Immune evasion by pathogens of bovine respiratory disease complex.

PubMed

Srikumaran, Subramaniam; Kelling, Clayton L; Ambagala, Aruna

2007-12-01

Bovine respiratory tract disease is a multi-factorial disease complex involving several viruses and bacteria. Viruses that play prominent roles in causing the bovine respiratory disease complex include bovine herpesvirus-1, bovine respiratory syncytial virus, bovine viral diarrhea virus and parinfluenza-3 virus. Bacteria that play prominent roles in this disease complex are Mannheimia haemolytica and Mycoplasma bovis. Other bacteria that infect the bovine respiratory tract of cattle are Histophilus (Haemophilus) somni and Pasteurella multocida. Frequently, severe respiratory tract disease in cattle is associated with concurrent infections of these pathogens. Like other pathogens, the viral and bacterial pathogens of this disease complex have co-evolved with their hosts over millions of years. As much as the hosts have diversified and fine-tuned the components of their immune system, the pathogens have also evolved diverse and sophisticated strategies to evade the host immune responses. These pathogens have developed intricate mechanisms to thwart both the innate and adaptive arms of the immune responses of their hosts. This review presents an overview of the strategies by which the pathogens suppress host immune responses, as well as the strategies by which the pathogens modify themselves or their locations in the host to evade host immune responses. These immune evasion strategies likely contribute to the failure of currently-available vaccines to provide complete protection to cattle against these pathogens.

Staphylococcal Immune Evasion Proteins: Structure, Function, and Host Adaptation.

PubMed

Koymans, Kirsten J; Vrieling, Manouk; Gorham, Ronald D; van Strijp, Jos A G

2017-01-01

Staphylococcus aureus is a successful human and animal pathogen. Its pathogenicity is linked to its ability to secrete a large amount of virulence factors. These secreted proteins interfere with many critical components of the immune system, both innate and adaptive, and hamper proper immune functioning. In recent years, numerous studies have been conducted in order to understand the molecular mechanism underlying the interaction of evasion molecules with the host immune system. Structural studies have fundamentally contributed to our understanding of the mechanisms of action of the individual factors. Furthermore, such studies revealed one of the most striking characteristics of the secreted immune evasion molecules: their conserved structure. Despite high-sequence variability, most immune evasion molecules belong to a small number of structural categories. Another remarkable characteristic is that S. aureus carries most of these virulence factors on mobile genetic elements (MGE) or ex-MGE in its accessory genome. Coevolution of pathogen and host has resulted in immune evasion molecules with a highly host-specific function and prevalence. In this review, we explore how these shared structures and genomic locations relate to function and host specificity. This is discussed in the context of therapeutic options for these immune evasion molecules in infectious as well as in inflammatory diseases.

Pseudomonas HopU1 modulates plant immune receptor levels by blocking the interaction of their mRNAs with GRP7.

PubMed

Nicaise, Valerie; Joe, Anna; Jeong, Byeong-ryool; Korneli, Christin; Boutrot, Freddy; Westedt, Isa; Staiger, Dorothee; Alfano, James R; Zipfel, Cyril

2013-03-06

Pathogens target important components of host immunity to cause disease. The Pseudomonas syringae type III-secreted effector HopU1 is a mono-ADP-ribosyltransferase required for full virulence on Arabidopsis thaliana. HopU1 targets several RNA-binding proteins including GRP7, whose role in immunity is still unclear. Here, we show that GRP7 associates with translational components, as well as with the pattern recognition receptors FLS2 and EFR. Moreover, GRP7 binds specifically FLS2 and EFR transcripts in vivo through its RNA recognition motif. HopU1 does not affect the protein-protein associations between GRP7, FLS2 and translational components. Instead, HopU1 blocks the interaction between GRP7 and FLS2 and EFR transcripts in vivo. This inhibition correlates with reduced FLS2 protein levels upon Pseudomonas infection in a HopU1-dependent manner. Our results reveal a novel virulence strategy used by a microbial effector to interfere with host immunity.

Parasitism and venom of ectoparasitoid Scleroderma guani impairs host cellular immunity.

PubMed

Li, Li-Fang; Xu, Zhi-Wen; Liu, Nai-Yong; Wu, Guo-Xing; Ren, Xue-Min; Zhu, Jia-Ying

2018-06-01

Venom is a prominently maternal virulent factor utilized by parasitoids to overcome hosts immune defense. With respect to roles of this toxic mixture involved in manipulating hosts immunity, great interest has been mostly restricted to Ichneumonoidea parasitoids associated with polydnavirus (PDV), of which venom is usually considered as a helper component to enhance the role of PDV, and limited Chalcidoidea species. In contrast, little information is available in other parasitoids, especially ectoparasitic species not carrying PDV. The ectoparasitoid Scleroderma guani injects venom into its host, Tenebrio molitor, implying its venom was involved in suppression of hosts immune response for successful parasitism. Thus, we investigated the effects of parasitism and venom of this parasitoid on counteracting the cellular immunity of its host by examining changes of hemocyte counts, and hemocyte spreading and encapsulation ability. Total hemocyte counts were elevated in parasitized and venom-injected pupae. The spreading behavior of both granulocytes and plasmatocytes was impaired by parasitization and venom. High concentration of venom led to more severely increased hemocyte counts and suppression of hemocyte spreading. The ability of hemocyte encapsulation was inhibited by venom in vitro. In addition to immediate effects observed, venom showed persistent interference in hosts cellular immunity. These results indicate that venom alone from S. guani plays a pivotal role in blocking hosts cellular immune response, serving as a regulator that guarantees the successful development of its progenies. The findings provide a foundation for further investigation of the underlying mechanisms in immune inhibitory action of S. guani venom. © 2018 Wiley Periodicals, Inc.

Protective and destructive immunity in the periodontium: Part 1--innate and humoral immunity and the periodontium.

PubMed

Teng, Y-T A

2006-03-01

Based on the results of recent research in the field, the present paper will discuss the protective and destructive aspects of the innate vs. adaptive (humoral and cell-mediated) immunity associated with the bacterial virulent factors or antigenic determinants during periodontal pathogenesis. Attention will be focused on: (i) the Toll-like receptors (TLR), the innate immune repertoire for recognizing the unique molecular patterns of microbial components that trigger innate and adaptive immunity for effective host defenses, in some general non-oral vs. periodontal microbial infections; (ii) T-cell-mediated immunity, Th-cytokines, and osteoclastogenesis in periodontal disease progression; and (iii) some molecular techniques developed and used to identify critical microbial virulence factors or antigens associated with host immunity (using Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis as the model species). Therefore, further understanding of the molecular interactions and mechanisms associated with the host's innate and adaptive immune responses will facilitate the development of new and innovative therapeutics for future periodontal treatments.

Peptidoglycan recognition proteins in Drosophila immunity.

PubMed

Kurata, Shoichiro

2014-01-01

Innate immunity is the front line of self-defense against infectious non-self in vertebrates and invertebrates. The innate immune system is mediated by germ-line encoding pattern recognition molecules (pathogen sensors) that recognize conserved molecular patterns present in the pathogens but absent in the host. Peptidoglycans (PGN) are essential cell wall components of almost all bacteria, except mycoplasma lacking a cell wall, which provides the host immune system an advantage for detecting invading bacteria. Several families of pattern recognition molecules that detect PGN and PGN-derived compounds have been indentified, and the role of PGRP family members in host defense is relatively well-characterized in Drosophila. This review focuses on the role of PGRP family members in the recognition of invading bacteria and the activation and modulation of immune responses in Drosophila. Copyright © 2013 Elsevier Ltd. All rights reserved.

Early-Life Food Nutrition, Microbiota Maturation and Immune Development Shape Life-Long Health.

PubMed

Zhou, Xiaoli; Du, Lina; Shi, Ronghua; Chen, Zhidong; Zhou, Yiming; Li, Zongjie

2018-06-06

The current knowledge about early-life nutrition and environmental factors that affect the interaction between the symbiotic microbiota and the host immune system has demonstrated novel regulatory target for treating allergic diseases, autoimmune disorders and metabolic syndrome. Various kinds of food nutrients (such as dietary fiber, starch, polyphenols and proteins) can provide energy resources for both intestinal microbiota and the host. The indigestible food components are fermented by the indigenous gut microbiota to produce diverse metabolites, including short-chain fatty acids, bile acids and trimethylamine-N-oxide, which can regulate the host metabolized physiology, immunity homeostasis and health state. Therefore it is commonly believed early-life perturbation of the microbial community structure and the dietary nutrition interference on the child mucosal immunity contribute to the whole life susceptibility to chronic diseases. In all, the combined interrelationship between food ingredients nutrition, intestinal microbiota configurations and host system immunity provides new therapeutic targets to treat various kinds of pathogenic inflammations and chronic diseases.

An immunologist's perspective on nutrition, immunity and infectious diseases: Introduction and overview

USDA-ARS?s Scientific Manuscript database

The immune system is a multifaceted arrangement of membranes (skin, epithelial, mucus), cells, and molecules whose function is to eradicate invading pathogens or cancer cells from a host. Working together, the various components of the immune system perform a balancing act of being lethal enough to...

Homeostatic Immunity and the Microbiota.

PubMed

Belkaid, Yasmine; Harrison, Oliver J

2017-04-18

The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. Here we review the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota. Published by Elsevier Inc.

Homeostatic immunity and the microbiota

PubMed Central

Belkaid, Yasmine; Harrison, Oliver J.

2017-01-01

The microbiota plays a fundamental role in the induction, education and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. In this review, we will highlight the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota. PMID:28423337

Commensal-innate immune miscommunication in IBD pathogenesis.

PubMed

Cario, Elke

2012-01-01

Commensal microbiota plays a key role in the health and disease of the host. The innate immune system comprises an essential functional component of the intestinal mucosal barrier, maintaining hyporesponsiveness to omnipresent harmless commensals in the lumen, but rapidly recognizing and combating invading bacteria through diverse antimicrobial mechanisms. Interactions between commensals and innate immune cells are constant, multidimensional and entirely context-dependent. Environment, genetics and host defense differentially modulate commensal-innate immune effects and functions in the intestinal mucosa. In IBD, dysbiosis, mucus layer disruption, impairment in bacterial clearance, intestinal epithelial cell barrier dysfunction and/or immune cell deregulation may lead to commensal-innate immune miscommunication, which critically drives mucosal inflammation and associated cancer. Copyright © 2012 S. Karger AG, Basel.

