen the septic response of animal cells to LPS, we propose that, in addition to their role in direct and lysozyme-assisted killing of microbes, they have a role in feedback regulation of cytokine responses. We are currently developing variant peptides as therapeutics against antibiotic-resistant infections.

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

    PubMed Central

    2015-01-01

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

  19. Interleukin 17-Mediated Host Defense against Candida albicans

    PubMed Central

    Sparber, Florian; LeibundGut-Landmann, Salomé

    2015-01-01

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

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

    PubMed

    Aratani, Yasuaki

    2006-01-01

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

  1. Salivary mucins in host defense and disease prevention.

    PubMed

    Frenkel, Erica Shapiro; Ribbeck, Katharina

    2015-01-01

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

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

    PubMed

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

    2011-04-01

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

  3. Salivary mucins in host defense and disease prevention

    PubMed Central

    Frenkel, Erica Shapiro; Ribbeck, Katharina

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  5. Modulation of pulmonary inflammatory responses and antimicrobial defenses in mice exposed to diesel exhaust

    SciTech Connect

    Gowdy, Kymberly; Krantz, Quentin T.; Daniels, Mary; Linak, William P.; Jaspers, Ilona; Gilmour, M. Ian

    2008-06-15

    Diesel exhaust (DE) is a major component of urban air pollution and has been shown to increase the severity of infectious and allergic lung disease. The purpose of this study was to evaluate the effects of DE exposure on pulmonary inflammation, mediator production and antimicrobial defenses in an exposure model that had previously been shown to increase susceptibility to influenza. BALB/c mice were exposed to filtered air, or to DE diluted to yield 0.5 or 2 mg/m{sup 3} of diesel exhaust particles (DEP) for 4 h per day for 1 or 5 days. Immediately and 18 h after one or five diesel exposures mice were euthanized to assess both immediate and delayed effects. DE exposure for 5 days at either concentration caused higher neutrophil numbers and lesion scoring compared to air controls. Intracellular adhesion molecule-1 (ICAM-1), which recruits inflammatory cells and is an entry site for rhinoviruses was increased immediately after 1 or 5 days of DE exposure. Several inflammatory and immune cytokines (TNF-{alpha}, MIP-2, IL-6, IFN-{gamma}, and IL-13) were also upregulated at various time points and concentrations. In contrast, clara cell secretory protein (CCSP), surfactant protein A (SP-A), and surfactant protein D (SP-D) which are important host defense molecules, were significantly decreased at both the message and protein level with DE exposure. We conclude that exposure to moderate and high occupational levels of DE caused an increase in lung injury and inflammation, and a decrease in host defense molecules, which could result in increased susceptibility to respiratory pathogens.

  6. Modulation of pulmonary inflammatory responses and antimicrobial defenses in mice exposed to diesel exhaust.

    PubMed

    Gowdy, Kymberly; Krantz, Quentin T; Daniels, Mary; Linak, William P; Jaspers, Ilona; Gilmour, M Ian

    2008-06-15

    Diesel exhaust (DE) is a major component of urban air pollution and has been shown to increase the severity of infectious and allergic lung disease. The purpose of this study was to evaluate the effects of DE exposure on pulmonary inflammation, mediator production and antimicrobial defenses in an exposure model that had previously been shown to increase susceptibility to influenza. BALB/c mice were exposed to filtered air, or to DE diluted to yield 0.5 or 2 mg/m(3) of diesel exhaust particles (DEP) for 4 h per day for 1 or 5 days. Immediately and 18 h after one or five diesel exposures mice were euthanized to assess both immediate and delayed effects. DE exposure for 5 days at either concentration caused higher neutrophil numbers and lesion scoring compared to air controls. Intracellular adhesion molecule-1 (ICAM-1), which recruits inflammatory cells and is an entry site for rhinoviruses was increased immediately after 1 or 5 days of DE exposure. Several inflammatory and immune cytokines (TNF-alpha, MIP-2, IL-6, IFN-gamma, and IL-13) were also upregulated at various time points and concentrations. In contrast, clara cell secretory protein (CCSP), surfactant protein A (SP-A), and surfactant protein D (SP-D) which are important host defense molecules, were significantly decreased at both the message and protein level with DE exposure. We conclude that exposure to moderate and high occupational levels of DE caused an increase in lung injury and inflammation, and a decrease in host defense molecules, which could result in increased susceptibility to respiratory pathogens. PMID:18343473

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2001-02-01

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

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

    PubMed

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

    2015-11-01

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

  12. Foreign Body Infection Models to Study Host-Pathogen Response and Antimicrobial Tolerance of Bacterial Biofilm

    PubMed Central

    Nowakowska, Justyna; Landmann, Regine; Khanna, Nina

    2014-01-01

    The number of implanted medical devices is steadily increasing and has become an effective intervention improving life quality, but still carries the risk of infection. These infections are mainly caused by biofilm-forming staphylococci that are difficult to treat due to the decreased susceptibility to both antibiotics and host defense mechanisms. To understand the particular pathogenesis and treatment tolerance of implant-associated infection (IAI) animal models that closely resemble human disease are needed. Applications of the tissue cage and catheter abscess foreign body infection models in the mouse will be discussed herein. Both models allow the investigation of biofilm and virulence of various bacterial species and a comprehensive insight into the host response at the same time. They have also been proven to serve as very suitable tools to study the anti-adhesive and anti-infective efficacy of different biomaterial coatings. The tissue cage model can additionally be used to determine pharmacokinetics, efficacy and cytotoxicity of antimicrobial compounds as the tissue cage fluid can be aspirated repeatedly without the need to sacrifice the animal. Moreover, with the advance in innovative imaging systems in rodents, these models may offer new diagnostic measures of infection. In summary, animal foreign body infection models are important tools in the development of new antimicrobials against IAI and can help to elucidate the complex interactions between bacteria, the host immune system, and prosthetic materials. PMID:27025752

  13. Antimicrobial proteins and peptides in human lung diseases: A friend and foe partnership with host proteases.

    PubMed

    Lecaille, Fabien; Lalmanach, Gilles; Andrault, Pierre-Marie

    2016-03-01

    Lung antimicrobial proteins and peptides (AMPs) are major sentinels of innate immunity by preventing microbial colonization and infection. Nevertheless bactericidal activity of AMPs against Gram-positive and Gram-negative bacteria is compromised in patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and asthma. Evidence is accumulating that expression of harmful human serine proteases, matrix metalloproteases and cysteine cathepsins is markedely increased in these chronic lung diseases. The local imbalance between proteases and protease inhibitors compromises lung tissue integrity and function, by not only degrading extracellular matrix components, but also non-matrix proteins. Despite the fact that AMPs are somewhat resistant to proteolytic degradation, some human proteases cleave them efficiently and impair their antimicrobial potency. By contrast, certain AMPs may be effective as antiproteases. Host proteases participate in concert with bacterial proteases in the degradation of key innate immunity peptides/proteins and thus may play immunomodulatory activities during chronic lung diseases. In this context, the present review highlights the current knowledge and recent discoveries on the ability of host enzymes to interact with AMPs, providing a better understanding of the role of human proteases in innate host defense. PMID:26341472

  14. Supramolecular amphipathicity for probing antimicrobial propensity of host defence peptides.

    PubMed

    Ravi, Jascindra; Bella, Angelo; Correia, Ana J V; Lamarre, Baptiste; Ryadnov, Maxim G

    2015-06-28

    Host defence peptides (HDPs) are effector components of innate immunity that provide defence against pathogens. These are small-to-medium sized proteins which fold into amphipathic conformations toxic to microbial membranes. Here we explore the concept of supramolecular amphipathicity for probing antimicrobial propensity of HDPs using elementary HDP-like amphiphiles. Such amphiphiles are individually inactive, but when ordered into microscopic micellar assemblies, respond to membrane binding according to the orthogonal type of their primary structure. The study demonstrates that inducible supramolecular amphipathicity can discriminate against bacterial growth and colonisation thereby offering a physico-chemical rationale for tuneable targeting of biological membranes. PMID:25966444

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-06-29

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-06-15

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

  20. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression

    PubMed Central

    Sperandio, Brice; Regnault, Béatrice; Guo, Jianhua; Zhang, Zhi; Stanley, Samuel L.; Sansonetti, Philippe J.; Pédron, Thierry

    2008-01-01

    Antimicrobial factors are efficient defense components of the innate immunity, playing a crucial role in the intestinal homeostasis and protection against pathogens. In this study, we report that upon infection of polarized human intestinal cells in vitro, virulent Shigella flexneri suppress transcription of several genes encoding antimicrobial cationic peptides, particularly the human β-defensin hBD-3, which we show to be especially active against S. flexneri. This is an example of targeted survival strategy. We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process. In vivo, in a model of human intestinal xenotransplant, we confirm at the transcriptional and translational level, the presence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of antimicrobial cationic peptides and promoting its deeper progression toward intestinal crypts. We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues. Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine. PMID:18426984

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2013-01-01

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

  3. THE ROLES OF CUTANEOUS LIPIDS IN HOST DEFENSE

    PubMed Central

    Fischer, Carol L.; Blanchette, Derek R.; Brogden, Kim A.; Dawson, Deborah V.; Drake, David R.; Hill, Jennifer R.; Wertz, Philip W.

    2013-01-01

    Lauric acid (C12:0) and sapienic acid (C16:1Δ6) derived from human sebaceous triglycerides are potent antimicrobials found at the human skin surface. Long-chain bases (sphingosine, dihydrosphingosine and 6-hydroxysphingosine) are also potent and broad-acting antimicrobials normally present at the skin surface. These antimicrobials are generated through the action of ceramidases on ceramides from the stratum corneum. These natural antimicrobials are thought to be part of the innate immune system of the skin. Exogenously providing these lipids to the skin may provide a new therapeutic option, or could potentially provide prophylaxis in people at risk of infection. PMID:23994607

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

    PubMed Central

    Caughey, George H.

    2008-01-01

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

  5. CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis

    PubMed Central

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

    2002-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. Plant chemical defenses: are all constitutive antimicrobial metabolites phytoanticipins?

    PubMed

    Pedras, M Soledade C; Yaya, Estifanos E

    2015-01-01

    A critical perspective on phytoanticipins, constitutive plant secondary metabolites with defensive roles against microbes is presented. This mini-review focuses on the chemical groups and structural types of defensive plant metabolites thus far not reviewed from the phytoanticipin perspective: i) fatty acid derivatives and polyketides, ii) terpenoids, iii) shikimates, phenylpropanoids and derivatives, and iv) benzylisoquinoline and pyrrolizidine alkaloids. The more traditional groups of phytoanticipins are briefly summarized, with particular focus on the latest results: i) benzoxazinoids, ii) cyanogenic glycosides, iii) glucosinolates and their metabolic products, and iv) saponins. Current evidence suggests that a better understanding of the functions of plant metabolites will drive their application to protect crops against microbial diseases. PMID:25920246

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    1992-01-01

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

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

    SciTech Connect

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

    2010-08-23

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

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

    PubMed

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

    2016-04-01

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

  14. Secretory IgA: Designed for Anti-Microbial Defense

    PubMed Central

    Brandtzaeg, Per

    2013-01-01

    Prevention of infections by vaccination remains a compelling goal to improve public health. Mucosal vaccines would make immunization procedures easier, be better suited for mass administration, and most efficiently induce immune exclusion – a term coined for non-inflammatory antibody shielding of internal body surfaces, mediated principally by secretory immunoglobulin A (SIgA). The exported antibodies are polymeric, mainly IgA dimers (pIgA), produced by local plasma cells (PCs) stimulated by antigens that target the mucose. SIgA was early shown to be complexed with an epithelial glycoprotein – the secretory component (SC). A common SC-dependent transport mechanism for pIgA and pentameric IgM was then proposed, implying that membrane SC acts as a receptor, now usually called the polymeric Ig receptor (pIgR). From the basolateral surface, pIg-pIgR complexes are taken up by endocytosis and then extruded into the lumen after apical cleavage of the receptor – bound SC having stabilizing and innate functions in the secretory antibodies. Mice deficient for pIgR show that this is the only receptor responsible for epithelial export of IgA and IgM. These knockout mice show a variety of defects in their mucosal defense and changes in their intestinal microbiota. In the gut, induction of B-cells occurs in gut-associated lymphoid tissue, particularly the Peyer’s patches and isolated lymphoid follicles, but also in mesenteric lymph nodes. PC differentiation is accomplished in the lamina propria to which the activated memory/effector B-cells home. The airways also receive such cells from nasopharynx-associated lymphoid tissue but by different homing receptors. This compartmentalization is a challenge for mucosal vaccination, as are the mechanisms used by the mucosal immune system to discriminate between commensal symbionts (mutualism), pathobionts, and overt pathogens (elimination). PMID:23964273

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

    PubMed Central

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

    2014-01-01

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

  16. Activation of Molecular Signatures for Antimicrobial and Innate Defense Responses in Skin with Transglutaminase 1 Deficiency