The host-pathogen interaction between wheat and yellow rust induces temporally coordinated waves of gene expression.

PubMed

Dobon, Albor; Bunting, Daniel C E; Cabrera-Quio, Luis Enrique; Uauy, Cristobal; Saunders, Diane G O

2016-05-20

Understanding how plants and pathogens modulate gene expression during the host-pathogen interaction is key to uncovering the molecular mechanisms that regulate disease progression. Recent advances in sequencing technologies have provided new opportunities to decode the complexity of such interactions. In this study, we used an RNA-based sequencing approach (RNA-seq) to assess the global expression profiles of the wheat yellow rust pathogen Puccinia striiformis f. sp. tritici (PST) and its host during infection. We performed a detailed RNA-seq time-course for a susceptible and a resistant wheat host infected with PST. This study (i) defined the global gene expression profiles for PST and its wheat host, (ii) substantially improved the gene models for PST, (iii) evaluated the utility of several programmes for quantification of global gene expression for PST and wheat, and (iv) identified clusters of differentially expressed genes in the host and pathogen. By focusing on components of the defence response in susceptible and resistant hosts, we were able to visualise the effect of PST infection on the expression of various defence components and host immune receptors. Our data showed sequential, temporally coordinated activation and suppression of expression of a suite of immune-response regulators that varied between compatible and incompatible interactions. These findings provide the framework for a better understanding of how PST causes disease and support the idea that PST can suppress the expression of defence components in wheat to successfully colonize a susceptible host.

Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor

PubMed Central

Rappleye, Chad A.; Eissenberg, Linda Groppe; Goldman, William E.

2007-01-01

Successful infection by fungal pathogens depends on subversion of host immune mechanisms that detect conserved cell wall components such as β-glucans. A less common polysaccharide, α-(1,3)-glucan, is a cell wall constituent of most fungal respiratory pathogens and has been correlated with pathogenicity or linked directly to virulence. However, the precise mechanism by which α-(1,3)-glucan promotes fungal virulence is unknown. Here, we show that α-(1,3)-glucan is present in the outermost layer of the Histoplasma capsulatum yeast cell wall and contributes to pathogenesis by concealing immunostimulatory β-glucans from detection by host phagocytic cells. Production of proinflammatory TNFα by phagocytes was suppressed either by the presence of the α-(1,3)-glucan layer on yeast cells or by RNA interference based depletion of the host β-glucan receptor dectin-1. Thus, we have functionally defined key molecular components influencing the initial host–pathogen interaction in histoplasmosis and have revealed an important mechanism by which H. capsulatum thwarts the host immune system. Furthermore, we propose that the degree of this evasion contributes to the difference in pathogenic potential between dimorphic fungal pathogens and opportunistic fungi. PMID:17227865

Molecular interactions between entomopathogenic fungi (Hypocreales) and their insect host: Perspectives from stressful cuticle and hemolymph battlefields and the potential of dual RNA sequencing for future studies.

PubMed

Pedrini, Nicolás

2018-06-01

Entomopathogenic fungi of the order Hypocreales infect their insect hosts mainly by penetrating through the cuticle and colonize them by proliferating throughout the body cavity. In order to ensure a successful infection, fungi first produce a variety of degrading enzymes that help to breach the insect cuticle, and then secrete toxic secondary metabolites that facilitate fungal invasion of the hemolymph. In response, insect hosts activate their innate immune system by triggering both cellular and humoral immune reactions. As fungi are exposed to stress in both cuticle and hemolymph, several mechanisms are activated not only to deal with this situation but also to mimic host epitopes and evade the insect's immune response. In this review, several components involved in the molecular interaction between insects and fungal pathogens are described including chemical, metabolomics, and dual transcriptomics approaches; with emphasis in the involvement of cuticle surface components in (pre-) infection processes, and fungal secondary metabolite (non-ribosomally synthesized peptides and polyketides) analysis. Some of the mechanisms involved in such interaction are also discussed. Copyright © 2017 British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Current understanding of HIV-1 and T-cell adaptive immunity: progress to date.

PubMed

Mohan, Teena; Bhatnagar, Santwana; Gupta, Dablu L; Rao, D N

2014-08-01

The cellular immune response to human immunodeficiency virus (HIV) has different components originating from both the adaptive and innate immune systems. HIV cleverly utilizes the host machinery to survive by its intricate nature of interaction with the host immune system. HIV evades the host immune system at innate ad adaptive, allows the pathogen to replicate and transmit from one host to another. Researchers have shown that HIV has multipronged effects especially on the adaptive immunity, with CD4(+) cells being the worst effect T-cell populations. Various analyses have revealed that, the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T-cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T-cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T-cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immune- pathogenesis of HIV that are still unknown and thus required further research in order to convert the malaise of HIV into a manageable epidemic. Copyright © 2014 Elsevier Ltd. All rights reserved.

Plant immunity: a lesson from pathogenic bacterial effector proteins.

PubMed

Cui, Haitao; Xiang, Tingting; Zhou, Jian-Min

2009-10-01

Phytopathogenic bacteria inject an array of effector proteins into host cells to alter host physiology and assist the infection process. Some of these effectors can also trigger disease resistance as a result of recognition in the plant cell by cytoplasmic immune receptors. In addition to effector-triggered immunity, plants immunity can be triggered upon the detection of Pathogen/Microbe-Associated Molecular Patterns by surface-localized immune receptors. Recent progress indicates that many bacterial effector proteins use a variety of biochemical properties to directly attack key components of PAMP-triggered immunity and effector-triggered immunity, providing new insights into the molecular basis of plant innate immunity. Emerging evidence indicate that the evolution of disease resistance in plants is intimately linked to the mechanism by which bacterial effectors promote parasitism. This review focuses on how these studies have conceptually advanced our understanding of plant-pathogen interactions.

The immune response to Nipah virus infection.

PubMed

Prescott, Joseph; de Wit, Emmie; Feldmann, Heinz; Munster, Vincent J

2012-09-01

Nipah virus has recently emerged as a zoonotic agent that is highly pathogenic in humans. Outbreaks have occurred regularly over the last two decades in South and Southeast Asia, where mortality rates reach as high as 100 %. The natural reservoir of Nipah virus has been identified as bats from the Pteropus family, where infection is largely asymptomatic. Human disease is characterized by both respiratory and encephalitic components, and thus far, no effective vaccine or intervention strategies are available. Little is know about how the immune response of either the reservoir host or incidental hosts responds to infection, and how this immune response is either inadequate or might contribute to disease in the dead-end host. Experimental vaccines strategies have given us some insight into the immunological requirements for protection. This review summarizes our current understanding of the immune response to Nipah virus infection and emphasizes the need for further research.

The immune response to Nipah virus infection

PubMed Central

Prescott, Joseph; de Wit, Emmie; Feldmann, Heinz; Munster, Vincent J.

2012-01-01

Nipah virus has recently emerged as a zoonotic agent that is highly pathogenic in humans. Outbreaks have occurred regularly over the last two decades in South and Southeast Asia, where mortality rates reach as high as 100%. The natural reservoir of Nipah virus has been identified as bats from the Pteropus family, where infection is largely asymptomatic. Human disease is characterized by both respiratory and encephalitic components, and thus far, no effective vaccine or intervention strategies are available. Little is know about how the immune response of either the reservoir host or incidental hosts responds to infection, and how this immune response is either inadequate or might contribute to disease in the dead-end host. Experimental vaccines strategies have given us some insight into the immunological requirements for protection. This review summarizes our current understanding of the immune response to Nipah virus infection and emphasizes the need for further research. PMID:22669317

Discrete Dynamical Modeling of Influenza Virus Infection Suggests Age-Dependent Differences in Immunity.

PubMed

Keef, Ericka; Zhang, Li Ang; Swigon, David; Urbano, Alisa; Ermentrout, G Bard; Matuszewski, Michael; Toapanta, Franklin R; Ross, Ted M; Parker, Robert S; Clermont, Gilles

2017-12-01

Immunosenescence, an age-related decline in immune function, is a major contributor to morbidity and mortality in the elderly. Older hosts exhibit a delayed onset of immunity and prolonged inflammation after an infection, leading to excess damage and a greater likelihood of death. Our study applies a rule-based model to infer which components of the immune response are most changed in an aged host. Two groups of BALB/c mice (aged 12 to 16 weeks and 72 to 76 weeks) were infected with 2 inocula: a survivable dose of 50 PFU and a lethal dose of 500 PFU. Data were measured at 10 points over 19 days in the sublethal case and at 6 points over 7 days in the lethal case, after which all mice had died. Data varied primarily in the onset of immunity, particularly the inflammatory response, which led to a 2-day delay in the clearance of the virus from older hosts in the sublethal cohort. We developed a Boolean model to describe the interactions between the virus and 21 immune components, including cells, chemokines, and cytokines, of innate and adaptive immunity. The model identifies distinct sets of rules for each age group by using Boolean operators to describe the complex series of interactions that activate and deactivate immune components. Our model accurately simulates the immune responses of mice of both ages and with both inocula included in the data (95% accurate for younger mice and 94% accurate for older mice) and shows distinct rule choices for the innate immunity arm of the model between younger and aging mice in response to influenza A virus infection. IMPORTANCE Influenza virus infection causes high morbidity and mortality rates every year, especially in the elderly. The elderly tend to have a delayed onset of many immune responses as well as prolonged inflammatory responses, leading to an overall weakened response to infection. Many of the details of immune mechanisms that change with age are currently not well understood. We present a rule-based model of the intrahost immune response to influenza virus infection. The model is fit to experimental data for young and old mice infected with influenza virus. We generated distinct sets of rules for each age group to capture the temporal differences seen in the immune responses of these mice. These rules describe a network of interactions leading to either clearance of the virus or death of the host, depending on the initial dosage of the virus. Our models clearly demonstrate differences in these two age groups, particularly in the innate immune responses. Copyright © 2017 American Society for Microbiology.

The interplay between the gut microbiota and the immune system.

PubMed

Geuking, Markus B; Köller, Yasmin; Rupp, Sandra; McCoy, Kathy D

2014-01-01

The impact of the gut microbiota on immune homeostasis within the gut and, importantly, also at systemic sites has gained tremendous research interest over the last few years. The intestinal microbiota is an integral component of a fascinating ecosystem that interacts with and benefits its host on several complex levels to achieve a mutualistic relationship. Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut while preventing uncontrolled immune responses against the beneficial commensal microbiota potentially leading to chronic inflammatory bowel diseases (IBD). Furthermore, recent studies suggest that the microbiota composition might impact on the susceptibility to immune-mediated disorders such as autoimmunity and allergy. Understanding how the microbiota modulates susceptibility to these diseases is an important step toward better prevention or treatment options for such diseases.

Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development

PubMed Central

Beheshti, Afshin; Wage, Justin; McDonald, J. Tyson; Lamont, Clare; Peluso, Michael; Hahnfeldt, Philip; Hlatky, Lynn

2015-01-01

The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease. PMID:26497558

Host-Specific Response to HCV Infection in the Chimeric SCID-beige/Alb-uPA Mouse Model: Role of the Innate Antiviral Immune Response

PubMed Central

Thompson, Jill C; Smith, Maria W; Yeh, Matthew M; Proll, Sean; Zhu, Lin-Fu; Gao, T. J; Kneteman, Norman M; Tyrrell, D. Lorne; Katze, Michael G

2006-01-01

The severe combined immunodeficiency disorder (SCID)-beige/albumin (Alb)-urokinase plasminogen activator (uPA) mouse containing a human-mouse chimeric liver is currently the only small animal model capable of supporting hepatitis C virus (HCV) infection. This model was utilized to characterize the host transcriptional response to HCV infection. The purpose of these studies was to investigate the genetic component of the host response to HCV infection and also to distinguish virus-induced gene expression changes from adaptive HCV-specific immune-mediated effects. Gene expression profiles from HCV-infected mice were also compared to those from HCV-infected patients. Analyses of the gene expression data demonstrate that host factors regulate the response to HCV infection, including the nature of the innate antiviral immune response. They also indicate that HCV mediates gene expression changes, including regulation of lipid metabolism genes, which have the potential to be directly cytopathic, indicating that liver pathology may not be exclusively mediated by HCV-specific adaptive immune responses. This effect appears to be inversely related to the activation of the innate antiviral immune response. In summary, the nature of the initial interferon response to HCV infection may determine the extent of viral-mediated effects on host gene expression. PMID:16789836

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.

PubMed

Gong, Lauren; Parikh, Sunil; Rosenthal, Philip J; Greenhouse, Bryan

2013-09-11

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria

PubMed Central

2013-01-01

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria. PMID:24025776

Complement factor H in host defense and immune evasion.

PubMed

Parente, Raffaella; Clark, Simon J; Inforzato, Antonio; Day, Anthony J

2017-05-01

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

A novel nematode effector suppresses plant immunity by activating host reactive oxygen species-scavenging system.

PubMed

Lin, Borong; Zhuo, Kan; Chen, Shiyan; Hu, Lili; Sun, Longhua; Wang, Xiaohong; Zhang, Lian-Hui; Liao, Jinling

2016-02-01

Evidence is emerging that plant-parasitic nematodes can secrete effectors to interfere with the host immune response, but it remains unknown how these effectors can conquer host immune responses. Here, we depict a novel effector, MjTTL5, that could suppress plant immune response. Immunolocalization and transcriptional analyses showed that MjTTL5 is expressed specifically within the subventral gland of Meloidogyne javanica and up-regulated in the early parasitic stage of the nematode. Transgenic Arabidopsis lines expressing MjTTL5 were significantly more susceptible to M. javanica infection than wild-type plants, and vice versa, in planta silencing of MjTTL5 substantially increased plant resistance to M. javanica. Yeast two-hybrid, coimmunoprecipitation and bimolecular fluorescent complementation assays showed that MjTTL5 interacts specifically with Arabidopsis ferredoxin : thioredoxin reductase catalytic subunit (AtFTRc), a key component of host antioxidant system. The expression of AtFTRc is induced by the infection of M. javanica. Interaction between AtFTRc and MjTTL could drastically increase host reactive oxygen species-scavenging activity, and result in suppression of plant basal defenses and attenuation of host resistance to the nematode infection. Our results demonstrate that the host ferredoxin : thioredoxin system can be exploited cunningly by M. javanica, revealing a novel mechanism utilized by plant-parasitic nematodes to subjugate plant innate immunity and thereby promoting parasitism. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection.

PubMed

Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C

2016-02-01

The interplay between Mycobacterium tuberculosis lipid metabolism, the immune response and lipid homeostasis in the host creates a complex and dynamic pathogen-host interaction. Advances in imaging and metabolic analysis techniques indicate that M. tuberculosis preferentially associates with foamy cells and employs multiple physiological systems to utilize exogenously derived fatty-acids and cholesterol. Moreover, novel insights into specific host pathways that control lipid accumulation during infection, such as the PPARγ and LXR transcriptional regulators, have begun to reveal mechanisms by which host immunity alters the bacterial micro-environment. As bacterial lipid metabolism and host lipid regulatory pathways are both important, yet inherently complex, components of active tuberculosis, delineating the heterogeneity in lipid trafficking within disease states remains a major challenge for therapeutic design. Copyright © 2015. Published by Elsevier Ltd.

Antiviral Innate Immunity through the lens of Systems Biology

PubMed Central

Tripathi, Shashank; García-Sastre, Adolfo

2015-01-01

Cellular innate immunity poses the first hurdle against invading viruses in their attempt to establish infection. This antiviral response is manifested with the detection of viral components by the host cell, followed by transduction of antiviral signals, transcription and translation of antiviral effectors and leads to the establishment of an antiviral state. These events occur in a rather branched and interconnected sequence than a linear path. Traditionally, these processes were studied in the context of a single virus and a host component. However, with the advent of rapid and affordable OMICS technologies it has become feasible to address such questions on a global scale. In the discipline of Systems Biology’, extensive omics datasets are assimilated using computational tools and mathematical models to acquire deeper understanding of complex biological processes. In this review we have catalogued and discussed the application of Systems Biology approaches in dissecting the antiviral innate immune responses. PMID:26657882

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

PubMed Central

Mostowy, Serge; Shenoy, Avinash R.

2016-01-01

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence. PMID:26292640

DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component.

PubMed

Han, Xiaozhe; LaRosa, Karen B; Kawai, Toshihisa; Taubman, Martin A

2014-01-03

Porphyromonas gingivalis (Pg) is one of a constellation of oral organisms associated with human chronic periodontitis. While adaptive immunity to periodontal pathogen proteins has been investigated and is an important component of periodontal bone resorption, the effect of periodontal pathogen DNA in eliciting systemic and mucosal antibody and modulating immune responses has not been investigated. Rowett rats were locally injected with whole genomic Pg DNA in alum. Escherichia coli (Ec) genomic DNA, Fusobacterium nucleatum (Fn) genomic DNA, and saline/alum injected rats served as controls. After various time points, serum IgG and salivary IgA antibody to Ec, Fn or Pg were detected by ELISA. Serum and salivary antibody reactions with Pg surface antigens were determined by Western blot analyses and the specific antigen was identified by mass spectrometry. Effects of genomic DNA immunization on Pg bacterial colonization and experimental periodontal bone resorption were also evaluated. Sera from Pg DNA, Ec DNA and Fn DNA-injected rats did not react with Ec or Fn bacteria. Serum IgG antibody levels to Pg and Pg surface extracts were significantly higher in animals immunized with Pg DNA as compared to the control groups. Rats injected with Pg DNA demonstrated a strong serum IgG and salivary IgA antibody reaction solely to Pg fimbrillin (41kDa), the major protein component of Pg fimbriae. In the Pg DNA-immunized group, the numbers of Pg bacteria in oral cavity and the extent of periodontal bone resorption were significantly reduced after Pg infection. This study suggests that infected hosts may select specific genes from whole genomic DNA of the periodontal pathogen for transcription and presentation. The results indicate that the unique gene selected can initiate a host protective immune response to the parent bacterium. Copyright © 2013 Elsevier Ltd. All rights reserved.

Host-pathogen interplay of Haemophilus ducreyi.

PubMed

Janowicz, Diane M; Li, Wei; Bauer, Margaret E

2010-02-01

Haemophilus ducreyi, the causative agent of the sexually transmitted infection chancroid, is primarily a pathogen of human skin. During infection, H. ducreyi thrives extracellularly in a milieu of professional phagocytes and other antibacterial components of the innate and adaptive immune responses. This review summarizes our understanding of the interplay between this pathogen and its host that leads to development and persistence of disease. H. ducreyi expresses key virulence mechanisms to resist host defenses. The secreted LspA proteins are tyrosine-phosphorylated by host kinases, which may contribute to their antiphagocytic effector function. The serum resistance and adherence functions of DsrA map to separate domains of this multifunctional virulence factor. An influx transporter protects H. ducreyi from killing by the antimicrobial peptide LL37. Regulatory genes have been identified that may coordinate virulence factor expression during disease. Dendritic cells and natural killer cells respond to H. ducreyi and may be involved in determining the differential outcomes of infection observed in humans. A human model of H. ducreyi infection has provided insights into virulence mechanisms that allow this human-specific pathogen to survive immune pressures. Components of the human innate immune system may also determine the ultimate fate of H. ducreyi infection by driving either clearance of the organism or an ineffective response that allows disease progression.

Production and regulation of functional amyloid curli fimbriae by Shiga toxin-producing Escherichia coli

USDA-ARS?s Scientific Manuscript database

Functional amyloid, in the form of adhesive fimbrial proteins termed curli, was first described in Salmonella and Escherichia coli. Curli fibers adhere to various host cells and structural proteins, interact with components of the host immune system, and participate in biofilm formation. Shiga toxin...

Molecular basis of Trypanosoma cruzi and Leishmania interaction with their host(s): exploitation of immune and defense mechanisms by the parasite leading to persistence and chronicity, features reminiscent of immune system evasion strategies in cancer diseases.

PubMed

Ouaissi, Ali; Ouaissi, Mehdi

2005-01-01

A number of features occurring during host-parasite interactions in Chagas disease caused by the protozoan parasite, Trypanosoma cruzi, and Leishmaniasis, caused by a group of kinetoplastid protozoan parasites are reminiscent of those observed in cancer diseases. In fact,although the cancer is not a single disease, and that T.cruzi and Leishmania are sophisticated eukaryotic parasites presenting a high level of genotypic variability the growth of the parasites in their host and that of cancer cells share at least one common feature, that is their mutual capacity for rapid cell division. Surprisingly, the parasitic diseases and cancers share some immune evasion strategies. Consideration of these immunological alterations must be added to the evaluation of the pathogenic processes. The molecular and functional characterization of virulence factors and the study of their effect on the arms of the immune system have greatly improved understanding of the regulation of immune effectors functions. The purpose of this review is to analyze some of the current data related to the regulatory components or processes originating from the parasite that control or interfere with host cell physiology. Attempts are also made to delineate some similarities between the immune evasion strategies that parasites and tumors employ. The elucidation of the mode of action of parasite virulence factors toward the host cell allow not only provide us with a more comprehensive view of the host-parasite relationships but may also represent a step forward in efforts aimed to identify new target molecules for therapeutic intervention.

Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion.

PubMed

Hopke, Alex; Brown, Alistair J P; Hall, Rebecca A; Wheeler, Robert T

2018-04-01

Deadly infections from opportunistic fungi have risen in frequency, largely because of the at-risk immunocompromised population created by advances in modern medicine and the HIV/AIDS pandemic. This review focuses on dynamics of the fungal polysaccharide cell wall, which plays an outsized role in fungal pathogenesis and therapy because it acts as both an environmental barrier and as the major interface with the host immune system. Human fungal pathogens use architectural strategies to mask epitopes from the host and prevent immune surveillance, and recent work elucidates how biotic and abiotic stresses present during infection can either block or enhance masking. The signaling components implicated in regulating fungal immune recognition can teach us how cell wall dynamics are controlled, and represent potential targets for interventions designed to boost or dampen immunity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cellular Signaling Pathways and Posttranslational Modifications Mediated by Nematode Effector Proteins.

PubMed

Hewezi, Tarek

2015-10-01

Plant-parasitic cyst and root-knot nematodes synthesize and secrete a suite of effector proteins into infected host cells and tissues. These effectors are the major virulence determinants mediating the transformation of normal root cells into specialized feeding structures. Compelling evidence indicates that these effectors directly hijack or manipulate refined host physiological processes to promote the successful parasitism of host plants. Here, we provide an update on recent progress in elucidating the molecular functions of nematode effectors. In particular, we emphasize how nematode effectors modify plant cell wall structure, mimic the activity of host proteins, alter auxin signaling, and subvert defense signaling and immune responses. In addition, we discuss the emerging evidence suggesting that nematode effectors target and recruit various components of host posttranslational machinery in order to perturb the host signaling networks required for immunity and to regulate their own activity and subcellular localization. © 2015 American Society of Plant Biologists. All Rights Reserved.

Plant immunity triggered by microbial molecular signatures.

PubMed

Zhang, Jie; Zhou, Jian-Min

2010-09-01

Pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) are recognized by host cell surface-localized pattern-recognition receptors (PRRs) to activate plant immunity. PAMP-triggered immunity (PTI) constitutes the first layer of plant immunity that restricts pathogen proliferation. PTI signaling components often are targeted by various Pseudomonas syringae virulence effector proteins, resulting in diminished plant defenses and increased bacterial virulence. Some of the proteins targeted by pathogen effectors have evolved to sense the effector activity by associating with cytoplasmic immune receptors classically known as resistance proteins. This allows plants to activate a second layer of immunity termed effector-triggered immunity (ETI). Recent studies on PTI regulation and P. syringae effector targets have uncovered new components in PTI signaling. Although MAP kinase (MAPK) cascades have been considered crucial for PTI, emerging evidence indicates that a MAPK-independent pathway also plays an important role in PTI signaling.

Surfactant Protein-D Is Essential for Immunity to Helminth Infection

PubMed Central

Schnoeller, Corinna; Chetty, Alisha; Smith, Katherine; Darby, Matthew; Roberts, Luke; Mackay, Rosie-Marie; Whitwell, Harry J.; Timms, John F.; Madsen, Jens; Selkirk, Murray E.; Brombacher, Frank; Clark, Howard William; Horsnell, William G. C.

2016-01-01

Pulmonary epithelial cell responses can enhance type 2 immunity and contribute to control of nematode infections. An important epithelial product is the collectin Surfactant Protein D (SP-D). We found that SP-D concentrations increased in the lung following Nippostrongylus brasiliensis infection; this increase was dependent on key components of the type 2 immune response. We carried out loss and gain of function studies of SP-D to establish if SP-D was required for optimal immunity to the parasite. N. brasiliensis infection of SP-D-/- mice resulted in profound impairment of host innate immunity and ability to resolve infection. Raising pulmonary SP-D levels prior to infection enhanced parasite expulsion and type 2 immune responses, including increased numbers of IL-13 producing type 2 innate lymphoid cells (ILC2), elevated expression of markers of alternative activation by alveolar macrophages (alvM) and increased production of the type 2 cytokines IL-4 and IL-13. Adoptive transfer of alvM from SP-D-treated parasite infected mice into naïve recipients enhanced immunity to N. brasiliensis. Protection was associated with selective binding by the SP-D carbohydrate recognition domain (CRD) to L4 parasites to enhance their killing by alvM. These findings are the first demonstration that the collectin SP-D is an essential component of host innate immunity to helminths. PMID:26900854

Bacterial effectors target the common signaling partner BAK1 to disrupt multiple MAMP receptor-signaling complexes and impede plant immunity.

PubMed

Shan, Libo; He, Ping; Li, Jianming; Heese, Antje; Peck, Scott C; Nürnberger, Thorsten; Martin, Gregory B; Sheen, Jen

2008-07-17

Successful pathogens have evolved strategies to interfere with host immune systems. For example, the ubiquitous plant pathogen Pseudomonas syringae injects two sequence-distinct effectors, AvrPto and AvrPtoB, to intercept convergent innate immune responses stimulated by multiple microbe-associated molecular patterns (MAMPs). However, the direct host targets and precise molecular mechanisms of bacterial effectors remain largely obscure. We show that AvrPto and AvrPtoB bind the Arabidopsis receptor-like kinase BAK1, a shared signaling partner of both the flagellin receptor FLS2 and the brassinosteroid receptor BRI1. This targeting interferes with ligand-dependent association of FLS2 with BAK1 during infection. It also impedes BAK1-dependent host immune responses to diverse other MAMPs and brassinosteroid signaling. Significantly, the structural basis of AvrPto-BAK1 interaction appears to be distinct from AvrPto-Pto association required for effector-triggered immunity. These findings uncover a unique strategy of bacterial pathogenesis where virulence effectors block signal transmission through a key common component of multiple MAMP-receptor complexes.

Serratia marcescens Induces Apoptotic Cell Death in Host Immune Cells via a Lipopolysaccharide- and Flagella-dependent Mechanism*

PubMed Central

Ishii, Kenichi; Adachi, Tatsuo; Imamura, Katsutoshi; Takano, Shinya; Usui, Kimihito; Suzuki, Kazushi; Hamamoto, Hiroshi; Watanabe, Takeshi; Sekimizu, Kazuhisa

2012-01-01

Injection of Serratia marcescens into the blood (hemolymph) of the silkworm, Bombyx mori, induced the activation of c-Jun NH2-terminal kinase (JNK), followed by caspase activation and apoptosis of blood cells (hemocytes). This process impaired the innate immune response in which pathogen cell wall components, such as glucan, stimulate hemocytes, leading to the activation of insect cytokine paralytic peptide. S. marcescens induced apoptotic cell death of silkworm hemocytes and mouse peritoneal macrophages in vitro. We searched for S. marcescens transposon mutants with attenuated ability to induce apoptosis of silkworm hemocytes. Among the genes identified, disruption mutants of wecA (a gene involved in lipopolysaccharide O-antigen synthesis), and flhD and fliR (essential genes in flagella synthesis) showed reduced motility and impaired induction of mouse macrophage cell death. These findings suggest that S. marcescens induces apoptosis of host immune cells via lipopolysaccharide- and flagella-dependent motility, leading to the suppression of host innate immunity. PMID:22859304

Protective Microbiota: From Localized to Long-Reaching Co-Immunity

PubMed Central

Chiu, Lynn; Bazin, Thomas; Truchetet, Marie-Elise; Schaeverbeke, Thierry; Delhaes, Laurence; Pradeu, Thomas

2017-01-01

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota. PMID:29270167

Pathogenesis of graft-versus-host disease: innate immunity amplifying acute alloimmune responses.

PubMed

Maeda, Yoshinobu

2013-09-01

In addition to reduced-intensity conditioning, which has expanded the eligibility for hematopoietic cell transplantation (HCT) to older patients, increased availability of alternative donors, including HLA-mismatched unrelated donors, has increased access to allogeneic HCT for more patients. However, acute graft-versus-host disease (GVHD) remains a lethal complication, even in HLA-matched donor-recipient pairs. The pathophysiology of GVHD depends on aspects of adaptive immunity and interactions between donor T-cells and host dendritic cells (DCs). Recent work has revealed that the role of other immune cells and endothelial cells and components of the innate immune response are also important. Tissue damage caused by the conditioning regimen leads to the release of exogenous and endogenous "danger signals". Exogenous danger signals called pathogen-associated molecular patterns and endogenous noninfectious molecules known as damage-associated molecular patterns (DAMPs) are responsible for initiating or amplifying acute GVHD by enhancing DC maturation and alloreactive T-cell responses. A significant association of innate immune receptor polymorphisms with outcomes, including GVHD severity, was observed in patients receiving allogeneic HCT. Understanding of the role of innate immunity in acute GVHD might offer new therapeutic approaches.

The potential management of oral candidiasis using anti-biofilm therapies.

PubMed

Chanda, Warren; Joseph, Thomson P; Wang, Wendong; Padhiar, Arshad A; Zhong, Mintao

2017-09-01

Candida albicans is a minor component of the oral microbiota and an opportunistic pathogen that takes advantage of the immunocompromised host and causes oral mucositis and oral candidiasis. This organism is able to undergo phenotypic modification from a yeast to hyphae growth phase, one of the key arsenals for immune cell evasion, tissue invasion and biofilm formation. The latter property coupled with overgrowth and immune compromising factors such as HIV/AIDS, cancer treatments, organ transplantation, diabetes, corticosteroid use, dentures, and broad-spectrum antibiotic use have modified the fungus from a normal component of the microflora to a foe of an oral cavity and resulting in reduced sensitivity towards commonly utilised antifungal agents. Hence, the need for alternative therapy to curb this plight is of importance. Making use of biomolecules produced by Streptococcus mutans, application of lactoferrin which is a nonspecific host defense factor found in saliva with metal chelating and broader antimicrobial properties, use of probiotics which have the capacity to boost the host immunity through eliciting Immunoglobulin A synthesis, and perturbing the pathogen's environment via competition of space and food, and application of photodynamic therapy can help to manage the burden of oral candidiasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Yersinia adhesin A (YadA)--beauty & beast.