    PubMed Central

    Uchiyama, Ryosuke; Jitsukawa, Orie; Yamanishi, Kiyofumi

    2016-01-01

    Mutations of the transglutaminase 1 gene (TGM1) are a major cause of autosomal recessive congenital ichthyoses (ARCIs) that are associated with defects in skin barrier structure and function. However, the molecular processes induced by the transglutaminase 1 deficiency are not fully understood. The aim of the present study was to uncover those processes by analysis of cutaneous molecular signatures. Gene expression profiles of wild-type and Tgm1–/–epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in Tgm1–/–epidermis. Based on that result, the induction of Il1b and antimicrobial peptide genes, S100a8, S100a9, Defb14, Camp, Slpi, Lcn2, Ccl20 and Wfdc12, was confirmed by quantitative real-time PCR. A protein array revealed that levels of IL-1β, G-CSF, GM-CSF, CXCL1, CXCL2, CXCL9 and CCL2 were increased in Tgm1–/–skin. Epidermal growth factor receptor (EGFR) ligand genes, Hbegf, Areg and Ereg, were activated in Tgm1–/–epidermis. Furthermore, the antimicrobial activity of an epidermal extract from Tgm1–/–mice was significantly increased against both Escherichia coli and Staphylococcus aureus. In the epidermis of ichthyosiform skins from patients with TGM1 mutations, S100A8/9 was strongly positive. The expression of those antimicrobial and defense response genes was also increased in the lesional skin of an ARCI patient with TGM1 mutations. These results suggest that the up-regulation of molecular signatures for antimicrobial and innate defense responses is characteristic of skin with a transglutaminase 1 deficiency, and this autonomous process might be induced to reinforce the defective barrier function of the skin. PMID:27442430

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

    PubMed Central

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

    2009-01-01

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

  18. Novel mode of action in plant defense peptides: hevein-like antimicrobial peptides from wheat inhibit fungal metalloproteases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The multilayered plant immune system relies on rapid recognition of pathogen-associated molecular patterns followed by activation of defense-related genes that results in the reinforcement of plant cell walls and production of antimicrobial compounds. To suppress plant defense, fungi secrete effecto...

  19. Novel mode of action of plant defense peptides: hevein-like antimicrobial peptides from wheat inhibit fungal metalloproteases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The multilayered plant immune system relies on rapid recognition of pathogen-associated molecular patterns followed by activation of defense-related genes that results in the reinforcement of plant cell walls and production of antimicrobial compounds. To suppress plant defense, fungi secrete effecto...

  20. Salmonella enterica Serovar Enteritidis Antimicrobial Peptide Resistance Genes Aid in Defense against Chicken Innate Immunity, Fecal Shedding, and Egg Deposition

    PubMed Central

    McKelvey, Jessica A.; Yang, Ming; Jiang, Yanhua

    2014-01-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major etiologic agent of nontyphoid salmonellosis in the United States. S. Enteritidis persistently and silently colonizes the intestinal and reproductive tract of laying hens, resulting in contaminated poultry products. The consumption of contaminated poultry products has been identified as a significant risk factor for human salmonellosis. To understand the mechanisms S. Enteritidis utilizes to colonize and persist in laying hens, we used selective capture of transcribed sequences to identify genes overexpressed in the HD11 chicken macrophage cell line and in primary chicken oviduct epithelial cells. From the 15 genes found to be overexpressed in both cell types, we characterized the antimicrobial peptide resistance (AMPR) genes, virK and ybjX, in vitro and in vivo. In vitro, AMPR genes were required for natural morphology, motility, secretion, defense against detergents such as EDTA and bile salts, and resistance to antimicrobial peptides polymyxin B and avian β-defensins. From this, we inferred the AMPR genes play a role in outer membrane stability and/or modulation. In the intestinal tract, AMPR genes were involved in early intestinal colonization and fecal shedding. In the reproductive tract, virK was required in early colonization whereas a deletion of ybjX caused prolonged ovary colonization and egg deposition. Data from the present study indicate that AMPR genes are differentially utilized in various host environments, which may ultimately assist S. Enteritidis in persistent and silent colonization of chickens. PMID:25267840

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

    PubMed Central

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

    2012-01-01

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

  2. Release of Luminal Exosomes Contributes to TLR4-Mediated Epithelial Antimicrobial Defense

    PubMed Central

    Hu, Guoku; Gong, Ai-Yu; Roth, Amanda L.; Huang, Bing Q.; Ward, Honorine D.; Zhu, Guan; LaRusso, Nicholas F.; Hanson, Nancy D.; Chen, Xian-Ming

    2013-01-01

    Exosomes are membranous nanovesicles released by most cell types from multi-vesicular endosomes. They are speculated to transfer molecules to neighboring or distant cells and modulate many physiological and pathological procedures. Exosomes released from the gastrointestinal epithelium to the basolateral side have been implicated in antigen presentation. Here, we report that luminal release of exosomes from the biliary and intestinal epithelium is increased following infection by the protozoan parasite Cryptosporidium parvum. Release of exosomes involves activation of TLR4/IKK2 signaling through promoting the SNAP23-associated vesicular exocytotic process. Downregulation of let-7 family miRNAs by activation of TLR4 signaling increases SNAP23 expression, coordinating exosome release in response to C. parvum infection. Intriguingly, exosomes carry antimicrobial peptides of epithelial cell origin, including cathelicidin-37 and beta-defensin 2. Activation of TLR4 signaling enhances exosomal shuttle of epithelial antimicrobial peptides. Exposure of C. parvum sporozoites to released exosomes decreases their viability and infectivity both in vitro and ex vivo. Direct binding to the C. parvum sporozoite surface is required for the anti-C. parvum activity of released exosomes. Biliary epithelial cells also increase exosomal release and display exosome-associated anti-C. parvum activity following LPS stimulation. Our data indicate that TLR4 signaling regulates luminal exosome release and shuttling of antimicrobial peptides from the gastrointestinal epithelium, revealing a new arm of mucosal immunity relevant to antimicrobial defense. PMID:23592986

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

    PubMed

    Mathew, Meril; Lopanik, Nicole B

    2014-04-01

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

  4. Antimicrobial terpenes from oleoresin of ponderosa pine tree Pinus ponderosa: A defense mechanism against microbial invasion

    SciTech Connect

    Himejima, Masaki; Hobson, K.R.; Otsuka, Toshikazu; Wood, D.L.; Kubo, Isao )

    1992-10-01

    The oleoresin of the ponderosa pine, Pinus ponderosa (Pinaceae) exhibited broad antimicrobial activity. In order to identify the active compounds, the oleoresin was steam distilled to give a distillate and residue. The distillate contained mainly monoterpenes and some sesquiterpenes, while the residue consisted chiefly of four structurally related diterpene acids. An antimicrobial assay with the pure compounds indicated that the monoterpenes were active primarily against fungi, but there was also some activity against gram-positive bacteria. The diterpene acids, in contrast, only exhibited activity against gram-positive bacteria. Although not all of the identified sesquiterpenes could be tested, longifolene showed activity only against gram-positive bacteria. Therefore, it appears that the oleoresin of P. ponderosa functions as a biochemical defense against microbial invasion.

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2016-05-10

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

  7. Interferon induced IFIT family genes in host antiviral defense

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  8. Coqui frogs persist with the deadly chytrid fungus despite a lack of defensive antimicrobial peptides.

    PubMed

    Rollins-Smith, Louise A; Reinert, Laura K; Burrowes, Patricia A

    2015-02-10

    The amphibian skin fungus Batrachochytrium dendrobatidis (Bd) occurs widely in Puerto Rico and is thought to be responsible for the apparent extinction of 3 species of endemic frogs in the genus Eleutherodactylus, known as coquis. To examine immune defenses which may protect surviving species, we induced secretion of skin peptides from adult common coqui frogs E. coqui collected from upland forests at El Yunque. By matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, we were unable to detect peptide signals suggestive of antimicrobial peptides, and enriched peptides showed no capacity to inhibit growth of Bd. Thus, it appears that E. coqui depend on other skin defenses to survive in the presence of this deadly fungus. PMID:25667340

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

    PubMed

    Han, SeungHye; Mallampalli, Rama K

    2015-05-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Day, J D; LeGrand, E K

    2015-02-21

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

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2016-06-01

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

  17. Clinical Use of Colistin Induces Cross-Resistance to Host Antimicrobials in Acinetobacter baumannii

    PubMed Central

    Napier, Brooke A.; Burd, Eileen M.; Satola, Sarah W.; Cagle, Stephanie M.; Ray, Susan M.; McGann, Patrick; Pohl, Jan; Lesho, Emil P.; Weiss, David S.

    2013-01-01

    ABSTRACT The alarming rise in antibiotic resistance has led to an increase in patient mortality and health care costs. This problem is compounded by the absence of new antibiotics close to regulatory approval. Acinetobacter baumannii is a human pathogen that causes infections primarily in patients in intensive care units (ICUs) and is highly antibiotic resistant. Colistin is one of the last-line antibiotics for treating A. baumannii infections; however, colistin-resistant strains are becoming increasingly common. This cationic antibiotic attacks negatively charged bacterial membranes in a manner similar to that seen with cationic antimicrobials of the innate immune system. We therefore set out to determine if the increasing use of colistin, and emergence of colistin-resistant strains, is concomitant with the generation of cross-resistance to host cationic antimicrobials. We found that there is indeed a positive correlation between resistance to colistin and resistance to the host antimicrobials LL-37 and lysozyme among clinical isolates. Importantly, isolates obtained before and after treatment of individual patients demonstrated that colistin use correlated with increased resistance to cationic host antimicrobials. These data reveal the overlooked risk of inducing cross-resistance to host antimicrobials when treating patients with colistin as a last-line antibiotic. PMID:23695834

  18. Hyperleptinemia is associated with impaired pulmonary host defense

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    Hyun, Jinhee; Kanagavelu, Saravana; Fukata, Masayuki

    2012-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

    Thorogood, Rose; Davies, Nicholas B

    2013-12-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

    Sharkey, Keith A.; Savidge, Tor C.

    2014-01-01

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

  5. Rapid evolution of antimicrobial peptide genes in an insect host-social parasite system.

    PubMed

    Erler, Silvio; Lhomme, Patrick; Rasmont, Pierre; Lattorff, H Michael G

    2014-04-01

    Selection, as a major driver for evolution in host-parasite interactions, may act on two levels; the virulence of the pathogen, and the hosts' defence system. Effectors of the host defence system might evolve faster than other genes e.g. those involved in adaptation to changes in life history or environmental fluctuations. Host-parasite interactions at the level of hosts and their specific social parasites, present a special setting for evolutionarily driven selection, as both share the same environmental conditions and pathogen pressures. Here, we study the evolution of antimicrobial peptide (AMP) genes, in six host bumblebee and their socially parasitic cuckoo bumblebee species. The selected AMP genes evolved much faster than non-immune genes, but only defensin-1 showed significant differences between host and social parasite. Nucleotide diversity and codon-by-codon analyses confirmed that purifying selection is the main selective force acting on bumblebee defence genes. PMID:24530902

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Thorogood, Rose; Davies, Nicholas B

    2013-01-01

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

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

    PubMed Central

    Subramanian, Hariharan; Gupta, Kshitij; Ali, Hydar

    2016-01-01

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

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

    PubMed Central

    An, Chuanfu; Mou, Zhonglin

    2012-01-01

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

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

    PubMed

    Thorogood, Rose; Davies, Nicholas B

    2012-08-01

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

  11. The immunology of host defence peptides: beyond antimicrobial activity.

    PubMed

    Hancock, Robert E W; Haney, Evan F; Gill, Erin E

    2016-05-01

    Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications. PMID:27087664

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

    Heinig, M J

    2001-02-01

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

  16. Are you my symbiont? Microbial polymorphic toxins and antimicrobial compounds as honest signals of beneficial symbiotic defensive traits.

    PubMed

    Hillman, Kai; Goodrich-Blair, Heidi

    2016-06-01

    In defensive symbioses where microbes benefit their host by killing competitors, predators or parasites, natural selection should favor the transmission of microbes with the most beneficial defensive traits. During the initiation of symbiosis, the host's ability to accurately pre-assess a symbiont's beneficial traits would be a selective advantage. We propose that one mechanism by which a host could recognize and select a beneficial partner would be if the latter displayed an honest signal of its defensive or other symbiotic capabilities. As one example, we suggest that polymorphic toxins and their surface receptors, which are involved in inter-microbial competition and predator killing activities, can be honest signals that facilitate partner choice in defensive symbioses. PMID:27128187

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

    PubMed

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

    2016-05-24

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

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

    SciTech Connect

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

    1983-01-01

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

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

    PubMed Central

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

    2009-01-01

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

  20. Increased survival of experimentally evolved antimicrobial peptide-resistant Staphylococcus aureus in an animal host

    PubMed Central

    Dobson, Adam J; Purves, Joanne; Rolff, Jens

    2014-01-01

    Antimicrobial peptides (AMPs) have been proposed as new class of antimicrobial drugs, following the increasing prevalence of bacteria resistant to antibiotics. Synthetic AMPs are functional analogues of highly evolutionarily conserved immune effectors in animals and plants, produced in response to microbial infection. Therefore, the proposed therapeutic use of AMPs bears the risk of ‘arming the enemy’: bacteria that evolve resistance to AMPs may be cross-resistant to immune effectors (AMPs) in their hosts. We used a panel of populations of Staphylococcus aureus that were experimentally selected for resistance to a suite of individual AMPs and antibiotics to investigate the ‘arming the enemy’ hypothesis. We tested whether the selected strains showed higher survival in an insect model (Tenebrio molitor) and cross-resistance against other antimicrobials in vitro. A population selected for resistance to the antimicrobial peptide iseganan showed increased in vivo survival, but was not more virulent. We suggest that increased survival of AMP-resistant bacteria almost certainly poses problems to immune-compromised hosts. PMID:25469169

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2007-11-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

    Ariumi, Yasuo

    2016-01-01

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

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

    PubMed

    Ariumi, Yasuo

    2016-01-01

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

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

    PubMed

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

    2013-09-10

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

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

    PubMed

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

    2016-09-01

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

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

    EPA Science Inventory

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

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

    2016-09-01

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

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

    PubMed

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

    2014-09-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Raison, C L; Miller, A H

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Krieger, M

    1997-10-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

    Upadhyay, Vaibhav; Fu, Yang-Xin

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

    Strober, Warren; Watanabe, Tomohiro

    2013-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Coers, Jörn; Haldar, Arun K

    2015-01-01

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2015-02-01

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

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

    PubMed Central

    Muralidharan, Sujatha; Mandrekar, Pranoti

    2013-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-07-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2015-03-01

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

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

    PubMed

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

    2016-09-01

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

  15. Induced Bacterial Cross-Resistance toward Host Antimicrobial Peptides: A Worrying Phenomenon

    PubMed Central

    Fleitas, Osmel; Franco, Octávio L.