PubMed

Mühlenkamp, Melanie; Oberhettinger, Philipp; Leo, Jack C; Linke, Dirk; Schütz, Monika S

2015-02-01

The trimeric autotransporter adhesin Yersinia adhesin A is the prototype of the type Vc secretion systems. It is expressed by enteropathogenic Yersinia enterocolitica and Yersinia pseudotuberculosis strains, but not by Yersinia pestis. A characteristic trait of YadA is its modular composition and trimeric nature. YadA consists of an N-terminal passenger domain which is exposed on the bacterial cell surface. The translocation of this passenger onto the surface is facilitated by a C-terminal β-barrel domain which concomitantly anchors YadA into the outer membrane with three YadA monomers contributing to the formation of a single β-barrel. In Y. enterocolitica, but not Y. pseudotuberculosis, YadA is a decisive virulence factor and its deletion renders the bacteria virtually avirulent in mouse models of infection. This striking importance of YadA in infection may derive from its manifold functions in host cell interaction. Presumably the most important function of YadA is that it mediates adhesion to extracellular matrix components of eukaryotic host cells. Only tight adhesion allows for the injection of "anti-host" effector proteins via a type III secretion system into the host cell cytosol. These effector proteins enable Yersinia to subvert the host immune system in order to replicate and establish infection. YadA is also essential for the survival of Y. enterocolitica upon contact with serum, an important immune-evasion mechanism called serum resistance. To this end, YadA interacts with several components of the host complement system, the first line of immune defense. This review will summarize recent findings about the structure and biogenesis of YadA and its interactions with the host complement system. Copyright © 2015 Elsevier GmbH. All rights reserved.

Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb.

PubMed

Li, Xueqin; Liu, Peng; Gan, Shuzhen; Zhang, Chunmao; Zheng, Yuling; Jiang, Yongqiang; Yuan, Yuan

2016-08-12

Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb*

PubMed Central

Li, Xueqin; Liu, Peng; Gan, Shuzhen; Zhang, Chunmao; Zheng, Yuling; Jiang, Yongqiang; Yuan, Yuan

2016-01-01

Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood. PMID:27342778

Overview of Basic Immunology for Clinical Investigators.

PubMed

Stephen, Bettzy; Hajjar, Joud

2017-01-01

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.

Inbreeding effects on immune response in free-living song sparrows (Melospiza melodia).

PubMed

Reid, Jane M; Arcese, Peter; Keller, Lukas F; Elliott, Kyle H; Sampson, Laura; Hasselquist, Dennis

2007-03-07

The consequences of inbreeding for host immunity to parasitic infection have broad implications for the evolutionary and dynamical impacts of parasites on populations where inbreeding occurs. To rigorously assess the magnitude and the prevalence of inbreeding effects on immunity, multiple components of host immune response should be related to inbreeding coefficient (f) in free-living individuals. We used a pedigreed, free-living population of song sparrows (Melospiza melodia) to test whether individual responses to widely used experimental immune challenges varied consistently with f. The patagial swelling response to phytohaemagglutinin declined markedly with f in both females and males in both 2002 and 2003, although overall inbreeding depression was greater in males. The primary antibody response to tetanus toxoid declined with f in females but not in males in both 2004 and 2005. Primary antibody responses to diphtheria toxoid were low but tended to decline with f in 2004. Overall inbreeding depression did not solely reflect particularly strong immune responses in outbred offspring of immigrant-native pairings or weak responses in highly inbred individuals. These data indicate substantial and apparently sex-specific inbreeding effects on immune response, implying that inbred hosts may be relatively susceptible to parasitic infection to differing degrees in males and females.

HIV neuropathogenesis: a tight rope walk of innate immunity.

PubMed

Yao, Honghong; Bethel-Brown, Crystal; Li, Cicy Zidong; Buch, Shilpa J

2010-12-01

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of these protective immune responses, however, can be a double-edged sword. As protective immune mediators, cytokines have the ability to function in networks and co-operate with other host/viral mediators to tip the balance from a protective to toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the key immune cell types of the CNS with their respective soluble immune mediators: (1) cooperative interaction of IFN-γ with the host/virus factor (platelet-derived host factor (PDGF)/viral Tat) in the induction of neurotoxic chemokine CXCL10 by macrophages, (2) response of astrocytes to viral infection, and (3) protective role of PDGF and MCP-1 in neuronal survival against HIV Tat toxicity. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. The ultimate outcome of HIV infection in the CNS will thus be dependent on the regulation of the net balance of cell-specific protective versus detrimental responses.

Evolutionary genetics of insect innate immunity.

PubMed

Viljakainen, Lumi

2015-11-01

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

Cutaneous immunology: basics and new concepts.

PubMed

Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran

2016-01-01

As one of the largest organs, the skin forms a mechanical and immunological barrier to the environment. The skin immune system harbors cells of the innate immune system and cells of the adaptive immune system. Signals of the innate immune system typically initiate skin immune responses, while cells and cytokines of the adaptive immune system perpetuate the inflammation. Skin immune responses ensure effective host defense against pathogens but can also cause inflammatory skin diseases. An extensive crosstalk between the different cell types of the immune system, tissue cells, and pathogens is responsible for the complexity of skin immune reactions. Here we summarize the major cellular and molecular components of the innate and adaptive skin immune system.

Colistin Heteroresistance in Enterobacter cloacae Is Associated with Cross-Resistance to the Host Antimicrobial Lysozyme

PubMed Central

Napier, Brooke A.; Band, Victor

2014-01-01

Here, we describe the first identification of colistin-heteroresistant Enterobacter cloacae in the United States. Treatment of this isolate with colistin increased the frequency of the resistant subpopulation and induced cross-resistance to the host antimicrobial lysozyme. This is the first description of heteroresistance conferring cross-resistance to a host antimicrobial and suggests that clinical treatment with colistin may inadvertently select for bacteria that are resistant to components of the host innate immune system. PMID:24982068

Host-pathogen interaction in Fusarium oxysporum infections: where do we stand?

PubMed

Husaini, Amjad M; Sakina, Aafreen; Cambay, Souliha R

2018-03-16

Fusarium oxysporum, a ubiquitous soil-borne pathogen causes devastating vascular wilt in more than 100 plant species and ranks fifth among top ten fungal plant pathogens. It has emerged as a human pathogen too, causing infections in immune-compromised patients. It is, therefore, important to gain insight into the molecular processes involved in the pathogenesis of this trans-kingdom pathogen. A complex network comprising of interconnected and over lapping signal pathways; mitogen-activated protein kinase (MAPK) signaling pathways, Ras proteins, G-protein signaling components and their downstream pathways, components of the velvet (LaeA/VeA/VelB) complex and cAMP pathways, is involved in perceiving the host. This network regulates the expression of various pathogenicity genes. Plants have however evolved an elaborate protection system to combat this attack. They too possess intricate mechanisms at molecular level, which once triggered by pathogen attack transduce signals to activate defense response. This review focuses on understanding and presenting a wholistic picture of the molecular mechanisms of F. oxysporum-host interactions in plant immunity.

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection

PubMed Central

2012-01-01

Background During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. Methods To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Results Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Conclusions Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses. PMID:22873687

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection.

PubMed

Feng, Yonghui; Zhu, Xiaotong; Wang, Qinghui; Jiang, Yongjun; Shang, Hong; Cui, Liwang; Cao, Yaming

2012-08-08

During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

Food-mediated modulation of immunity in a phytophagous insect: An effect of nutrition rather than parasitic contamination.

PubMed

Vogelweith, Fanny; Moreau, Jérôme; Thiéry, Denis; Moret, Yannick

2015-06-01

Inherent to the cost of immunity, the immune system itself can exhibit tradeoffs between its arms. Phytophagous insects face a wide range of microbial and eukaryotic parasites, each activating different immune pathways that could compromise the activity of the others. Feeding larvae are primarily exposed to microbes, which growth is controlled by antibiotic secondary metabolites produced by the host plant. The resulting variation in abundance of microbes on plants is expected to differentially stimulate the insect antimicrobial immune defenses. Under the above tradeoff hypothesis, stimulation of the insect antimicrobial defenses is expected to compromise immune activity against eukaryote parasites. In the European grape berry moth, Eupoecilia ambiguella, immune effectors directed towards microbes are negatively correlated to those directed towards eukaryotic parasites among host plants. Here, we hypothesize this relationship is caused by a variable control of the microbial community among host plants by their antibiotic metabolites. To test this hypothesis, we first quantified antimicrobial activity in berries of several grape varieties. We then measured immune defenses of E. ambiguella larvae raised on artificial diets in which we mimicked levels of antimicrobial activity of grape berries using tetracycline to control the abundance of growing microbes. Another group of larvae was raised on artificial diets made of berry extracts only to control for the effect of nutrition. We found that controlling microbe abundance with tetracycline in diets did not explain variation in the immune function whereas the presence of berry extracts did. This suggests that variation in immune defenses of E. ambiguella among grape varieties is caused by nutritional difference among host plants rather than microbe abundance. Further study of the effects of berry compounds on larval immune parameters will be needed to explain the observed tradeoff among immune system components. Copyright © 2015 Elsevier Ltd. All rights reserved.

Drosophila as a model system to unravel the layers of innate immunity to infection.

PubMed

Kounatidis, Ilias; Ligoxygakis, Petros

2012-05-01

Innate immunity relies entirely upon germ-line encoded receptors, signalling components and effector molecules for the recognition and elimination of invading pathogens. The fruit fly Drosophila melanogaster with its powerful collection of genetic and genomic tools has been the model of choice to develop ideas about innate immunity and host-pathogen interactions. Here, we review current research in the field, encompassing all layers of defence from the role of the microbiota to systemic immune activation, and attempt to speculate on future directions and open questions.

VPS9a Activates the Rab5 GTPase ARA7 to Confer Distinct Pre- and Postinvasive Plant Innate Immunity.