    2016-01-01

    Bacterial resistance to conventional antibiotics has reached alarming levels, threatening to return to the pre-antibiotic era. Therefore, the search for new antimicrobial compounds that overcome the resistance phenomenon has become a priority. Antimicrobial peptides (AMPs) appear as one of the most promising antibiotic medicines. However, in recent years several AMP-resistance mechanisms have been described. Moreover, the AMP-resistance phenomenon has become more complex due to its association with cross-resistance toward AMP effectors of the host innate immune system. In this context, the use of AMPs as a therapeutic option could be potentially hazardous, since bacteria could develop resistance toward our innate immune system. Here, we review the findings of major studies that deal with the AMP cross-resistance phenomenon. PMID:27047486

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    Cassady, Katherine R.; Noga, Edward J.

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  19. A novel mechanism for NETosis provides antimicrobial defense at the oral mucosa.

    PubMed

    Mohanty, Tirthankar; Sjögren, Jonathan; Kahn, Fredrik; Abu-Humaidan, Anas H A; Fisker, Niels; Assing, Kristian; Mörgelin, Matthias; Bengtsson, Anders A; Borregaard, Niels; Sørensen, Ole E

    2015-10-29

    Neutrophils are essential for host defense at the oral mucosa and neutropenia or functional neutrophil defects lead to disordered oral homeostasis. We found that neutrophils from the oral mucosa harvested from morning saliva had released neutrophil extracellular traps (undergone NETosis) in vivo. The NETosis was mediated through intracellular signals elicited by binding of sialyl Lewis(X) present on salival mucins to l-selectin on neutrophils. This led to rapid loss of nuclear membrane and intracellular release of granule proteins with subsequent neutrophil extracellular trap (NET) release independent of elastase and reduced NAD phosphate-oxidase activation. The saliva-induced NETs were more DNase-resistant and had higher capacity to bind and kill bacteria than NETs induced by bacteria or by phorbol-myristate acetate. Furthermore, saliva/sialyl Lewis(X) mediated signaling enhanced intracellular killing of bacteria by neutrophils. Saliva from patients with aphthous ulcers and Behçet disease prone to oral ulcers failed to induce NETosis, but for different reasons it demonstrated that disordered homeostasis in the oral cavity may result in deficient saliva-mediated NETosis. PMID:26243777

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2011-10-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    1993-01-01

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

  4. The acute and sub-chronic exposures of goldfish to naphthenic acids induce different host defense responses.

    PubMed

    Hagen, Mariel O; Garcia-Garcia, Erick; Oladiran, Ayoola; Karpman, Matthew; Mitchell, Scott; El-Din, Mohamed Gamal; Martin, Jonathan W; Belosevic, Miodrag

    2012-03-01

    Naphthenic acids (NAs) are believed to be the major toxic component in oil sands process-affected water (OSPW) produced by the oil sands mining industry in Northern Alberta, Canada. We recently reported that oral exposure to NAs alters mammalian immune responses, but the effect of OSPW or NAs on the immune mechanisms of aquatic organisms has not been fully elucidated. We analyzed the effects of acute and sub-chronic NAs exposures on goldfish immune responses by measuring the expression of three pro-inflammatory cytokine genes, antimicrobial functions of macrophages, and host defense after challenge with a protozoan pathogen (Trypanosoma carassii). One week after NAs exposure, fish exhibited increased expression of pro-inflammatory cytokines (IFNγ, IL-1β1, TNF-α2) in the gills, kidney and spleen. Primary macrophages from fish exposed to NAs for one week, exhibited increased production of nitric oxide and reactive oxygen intermediates. Goldfish exposed for one week to 20 mg/L NAs were more resistant to infection by T. carassii. In contrast, sub-chronic exposure of goldfish (12 weeks) to NAs resulted in decreased expression of pro-inflammatory cytokines in the gills, kidney and spleen. The sub-chronic exposure to NAs reduced the ability of goldfish to control the T. carassii infection, exemplified by a drastic increase in fish mortality and increased blood parasite loads. This is the first report analyzing the effects of OSPW contaminants on the immune system of aquatic vertebrates. We believe that the bioassays depicted in this work will be valuable tools for analyzing the efficacy of OSPW remediation techniques and assessment of diverse environmental pollutants. PMID:22227375

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Ferrandon, Dominique

    2013-02-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Adamo, Shelley A

    2014-07-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2001-12-01

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

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  17. Multidimensional signatures in antimicrobial peptides

    PubMed Central

    Yount, Nannette Y.; Yeaman, Michael R.

    2004-01-01

    Conventional analyses distinguish between antimicrobial peptides by differences in amino acid sequence. Yet structural paradigms common to broader classes of these molecules have not been established. The current analyses examined the potential conservation of structural themes in antimicrobial peptides from evolutionarily diverse organisms. Using proteomics, an antimicrobial peptide signature was discovered to integrate stereospecific sequence patterns and a hallmark three-dimensional motif. This striking multidimensional signature is conserved among disulfide-containing antimicrobial peptides spanning biological kingdoms, and it transcends motifs previously limited to defined peptide subclasses. Experimental data validating this model enabled the identification of previously unrecognized antimicrobial activity in peptides of known identity. The multidimensional signature model provides a unifying structural theme in broad classes of antimicrobial peptides, will facilitate discovery of antimicrobial peptides as yet unknown, and offers insights into the evolution of molecular determinants in these and related host defense effector molecules. PMID:15118082

  18. Insect Gut Symbiont Susceptibility to Host Antimicrobial Peptides Caused by Alteration of the Bacterial Cell Envelope*

    PubMed Central

    Kim, Jiyeun Kate; Son, Dae Woo; Kim, Chan-Hee; Cho, Jae Hyun; Marchetti, Roberta; Silipo, Alba; Sturiale, Luisa; Park, Ha Young; Huh, Ye Rang; Nakayama, Hiroshi; Fukatsu, Takema; Molinaro, Antonio; Lee, Bok Luel

    2015-01-01

    The molecular characterization of symbionts is pivotal for understanding the cross-talk between symbionts and hosts. In addition to valuable knowledge obtained from symbiont genomic studies, the biochemical characterization of symbionts is important to fully understand symbiotic interactions. The bean bug (Riptortus pedestris) has been recognized as a useful experimental insect gut symbiosis model system because of its cultivatable Burkholderia symbionts. This system is greatly advantageous because it allows the acquisition of a large quantity of homogeneous symbionts from the host midgut. Using these naïve gut symbionts, it is possible to directly compare in vivo symbiotic cells with in vitro cultured cells using biochemical approaches. With the goal of understanding molecular changes that occur in Burkholderia cells as they adapt to the Riptortus gut environment, we first elucidated that symbiotic Burkholderia cells are highly susceptible to purified Riptortus antimicrobial peptides. In search of the mechanisms of the increased immunosusceptibility of symbionts, we found striking differences in cell envelope structures between cultured and symbiotic Burkholderia cells. The bacterial lipopolysaccharide O antigen was absent from symbiotic cells examined by gel electrophoretic and mass spectrometric analyses, and their membranes were more sensitive to detergent lysis. These changes in the cell envelope were responsible for the increased susceptibility of the Burkholderia symbionts to host innate immunity. Our results suggest that the symbiotic interactions between the Riptortus host and Burkholderia gut symbionts induce bacterial cell envelope changes to achieve successful gut symbiosis. PMID:26116716

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2013-01-15

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    1977-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  5. Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression

    PubMed Central

    Grether-Beck, Susanne; Felsner, Ingo; Brenden, Heidi; Kohne, Zippora; Majora, Marc; Marini, Alessandra; Jaenicke, Thomas; Rodriguez-Martin, Marina; Trullas, Carles; Hupe, Melanie; Elias, Peter M.; Krutmann, Jean

    2012-01-01

    Urea is an endogenous metabolite, known to enhance stratum corneum hydration. Yet, topical urea anecdotally also improves permeability barrier function, and it appears to exhibit antimicrobial activity. Hence, we hypothesized that urea is not merely a passive metabolite, but a small-molecule regulator of epidermal structure and function. In 21 human volunteers, topical urea improved barrier function in parallel with enhanced antimicrobial peptide (LL-37 and β-defensin-2) expression. Urea both stimulates expression of, and is transported into keratinocytes by two urea transporters, UT-A1 and UT-A2, and by aquaporin 3, 7 and 9. Inhibitors of these urea transporters block the downstream biological effects of urea, which include increased mRNA and protein levels for: (i) transglutaminase-1, involucrin, loricrin and filaggrin; (ii) epidermal lipid synthetic enzymes, and (iii) cathelicidin/LL-37 and β-defensin-2. Finally, we explored the potential clinical utility of urea, showing that topical urea applications normalized both barrier function and antimicrobial peptide expression in a murine model of atopic dermatitis (AD). Together, these results show that urea is a small-molecule regulator of epidermal permeability barrier function and antimicrobial peptide expression after transporter uptake, followed by gene regulatory activity in normal epidermis, with potential therapeutic applications in diseased skin. PMID:22418868

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2010-08-01

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

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

    PubMed Central

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

    2006-01-01

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

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

    PubMed

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

    2000-03-01

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

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

    PubMed Central

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

    2000-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    Galli, Stephen J.; Tsai, Mindy

    2009-01-01

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

  15. Development of antimicrobial peptide defenses of southern leopard frogs, Rana sphenocephala, against the pathogenic chytrid fungus, Batrachochytrium dendrobatidis.

    PubMed

    Holden, Whitney M; Reinert, Laura K; Hanlon, Shane M; Parris, Matthew J; Rollins-Smith, Louise A

    2015-01-01

    Amphibian species face the growing threat of extinction due to the emerging fungal pathogen Batrachochytrium dendrobatidis, which causes the disease chytridiomycosis. Antimicrobial peptides (AMPs) produced in granular glands of the skin are an important defense against this pathogen. Little is known about the ontogeny of AMP production or the impact of AMPs on potentially beneficial symbiotic skin bacteria. We show here that Rana (Lithobates) sphenocephala produces a mixture of four AMPs with activity against B. dendrobatidis, and we report the minimum inhibitory concentration (MIC) of synthesized replicates of these four AMPs tested against B. dendrobatidis. Using mass spectrometry and protein quantification assays, we observed that R. sphenocephala does not secrete a mature suite of AMPs until approximately 12 weeks post-metamorphosis, and geographically disparate populations produce a different suite of peptides. Use of norepinephrine to induce maximal secretion significantly reduced levels of culturable skin bacteria. PMID:25218643

  16. AMPed Up immunity: how antimicrobial peptides have multiple roles in immune defense

    PubMed Central

    Lai, Yuping; Gallo, Richard L.

    2009-01-01

    Antimicrobial peptides (AMPs) are widely expressed and rapidly induced at epithelial surfaces to repel assault from diverse infectious agents including bacteria, viruses, fungi and parasites. Much information suggests that AMPs act by mechanisms that extend beyond their capacity to serve as gene-encoded antibiotics. For example, some AMPs alter the properties of the mammalian membrane or interact with its receptors to influence diverse cellular processes including cytokine release, chemotaxis, antigen presentation, angiogenesis and wound healing. These functions complement their antimicrobial action and favor resolution of infection and repair of damaged epithelia. Opposing this, some microbes have evolved mechanisms to inactivate or avoid AMPs and subsequently become pathogens. Thus, AMPs are multifunctional molecules that have a central role in infection and Inflammation. PMID:19217824

  17. Production and Release of Antimicrobial and Immune Defense Proteins by Mammary Epithelial Cells following Streptococcus uberis Infection of Sheep

    PubMed Central

    Pisanu, Salvatore; Marogna, Gavino; Cubeddu, Tiziana; Pagnozzi, Daniela; Cacciotto, Carla; Campesi, Franca; Schianchi, Giuseppe; Rocca, Stefano

    2013-01-01

    Investigating the innate immune response mediators released in milk has manifold implications, spanning from elucidation of the role played by mammary epithelial cells (MECs) in fighting microbial infections to the discovery of novel diagnostic markers for monitoring udder health in dairy animals. Here, we investigated the mammary gland response following a two-step experimental infection of lactating sheep with the mastitis-associated bacterium Streptococcus uberis. The establishment of infection was confirmed both clinically and by molecular methods, including PCR and fluorescent in situ hybridization of mammary tissues. Proteomic investigation of the milk fat globule (MFG), a complex vesicle released by lactating MECs, enabled detection of enrichment of several proteins involved in inflammation, chemotaxis of immune cells, and antimicrobial defense, including cathelicidins and calprotectin (S100A8/S100A9), in infected animals, suggesting the consistent involvement of MECs in the innate immune response to pathogens. The ability of MECs to produce and release antimicrobial and immune defense proteins was then demonstrated by immunohistochemistry and confocal immunomicroscopy of cathelicidin and the calprotectin subunit S100A9 on mammary tissues. The time course of their release in milk was also assessed by Western immunoblotting along the course of the experimental infection, revealing the rapid increase of these proteins in the MFG fraction in response to the presence of bacteria. Our results support an active role of MECs in the innate immune response of the mammary gland and provide new potential for the development of novel and more sensitive tools for monitoring mastitis in dairy animals. PMID:23774600

  18. Production and release of antimicrobial and immune defense proteins by mammary epithelial cells following Streptococcus uberis infection of sheep.