PubMed

Nielsen, Mads E; Jürgens, Gerd; Thordal-Christensen, Hans

2017-08-01

Plant innate immunity can effectively prevent the proliferation of filamentous pathogens. Papilla formation at the site of attack is essential for preinvasive immunity; in postinvasive immunity, the encasement of pathogen structures inside host cells can hamper disease. Whereas papillae are highly dependent on transcytosis of premade material, little is known about encasement formation. Here, we show that endosome-associated VPS9a, the conserved guanine-nucleotide exchange factor activating Rab5 GTPases, is required for both pre- and postinvasive immunity against a nonadapted powdery mildew fungus ( Blumeria graminis f. sp hordei ) in Arabidopsis thaliana Surprisingly, VPS9a acts in addition to two previously well-described innate immunity components and thus represents an additional step in the regulation of how plants resist pathogens. We found VPS9a to be important for delivering membrane material to the encasement and VPS9a also plays a predominant role in postinvasive immunity. GTP-bound Rab5 GTPases accumulate in the encasement, but not the papillae, suggesting that two independent pathways form these defense structures. VPS9a also mediates defense to an adapted powdery mildew fungus, thus regulating a durable type of defense that works in both host and nonhost resistance. We propose that VPS9a plays a conserved role in organizing cellular endomembrane trafficking, required for delivery of defense components in response to powdery mildew fungi. © 2017 American Society of Plant Biologists. All rights reserved.

VPS9a Activates the Rab5 GTPase ARA7 to Confer Distinct Pre- and Postinvasive Plant Innate Immunity[OPEN

PubMed Central

2017-01-01

Plant innate immunity can effectively prevent the proliferation of filamentous pathogens. Papilla formation at the site of attack is essential for preinvasive immunity; in postinvasive immunity, the encasement of pathogen structures inside host cells can hamper disease. Whereas papillae are highly dependent on transcytosis of premade material, little is known about encasement formation. Here, we show that endosome-associated VPS9a, the conserved guanine-nucleotide exchange factor activating Rab5 GTPases, is required for both pre- and postinvasive immunity against a nonadapted powdery mildew fungus (Blumeria graminis f. sp hordei) in Arabidopsis thaliana. Surprisingly, VPS9a acts in addition to two previously well-described innate immunity components and thus represents an additional step in the regulation of how plants resist pathogens. We found VPS9a to be important for delivering membrane material to the encasement and VPS9a also plays a predominant role in postinvasive immunity. GTP-bound Rab5 GTPases accumulate in the encasement, but not the papillae, suggesting that two independent pathways form these defense structures. VPS9a also mediates defense to an adapted powdery mildew fungus, thus regulating a durable type of defense that works in both host and nonhost resistance. We propose that VPS9a plays a conserved role in organizing cellular endomembrane trafficking, required for delivery of defense components in response to powdery mildew fungi. PMID:28808134

[Protective immunity against Mycobacterium tuberculosis].

PubMed

Kawamura, Ikuo

2006-11-01

Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen with which over a billion people have been infected and 3 million people die annually. The bacterium induces vigorous immune responses, yet evades host immunity, persisting within phagosomes of the infected macrophages. Thus, it is necessary to delineate that the virulence-related intracellular survival mechanism and the host immune responses to eradicate M. tuberculosis on the molecular basis. In this regard, recent findings clearly indicated that Toll-like receptors (TLRs) play an essential role in the recognition of MTB components by macrophages and dendritic cells, resulting in not only activation of innate immunity but also development of antigen-specific adaptive immunity. It has been also reported that induction of early death of the infected cells may be one of the strategy of host defense against MTB because macrophages go into apoptosis upon infection with MTB, resulting in suppression of the intracellular replication. Furthermore, recent report has shown that autophagy is induced by IFN-gamma and suppress intracellular survival of mycobacteria, suggesting that activation of autophagy pathway is required to overcome phagosome maturation arrest induced by MTB. In addition, it is known that IFN-gamma plays an important role in protection. The cytokine that is produced from NK cells and dendritic cells at the early period of infection strongly induces not only macrophage activation but also development of antigen-specific IFN-gamma-producing CD4+T cells. Since antigen-specific CD8+ T cells and CD1-restricted T cells are also reported to contribute to the protective immunity, cooperation of these T cells is essential for the host resistance. In this paper, I am going to summarize the recent progress of the understanding of protective immunity against MTB.

Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity.

PubMed

Ogawa, Mikako; Tomita, Yusuke; Nakamura, Yuko; Lee, Min-Jung; Lee, Sunmin; Tomita, Saori; Nagaya, Tadanobu; Sato, Kazuhide; Yamauchi, Toyohiko; Iwai, Hidenao; Kumar, Abhishek; Haystead, Timothy; Shroff, Hari; Choyke, Peter L; Trepel, Jane B; Kobayashi, Hisataka

2017-02-07

Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membrane function leading to swelling and bursting, releasing intracellular components due to the influx of water into the cell. The process also induces relocation of ICD bio markers including calreticulin, Hsp70 and Hsp90 to the cell surface and the rapid release of immunogenic signals including ATP and HMGB1 followed by maturation of immature dendritic cells. Thus, NIR-PIT is a therapy that kills tumor cells by ICD, eliciting a host immune response against tumor.

A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease.

PubMed

Alvarado, Raquel; O'Brien, Bronwyn; Tanaka, Akane; Dalton, John P; Donnelly, Sheila

2015-02-01

Parasitic worms (helminths) reside in their mammalian hosts for many years. This is attributable, in part, to their ability to skew the host's immune system away from pro-inflammatory responses and towards anti-inflammatory or regulatory responses. This immune modulatory ability ensures helminth longevity within the host, while simultaneously minimises tissue destruction for the host. The molecules that the parasite releases clearly exert potent immune-modulatory actions, which could be exploited clinically, for example in the prophylactic and therapeutic treatment of pro-inflammatory and autoimmune diseases. We have identified a novel family of immune-modulatory proteins, termed helminth defence molecules (HDMs), which are secreted by several medically important helminth parasites. These HDMs share biochemical and structural characteristics with mammalian cathelicidin-like host defence peptides (HDPs), which are significant components of the innate immune system. Like their mammalian counterparts, parasite HDMs block the activation of macrophages via toll like receptor (TLR) 4 signalling, however HDMs are significantly less cytotoxic than HDPs. HDMs can traverse the cell membrane of macrophages and enter the endolysosomal system where they reduce the acidification of lysosomal compartments by inhibiting vacuolar (v)-ATPase activity. In doing this, HDMs can modulate critical cellular functions, such as cytokine secretion and antigen processing/presentation. Here, we review the role of macrophages, specifically their lysosomal mediated activities, in the initiation and perpetuation of pro-inflammatory immune responses. We also discuss the potential of helminth defence molecules (HDMs) as therapeutics to counteract the pro-inflammatory responses underlying autoimmune disease. Given the current lack of effective, non-cytotoxic treatment options to limit the progression of autoimmune pathologies, HDMs open novel treatment avenues. Crown Copyright © 2014. Published by Elsevier GmbH. All rights reserved.

DYSMICROBISM, INFLAMMATORY BOWEL DISEASE AND THYROIDITIS: ANALYSIS OF THE LITERATURE.

PubMed

Tomasello, G; Tralongo, P; Amoroso, F; Damiani, P; Sinagra, E; Noto, M; Arculeo, V M; Jurjus Zein, R; Saad, W; Jurjus, A; Gerbino, A; Leone, A

2015-01-01

The human body is colonized by a large number of microbes that are collectively referred to as the microbiota. They interact with the hosting organism and some do contribute to the physiological maintenance of the general good health thru regulation of some metabolic processes while some others are essential for the synthesis of vitamins and short-chain fatty acids. The abnormal variation, in the quality and/or quantity of individual bacterial species residing in the gastro-intestinal tract, is called “dysmicrobism”. The immune system of the host will respond to these changes at the intestinal mucosa level which could lead to Inflammatory Bowel Diseases (IBD). This inflammatory immune response could subsequently extend to other organs and systems outside the digestive tract such as the thyroid, culminating in thyroiditis. The goal of the present study is to review and analyze data reported in the literature about thyroiditis associated with inflammatory bowel diseases such as Ulcerative Colitis (UC) and Crohn’s Disease (CD). It was reported that similarities of some molecular bacterial components with molecular components of the host are considered among the factors causing IBD through an autoimmune reaction which could involve other non-immune cell types. The axis dysmicrobism-IBD-autoimmune reaction will be investigated as a possible etiopathogenic mechanism to Autoimmune Thyroiditis. If such is the case, then the employment of specific probiotic strains may represent a useful approach to moderate the immune system.

Structural modifications of Helicobacter pylori lipopolysaccharide: An idea for how to live in peace

PubMed Central

Chmiela, Magdalena; Miszczyk, Eliza; Rudnicka, Karolina

2014-01-01

In this review, we discuss the findings and concepts underlying the “persistence mechanisms” of Helicobacter pylori (H. pylori), a spiral-shaped, Gram-negative rod bacterium that was discovered as a gastric pathogen by Marshall and Warren in 1984. H. pylori colonizes the gastric mucosa of nearly half of the human population. Infections appear in early childhood and, if not treated, persist for life. The presence or absence of symptoms and their severity depend on multiple bacterial components, host susceptibility and environmental factors, which allow H. pylori to switch between pathogenicity and commensalism. Many studies have shown that H. pylori components may facilitate the colonization process and the immune response of the host during the course of H. pylori infection. These H. pylori-driven interactions might result from positive or negative modulation. Among the negative immunomodulators, a prominent position is occupied by a vacuolating toxin A (VacA) and cytotoxin-associated gene A (CagA) protein. However, in light of the recent studies that are presented in this review, it is necessary to enrich this panel with H. pylori lipopolysaccharide (LPS). Together with CagA and VacA, LPS suppresses the elimination of H. pylori bacteria from the gastric mucosa by interfering with the activity of innate and adaptive immune cells, diminishing the inflammatory response, and affecting the adaptive T lymphocyte response, thus facilitating the development of chronic infections. The complex strategy of H. pylori bacteria for survival in the gastric mucosa of the host involves both structural modifications of LPS lipid A to diminish its endotoxic properties and the expression and variation of Lewis determinants, arranged in O-specific chains of H. pylori LPS. By mimicking host components, this phenomenon leaves these bacteria “invisible” to immune cells. Together, these mechanisms allow H. pylori to survive and live for many years within their hosts. PMID:25110419

Disentangling the influence of parasite genotype, host genotype and maternal environment on different stages of bacterial infection in Daphnia magna.