    PubMed

    Addis, Maria Filippa; Pisanu, Salvatore; Marogna, Gavino; Cubeddu, Tiziana; Pagnozzi, Daniela; Cacciotto, Carla; Campesi, Franca; Schianchi, Giuseppe; Rocca, Stefano; Uzzau, Sergio

    2013-09-01

    Investigating the innate immune response mediators released in milk has manifold implications, spanning from elucidation of the role played by mammary epithelial cells (MECs) in fighting microbial infections to the discovery of novel diagnostic markers for monitoring udder health in dairy animals. Here, we investigated the mammary gland response following a two-step experimental infection of lactating sheep with the mastitis-associated bacterium Streptococcus uberis. The establishment of infection was confirmed both clinically and by molecular methods, including PCR and fluorescent in situ hybridization of mammary tissues. Proteomic investigation of the milk fat globule (MFG), a complex vesicle released by lactating MECs, enabled detection of enrichment of several proteins involved in inflammation, chemotaxis of immune cells, and antimicrobial defense, including cathelicidins and calprotectin (S100A8/S100A9), in infected animals, suggesting the consistent involvement of MECs in the innate immune response to pathogens. The ability of MECs to produce and release antimicrobial and immune defense proteins was then demonstrated by immunohistochemistry and confocal immunomicroscopy of cathelicidin and the calprotectin subunit S100A9 on mammary tissues. The time course of their release in milk was also assessed by Western immunoblotting along the course of the experimental infection, revealing the rapid increase of these proteins in the MFG fraction in response to the presence of bacteria. Our results support an active role of MECs in the innate immune response of the mammary gland and provide new potential for the development of novel and more sensitive tools for monitoring mastitis in dairy animals. PMID:23774600

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

    Song, Junqi; Bent, Andrew F.

    2014-01-01

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

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

    PubMed

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

    2014-07-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

  6. The use of ECAS in plant protection: a green and efficient antimicrobial approach that primes selected defense genes.

    PubMed

    Zarattini, Marco; De Bastiani, Morena; Bernacchia, Giovanni; Ferro, Sergio; De Battisti, Achille

    2015-11-01

    The use of highly polluting chemicals for plant and crop protection is one of the components of the negative environmental impact of agricultural activities. In the present paper, an environmentally friendly alternative to pesticide application has been studied, based on the so-called electrochemically activated solutions (ECAS). Experiments have been carried out, by applying ECAS having different contents of active ingredients, on tobacco plants at a laboratory scale and on apple trees at fruit garden scale. The results, accumulated during a couple of years, have shown that properly selected dilute solutions of chlorides, once activated by an electrochemical treatment, exhibit a very effective protecting action of plants, irrespective of their nature. Extension of the research has shown that the observed effect is the result of two distinct factors: the expected anti-microbial action of the electrochemically synthesized oxidants, and an unexpected priming of immune plant defenses, which is clearly due to the treatment with ECAS. Interestingly, the repetition of ECAS application triggers an even stronger activation of defense genes. No oxidative damages, due to the use of the activated solutions, could be detected. PMID:26350548

  7. Microarray analysis of gene expression in eastern oyster (Crassostrea virginica) reveals a novel combination of antimicrobial and oxidative stress host responses after dermo (Perkinsus marinus) challenge.

    PubMed

    Wang, Shaolin; Peatman, Eric; Liu, Hong; Bushek, David; Ford, Susan E; Kucuktas, Huseyin; Quilang, Jonas; Li, Ping; Wallace, Richard; Wang, Yongping; Guo, Ximing; Liu, Zhanjiang

    2010-12-01

    Dermo disease, caused by Perkinsus marinus, is one of the most severe diseases of eastern oysters, Crassostrea virginica. It causes serious mortalities in both wild and aquacultured oysters. Using existing expressed sequence tag (EST) resources, we developed a 12K in situ oligonucleotide microarray and used it for the analysis of gene expression profiles of oysters during the interactions between P. marinus and its oyster host. Significant gene expression regulation was found at day 30 post-challenge in the eastern oyster. Putative identities of the differentially expressed genes revealed a set of genes involved in several processes including putative antimicrobial defenses, pathogen recognition and uptake, anti-oxidation and apoptosis. Consistent with results obtained from previous, smaller-scale experiments, expression profiles revealed a large set of genes likely involved in an active mitigating response to oxidative stress and apoptosis induced by P. marinus. Additionally, a unique galectin from C. virginica, CvGal, which serves as a preferential receptor for P. marinus trophozoites, was found to be significantly down-regulated in gill tissue of oysters with both light and heavy infection, suggesting an attempt to control parasite uptake and proliferation in the later stages of infection. Potential histone-derived antimicrobial responses to P. marinus were also revealed in the gene expression profiles. PMID:20708691

  8. Antimicrobial peptides.

    PubMed

    Zhang, Ling-Juan; Gallo, Richard L

    2016-01-11

    Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs. PMID:26766224

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

    PubMed Central

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

    2002-01-01

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

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

    PubMed

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

    2007-07-01

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

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

    PubMed

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

    2011-07-21

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

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

    PubMed

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

    2015-06-15

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2001-01-01

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

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

    PubMed

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

    2012-08-01

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

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

    SciTech Connect

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

    2012-10-10

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

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

    PubMed

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

    2012-12-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

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

  20. LPS inmobilization on porous and non-porous supports as an approach for the isolation of anti-LPS host-defense peptides

    PubMed Central

    López-Abarrategui, Carlos; del Monte-Martínez, Alberto; Reyes-Acosta, Osvaldo; Franco, Octavio L.; Otero-González, Anselmo J.

    2013-01-01

    Lipopolysaccharides (LPSs) are the major molecular component of the outer membrane of Gram-negative bacteria. This molecule is recognized as a sign of bacterial infection, responsible for the development of local inflammatory response and, in extreme cases, septic shock. Unfortunately, despite substantial advances in the pathophysiology of sepsis, there is no efficacious therapy against this syndrome yet. As a consequence, septic shock syndrome continues to increase, reaching mortality rates over 50% in some cases. Even though many preclinical studies and clinical trials have been conducted, there is no Food and Drug Administration-approved drug yet that interacts directly against LPS. Cationic host-defense peptides (HDPs) could be an alternative solution since they possess both antimicrobial and antiseptic properties. HDPs are small, positively charged peptides which are evolutionarily conserved components of the innate immune response. In fact, binding to diverse chemotypes of LPS and inhibition of LPS-induced pro-inflammatory cytokines from macrophages have been demonstrated for different HDPs. Curiously, none of them have been isolated by their affinity to LPS. A diversity of supports could be useful for such biological interaction and suitable for isolating HDPs that recognize LPS. This approach could expand the rational search for anti-LPS HDPs. PMID:24409171

  1. LPS inmobilization on porous and non-porous supports as an approach for the isolation of anti-LPS host-defense peptides.

    PubMed

    López-Abarrategui, Carlos; Del Monte-Martínez, Alberto; Reyes-Acosta, Osvaldo; Franco, Octavio L; Otero-González, Anselmo J

    2013-01-01

    Lipopolysaccharides (LPSs) are the major molecular component of the outer membrane of Gram-negative bacteria. This molecule is recognized as a sign of bacterial infection, responsible for the development of local inflammatory response and, in extreme cases, septic shock. Unfortunately, despite substantial advances in the pathophysiology of sepsis, there is no efficacious therapy against this syndrome yet. As a consequence, septic shock syndrome continues to increase, reaching mortality rates over 50% in some cases. Even though many preclinical studies and clinical trials have been conducted, there is no Food and Drug Administration-approved drug yet that interacts directly against LPS. Cationic host-defense peptides (HDPs) could be an alternative solution since they possess both antimicrobial and antiseptic properties. HDPs are small, positively charged peptides which are evolutionarily conserved components of the innate immune response. In fact, binding to diverse chemotypes of LPS and inhibition of LPS-induced pro-inflammatory cytokines from macrophages have been demonstrated for different HDPs. Curiously, none of them have been isolated by their affinity to LPS. A diversity of supports could be useful for such biological interaction and suitable for isolating HDPs that recognize LPS. This approach could expand the rational search for anti-LPS HDPs. PMID:24409171

  2. Host-defense peptides from skin secretions of Fraser's clawed frog Xenopus fraseri (Pipidae): Further insight into the evolutionary history of the Xenopodinae.

    PubMed

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

    2014-12-01

    Peptidomic analysis of norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus fraseri Boulenger, 1905 (Pipidae) led to identification of 13 host-defense peptides. The primary structures of the peptides demonstrate that they belong to the magainin (3 peptides), peptide glycine-leucine-amide, PGLa (4 peptides), and xenopsin-precursor fragment, XPF (2 peptides) families, first identified in Xenopus laevis, together with caerulein precursor fragment-related peptides, CPF-RP (4 peptides), first identified in Silurana tropicalis. In addition, the secretions contain a molecular variant of xenopsin displaying the substitution Arg(4)→Lys compared with X. laevis xenopsin and peptide glycine-tyrosine-amide (PGYa) (GRIIPIYPEFERVFA KKVYPLY.NH2) whose function is unknown. The most potent antimicrobial peptide identified is CPF-RP-F1 (GFGSVLGKALKFGANLL.NH2) with MIC=12.5μM against Staphylococcus aureus and 50μM against Escherichia coli. On the basis of similarities in morphology and advertisement calls, X. fraseri has been placed in a species group that includes the octoploids Xenopus amieti and Xenopus andrei, and the tetraploid Xenopus pygmaeus. Cladistic analyses based upon the primary structures of magainin, PGLa, and CPF-RP peptides support a close evolutionary relationship between X. fraseri, X. amieti and X. andrei but suggest a more distant relationship with X. pygmaeus. PMID:25463057

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

    PubMed Central

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

    2015-01-01

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

  4. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis.

    PubMed

    Zindl, Carlene L; Lai, Jen-Feng; Lee, Yun Kyung; Maynard, Craig L; Harbour, Stacey N; Ouyang, Wenjun; Chaplin, David D; Weaver, Casey T

    2013-07-30

    IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23-dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNF-α. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22-competent neutrophils to Il22a-deficient mice protected the colonic epithelium from dextran sodium sulfate-induced damage. In addition, IL-22-producing neutrophils targeted colonic epithelial cells to up-regulate the antimicrobial peptides, RegIIIβ and S100A8. This study establishes a role for neutrophils in providing IL-22-dependent mucosal epithelial support that contributes to the resolution of colitis. PMID:23781104

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

    PubMed Central

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

    2010-01-01

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

  6. Neutrophil antimicrobial defense against Staphylococcus aureus is mediated by phagolysosomal but not extracellular trap-associated cathelicidin

    PubMed Central

    Jann, Naja J.; Schmaler, Mathias; Kristian, Sascha A.; Radek, Katherine A.; Gallo, Richard L.; Nizet, Victor; Peschel, Andreas; Landmann, Regine

    2009-01-01

    Neutrophils kill invading pathogens by AMPs, including cathelicidins, ROS, and NETs. The human pathogen Staphylococcus aureus exhibits enhanced resistance to neutrophil AMPs, including the murine cathelicidin CRAMP, in part, as a result of alanylation of teichoic acids by the dlt operon. In this study, we took advantage of the hypersusceptible phenotype of S. aureus ΔdltA against cationic AMPs to study the impact of the murine cathelicidin CRAMP on staphylococcal killing and to identify its key site of action in murine neutrophils. We demonstrate that CRAMP remained intracellular during PMN exudation from blood and was secreted upon PMA stimulation. We show first evidence that CRAMP was recruited to phagolysosomes in infected neutrophils and exhibited intracellular activity against S. aureus. Later in infection, neutrophils produced NETs, and immunofluorescence revealed association of CRAMP with S. aureus in NETs, which similarly killed S. aureus wt and ΔdltA, indicating that CRAMP activity was reduced when associated with NETs. Indeed, the presence of DNA reduced the antimicrobial activity of CRAMP, and CRAMP localization in response to S. aureus was independent of the NADPH oxidase, whereas killing was partially dependent on a functional NADPH oxidase. Our study indicates that neutrophils use CRAMP in a timed and locally coordinated manner in defense against S. aureus. PMID:19638500

  7. Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo.

    PubMed

    Rieg, Siegbert; Steffen, Heiko; Seeber, Silke; Humeny, Andreas; Kalbacher, Hubert; Dietz, Klaus; Garbe, Claus; Schittek, Birgit

    2005-06-15

    Antimicrobial peptides are an integral part of the epithelial innate defense system. Dermcidin (DCD) is a recently discovered antimicrobial peptide with a broad spectrum of activity. It is constitutively expressed in human eccrine sweat glands and secreted into sweat. Patients with atopic dermatitis (AD) have recurrent bacterial or viral skin infections and pronounced colonization with Staphylococcus aureus. We hypothesized that patients with AD have a reduced amount of DCD peptides in sweat contributing to the compromised constitutive innate skin defense. Therefore, we performed semiquantitative and quantitative analyses of DCD peptides in sweat of AD patients and healthy subjects using surface-enhanced laser desorption ionization time-of-flight mass spectrometry and ELISA. The data indicate that the amount of several DCD-derived peptides in sweat of patients with AD is significantly reduced. Furthermore, compared with atopic patients without previous infectious complications, AD patients with a history of bacterial and viral skin infections were found to have significantly less DCD-1 and DCD-1L in their sweat. To analyze whether the reduced amount of DCD in sweat of AD patients correlates with a decreased innate defense, we determined the antimicrobial activity of sweat in vivo. We showed that in healthy subjects, sweating leads to a reduction of viable bacteria on the skin surface, but this does not occur in patients with AD. These data indicate that reduced expression of DCD in sweat of patients with AD may contribute to the high susceptibility of these patients to skin infections and altered skin colonization. PMID:15944307

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

    PubMed

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

    2015-11-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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