PubMed

Hall, Matthew D; Ebert, Dieter

2012-08-22

Individuals naturally vary in the severity of infectious disease when exposed to a parasite. Dissecting this variation into genetic and environmental components can reveal whether or not this variation depends on the host genotype, parasite genotype or a range of environmental conditions. Complicating this task, however, is that the symptoms of disease result from the combined effect of a series of events, from the initial encounter between a host and parasite, through to the activation of the host immune system and the exploitation of host resources. Here, we use the crustacean Daphnia magna and its parasite Pasteuria ramosa to show how disentangling genetic and environmental factors at different stages of infection improves our understanding of the processes shaping infectious disease. Using compatible host-parasite combinations, we experimentally exclude variation in the ability of a parasite to penetrate the host, from measures of parasite clearance, the reduction in host fecundity and the proliferation of the parasite. We show how parasite resistance consists of two components that vary in environmental sensitivity, how the maternal environment influences all measured aspects of the within-host infection process and how host-parasite interactions following the penetration of the parasite into the host have a distinct temporal component.

Monoclonal antibodies for diagnosis and treatment.

PubMed

Dunn, D L

1993-11-01

One of the marvels of the host immune response is its response to antigenic foreign substances by manufacturing proteins that bind tenaciously to their targets. These proteins are antibodies or immunoglobulins produced in vast diversity during an individual's lifetime. By virtue of this process, the mammalian host possesses the innate ability to mount an initial response to antigens to which there has been no prior experience and to develop an even more effective response on reexposure to these same substances. This capacity to distinguish self from nonself is one of the most basic aspects of the cellular and humoral arms of the immune response and is one of the primary means by which the host combats infection caused by many different types of pathogens. In this context, antibodies have long been recognized as a critical component of host defenses and are capable of binding to invading microbes and microbial toxins.

Copper tolerance and virulence in bacteria

PubMed Central

Ladomersky, Erik; Petris, Michael J.

2015-01-01

Copper (Cu) is an essential trace element for all aerobic organisms. It functions as a cofactor in enzymes that catalyze a wide variety of redox reactions due to its ability to cycle between two oxidation states, Cu(I) and Cu(II). This same redox property of copper has the potential to cause toxicity if copper homeostasis is not maintained. Studies suggest that the toxic properties of copper are harnessed by the innate immune system of the host to kill bacteria. To counter such defenses, bacteria rely on copper tolerance genes for virulence within the host. These discoveries suggest bacterial copper intoxication is a component of host nutritional immunity, thus expanding our knowledge of the roles of copper in biology. This review summarizes our current understanding of copper tolerance in bacteria, and the extent to which these pathways contribute to bacterial virulence within the host. PMID:25652326

Comparative Genomics and Host Resistance against Infectious Diseases

PubMed Central

Qureshi, Salman T.; Skamene, Emil

1999-01-01

The large size and complexity of the human genome have limited the identification and functional characterization of components of the innate immune system that play a critical role in front-line defense against invading microorganisms. However, advances in genome analysis (including the development of comprehensive sets of informative genetic markers, improved physical mapping methods, and novel techniques for transcript identification) have reduced the obstacles to discovery of novel host resistance genes. Study of the genomic organization and content of widely divergent vertebrate species has shown a remarkable degree of evolutionary conservation and enables meaningful cross-species comparison and analysis of newly discovered genes. Application of comparative genomics to host resistance will rapidly expand our understanding of human immune defense by facilitating the translation of knowledge acquired through the study of model organisms. We review the rationale and resources for comparative genomic analysis and describe three examples of host resistance genes successfully identified by this approach. PMID:10081670

Policing of gut microbiota by the adaptive immune system.

PubMed

Dollé, Laurent; Tran, Hao Q; Etienne-Mesmin, Lucie; Chassaing, Benoit

2016-02-12

The intestinal microbiota is a large and diverse microbial community that inhabits the intestine, containing about 100 trillion bacteria of 500-1000 distinct species that, collectively, provide benefits to the host. The human gut microbiota composition is determined by a myriad of factors, among them genetic and environmental, including diet and medication. The microbiota contributes to nutrient absorption and maturation of the immune system. As reciprocity, the host immune system plays a central role in shaping the composition and localization of the intestinal microbiota. Secretory immunoglobulins A (sIgAs), component of the adaptive immune system, are important player in the protection of epithelium, and are known to have an important impact on the regulation of microbiota composition. A recent study published in Immunity by Fransen and colleagues aimed to mechanistically decipher the interrelationship between sIgA and microbiota diversity/composition. This commentary will discuss these important new findings, as well as how future therapies can ultimately benefit from such discovery.

The activity of phenoloxidase in haemolymph plasma is not a predictor of Lymantria dispar resistance to its baculovirus

Treesearch

Nikita S. Kasianov; Irina A. Belousova; Sergey V. Pavlushin; Ivan M. Dubovskiy; John D. Podgwaite; Vyacheslav V. Martemyanov; Stanislav A. Bakhvalov; Erjun Ling

2017-01-01

Host innate immunity is one of the factors that determines the resistance of insects to their entomopathogens. In the research reported here we studied whether or not phenoloxidase (PO), a key enzyme in the melanogenesis component of humoral immunity of insects, plays a role in the protection of Lymantria dispar larvae from infection by L...

Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model.

PubMed

Alegado, Rosanna A; Campbell, Marianne C; Chen, Will C; Slutz, Sandra S; Tan, Man-Wah

2003-07-01

The soil-borne nematode, Caenorhabditis elegans, is emerging as a versatile model in which to study host-pathogen interactions. The worm model has shown to be particularly effective in elucidating both microbial and animal genes involved in toxin-mediated killing. In addition, recent work on worm infection by a variety of bacterial pathogens has shown that a number of virulence regulatory genes mediate worm susceptibility. Many of these regulatory genes, including the PhoP/Q two-component regulators in Salmonella and LasR in Pseudomonas aeruginosa, have also been implicated in mammalian models suggesting that findings in the worm model will be relevant to other systems. In keeping with this concept, experiments aimed at identifying host innate immunity genes have also implicated pathways that have been suggested to play a role in plants and animals, such as the p38 MAP kinase pathway. Despite rapid forward progress using this model, much work remains to be done including the design of more sensitive methods to find effector molecules and further characterization of the exact interaction between invading pathogens and C. elegans' cellular components.

Immunity to fish rhabdoviruses

USGS Publications Warehouse

Purcell, Maureen K.; Laing, Kerry J.; Winton, James R.

2012-01-01

Members of the family Rhabdoviridae are single-stranded RNA viruses and globally important pathogens of wild and cultured fish and thus relatively well studied in their respective hosts or other model systems. Here, we review the protective immune mechanisms that fish mount in response to rhabdovirus infections. Teleost fish possess the principal components of innate and adaptive immunity found in other vertebrates. Neutralizing antibodies are critical for long-term protection from fish rhabdoviruses, but several studies also indicate a role for cell-mediated immunity. Survival of acute rhabdoviral infection is also dependent on innate immunity, particularly the interferon (IFN) system that is rapidly induced in response to infection. Paradoxically, rhabdoviruses are sensitive to the effects of IFN but virulent rhabdoviruses can continue to replicate owing to the abilities of the matrix (M) protein to mediate host-cell shutoff and the non-virion (NV) protein to subvert programmed cell death and suppress functional IFN. While many basic features of the fish immune response to rhabdovirus infections are becoming better understood, much less is known about how factors in the environment affect the ecology of rhabdovirus infections in natural populations of aquatic animals.

Immunity to fish rhabdoviruses.

PubMed

Purcell, Maureen K; Laing, Kerry J; Winton, James R

2012-01-01

Members of the family Rhabdoviridae are single-stranded RNA viruses and globally important pathogens of wild and cultured fish and thus relatively well studied in their respective hosts or other model systems. Here, we review the protective immune mechanisms that fish mount in response to rhabdovirus infections. Teleost fish possess the principal components of innate and adaptive immunity found in other vertebrates. Neutralizing antibodies are critical for long-term protection from fish rhabdoviruses, but several studies also indicate a role for cell-mediated immunity. Survival of acute rhabdoviral infection is also dependent on innate immunity, particularly the interferon (IFN) system that is rapidly induced in response to infection. Paradoxically, rhabdoviruses are sensitive to the effects of IFN but virulent rhabdoviruses can continue to replicate owing to the abilities of the matrix (M) protein to mediate host-cell shutoff and the non‑virion (NV) protein to subvert programmed cell death and suppress functional IFN. While many basic features of the fish immune response to rhabdovirus infections are becoming better understood, much less is known about how factors in the environment affect the ecology of rhabdovirus infections in natural populations of aquatic animals.

The effects of Candida albicans cell wall protein fraction on dendritic cell maturation.

PubMed

Roudbary, Maryam; Roudbar Mohammadi, Shahla; Bozorgmehr, Mahmood; Moazzeni, Seyed Mohammad

2009-06-01

Candida albicans is a member of the normal human microflora. C. albicans cell wall is composed of several protein and carbohydrate components which have been shown to play a crucial role in C. albicans interaction with the host immune system. Major components of C. albican cell wall are carbohydrates such as mannans, beta glucans and chitins, and proteins that partially modulate the host immune responses. Dendritic cells (DC), as the most important antigen-presenting cells of the immune system, play a critical role in inducing immune responses against different pathogens. We investigated the effect of the cell wall protein fraction (CPF) of C. albicans on DC maturation. The CPF of C. albicans cells was extracted by a lysis buffer containing sodium dodecyl sulphate, 2-mercaptoethanol and phosphate-buffered saline. The extract was dialyzed and its protein pattern was evaluated by electrophoresis. Dendritic cells were purified from Balb/c mice spleens through a three-step method including mononuclear cell separation, as well as 2-h and overnight cultures. The purified CPF was added at different concentrations to DC. The purity and maturation status of DC were determined by flow cytometry using monoclonal antibodies against CD11c, MHC-II, CD40 and CD86. Treatment of DC with 10 microg/ml of CPF increased the expression of maturation markers including MHC-II, CD86 and CD40 on DC compared to the control group. In this study we used C. albicans CPF with the molecular weight of 40-45 kDa for pulsing and maturation of dendritic cells. Since according to our results CPF significantly increased the expression of maturation markers on DC, we suggest that CPF may act as an efficient immunomodulator, or may be used as a potential adjuvant to boost the host immune system against infections.

Borrelia burgdorferi protein interactions critical for microbial persistence in mammals.

PubMed

Bernard, Quentin; Thakur, Meghna; Smith, Alexis A; Kitsou, Chrysoula; Yang, Xiuli; Pal, Utpal

2018-06-22

Borrelia burgdorferi is the causative agent of Lyme disease that persists in a complex enzootic life cycle, involving Ixodes ticks and vertebrate hosts. The microbe invades ticks and vertebrate hosts in spite of active immune surveillance and potent microbicidal responses, and establishes long-term infection utilizing mechanisms that are yet to be unraveled. The pathogen can cause multi-system disorders when transmitted to susceptible mammalian hosts, including in humans. In the past decades, several studies identified a limited number of B. burgdorferi gene-products critical for pathogen persistence, transmission between the vectors and the host, and host-pathogen interactions. This review will focus on the interactions between B. burgdorferi proteins, as well between microbial proteins and host components, protein and non-protein components, highlighting their roles in pathogen persistence in the mammalian host. A better understanding of the contributions of protein interactions in the microbial virulence and persistence of B. burgdorferi would support development of novel therapeutics against the infection. This article is protected by copyright. All rights reserved.

Post-translational modification of host proteins in pathogen-triggered defence signalling in plants.

PubMed

Stulemeijer, Iris J E; Joosten, Matthieu H A J

2008-07-01

Microbial plant pathogens impose a continuous threat to global food production. Similar to animals, an innate immune system allows plants to recognize pathogens and swiftly activate defence. To activate a rapid response, receptor-mediated pathogen perception and subsequent downstream signalling depends on post-translational modification (PTM) of components essential for defence signalling. We discuss different types of PTMs that play a role in mounting plant immunity, which include phosphorylation, glycosylation, ubiquitination, sumoylation, nitrosylation, myristoylation, palmitoylation and glycosylphosphatidylinositol (GPI)-anchoring. PTMs are rapid, reversible, controlled and highly specific, and provide a tool to regulate protein stability, activity and localization. Here, we give an overview of PTMs that modify components essential for defence signalling at the site of signal perception, during secondary messenger production and during signalling in the cytoplasm. In addition, we discuss effectors from pathogens that suppress plant defence responses by interfering with host PTMs.

Immune indexes of larks from desert and temperate regions show weak associations with life history but stronger links to environmental variation in microbial abundance.

PubMed

Horrocks, Nicholas P C; Hegemann, Arne; Matson, Kevin D; Hine, Kathryn; Jaquier, Sophie; Shobrak, Mohammed; Williams, Joseph B; Tinbergen, Joost M; Tieleman, B Irene

2012-01-01

Immune defense may vary as a result of trade-offs with other life-history traits or in parallel with variation in antigen levels in the environment. We studied lark species (Alaudidae) in the Arabian Desert and temperate Netherlands to test opposing predictions from these two hypotheses. Based on their slower pace of life, the trade-off hypothesis predicts relatively stronger immune defenses in desert larks compared with temperate larks. However, as predicted by the antigen exposure hypothesis, reduced microbial abundances in deserts should result in desert-living larks having relatively weaker immune defenses. We quantified host-independent and host-dependent microbial abundances of culturable microbes in ambient air and from the surfaces of birds. We measured components of immunity by quantifying concentrations of the acute-phase protein haptoglobin, natural antibody-mediated agglutination titers, complement-mediated lysis titers, and the microbicidal ability of whole blood. Desert-living larks were exposed to significantly lower concentrations of airborne microbes than temperate larks, and densities of some bird-associated microbes were also lower in desert species. Haptoglobin concentrations and lysis titers were also significantly lower in desert-living larks, but other immune indexes did not differ. Thus, contrary to the trade-off hypothesis, we found little evidence that a slow pace of life predicted increased immunological investment. In contrast, and in support of the antigen exposure hypothesis, associations between microbial exposure and some immune indexes were apparent. Measures of antigen exposure, including assessment of host-independent and host-dependent microbial assemblages, can provide novel insights into the mechanisms underlying immunological variation.

The immune system: a target for functional foods?

PubMed

Calder, Philip C; Kew, Samantha

2002-11-01

The immune system acts to protect the host from infectious agents that exist in the environment (bacteria, viruses, fungi, parasites) and from other noxious insults. The immune system is constantly active, acting to discriminate 'non-self' from 'self'. The immune system has two functional divisions: the innate and the acquired. Both components involve various blood-borne factors (complement, antibodies, cytokines) and cells. A number of methodologies exist to assess aspects of immune function; many of these rely upon studying cells in culture ex vivo. There are large inter-individual variations in many immune functions even among the healthy. Genetics, age, gender, smoking habits, habitual levels of exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress, history of infections and vaccinations, and early life experiences are likely to be important contributors to the observed variation. While it is clear that individuals with immune responses significantly below 'normal' are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection. Nutrient status is an important factor contributing to immune competence: undernutrition impairs the immune system, suppressing immune functions that are fundamental to host protection. Undernutrition leading to impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. Often these occur in combination. Nutrients that have been demonstrated (in either animal or human studies) to be required for the immune system to function efficiently include essential amino acids, the essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin B12, vitamin C, vitamin E, Zn, Cu, Fe and Se. Practically all forms of immunity may be affected by deficiencies in one or more of these nutrients. Animal and human studies have demonstrated that adding the deficient nutrient back to the diet can restore immune function and resistance to infection. Among the nutrients studied most in this regard are vitamin E and Zn. Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function. However, excess amounts of some nutrients also impair immune function. There is increasing evidence that probiotic bacteria improve host immune function. The effect of enhancing immune function on host resistance to infection in healthy individuals is not clear.

Whole transcriptome analysis reveals changes in expression of immune-related genes during and after bleaching in a reef-building coral.

PubMed

Pinzón, Jorge H; Kamel, Bishoy; Burge, Colleen A; Harvell, C Drew; Medina, Mónica; Weil, Ernesto; Mydlarz, Laura D

2015-04-01

Climate change is negatively affecting the stability of natural ecosystems, especially coral reefs. The dissociation of the symbiosis between reef-building corals and their algal symbiont, or coral bleaching, has been linked to increased sea surface temperatures. Coral bleaching has significant impacts on corals, including an increase in disease outbreaks that can permanently change the entire reef ecosystem. Yet, little is known about the impacts of coral bleaching on the coral immune system. In this study, whole transcriptome analysis of the coral holobiont and each of the associate components (i.e. coral host, algal symbiont and other associated microorganisms) was used to determine changes in gene expression in corals affected by a natural bleaching event as well as during the recovery phase. The main findings include evidence that the coral holobiont and the coral host have different responses to bleaching, and the host immune system appears suppressed even a year after a bleaching event. These results support the hypothesis that coral bleaching changes the expression of innate immune genes of corals, and these effects can last even after recovery of symbiont populations. Research on the role of immunity on coral's resistance to stressors can help make informed predictions on the future of corals and coral reefs.

Whole transcriptome analysis reveals changes in expression of immune-related genes during and after bleaching in a reef-building coral

PubMed Central

Pinzón, Jorge H.; Kamel, Bishoy; Burge, Colleen A.; Harvell, C. Drew; Medina, Mónica; Weil, Ernesto; Mydlarz, Laura D.

2015-01-01

Climate change is negatively affecting the stability of natural ecosystems, especially coral reefs. The dissociation of the symbiosis between reef-building corals and their algal symbiont, or coral bleaching, has been linked to increased sea surface temperatures. Coral bleaching has significant impacts on corals, including an increase in disease outbreaks that can permanently change the entire reef ecosystem. Yet, little is known about the impacts of coral bleaching on the coral immune system. In this study, whole transcriptome analysis of the coral holobiont and each of the associate components (i.e. coral host, algal symbiont and other associated microorganisms) was used to determine changes in gene expression in corals affected by a natural bleaching event as well as during the recovery phase. The main findings include evidence that the coral holobiont and the coral host have different responses to bleaching, and the host immune system appears suppressed even a year after a bleaching event. These results support the hypothesis that coral bleaching changes the expression of innate immune genes of corals, and these effects can last even after recovery of symbiont populations. Research on the role of immunity on coral's resistance to stressors can help make informed predictions on the future of corals and coral reefs. PMID:26064625

Disentangling the influence of parasite genotype, host genotype and maternal environment on different stages of bacterial infection in Daphnia magna

PubMed Central

Hall, Matthew D.; Ebert, Dieter

2012-01-01

Individuals naturally vary in the severity of infectious disease when exposed to a parasite. Dissecting this variation into genetic and environmental components can reveal whether or not this variation depends on the host genotype, parasite genotype or a range of environmental conditions. Complicating this task, however, is that the symptoms of disease result from the combined effect of a series of events, from the initial encounter between a host and parasite, through to the activation of the host immune system and the exploitation of host resources. Here, we use the crustacean Daphnia magna and its parasite Pasteuria ramosa to show how disentangling genetic and environmental factors at different stages of infection improves our understanding of the processes shaping infectious disease. Using compatible host–parasite combinations, we experimentally exclude variation in the ability of a parasite to penetrate the host, from measures of parasite clearance, the reduction in host fecundity and the proliferation of the parasite. We show how parasite resistance consists of two components that vary in environmental sensitivity, how the maternal environment influences all measured aspects of the within-host infection process and how host–parasite interactions following the penetration of the parasite into the host have a distinct temporal component. PMID:22593109

Plant immunity in plant–aphid interactions

PubMed Central

Jaouannet, Maëlle; Rodriguez, Patricia A.; Lenoir, Camille J. G.; MacLeod, Ruari; Escudero-Martinez, Carmen; Bos, Jorunn I.B.

2014-01-01

Aphids are economically important pests that cause extensive feeding damage and transmit viruses. While some species have a broad host range and cause damage to a variety of crops, others are restricted to only closely related plant species. While probing and feeding aphids secrete saliva, containing effectors, into their hosts to manipulate host cell processes and promote infestation. Aphid effector discovery studies pointed out parallels between infection and infestation strategies of plant pathogens and aphids. Interestingly, resistance to some aphid species is known to involve plant resistance proteins with a typical NB-LRR domain structure. Whether these resistance proteins indeed recognize aphid effectors to trigger ETI remains to be elucidated. In addition, it was recently shown that unknown aphid derived elicitors can initiate reactive oxygen species (ROS) production and callose deposition and that these responses were dependent on BAK1 (BRASSINOSTERIOD INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1) which is a key component of the plant immune system. In addition, BAK-1 contributes to non-host resistance to aphids pointing to another parallel between plant-pathogen and – aphid interactions. Understanding the role of plant immunity and non-host resistance to aphids is essential to generate durable and sustainable aphid control strategies. Although insect behavior plays a role in host selection and non-host resistance, an important observation is that aphids interact with non-host plants by probing the leaf surface, but are unable to feed or establish colonization. Therefore, we hypothesize that aphids interact with non-host plants at the molecular level, but are potentially not successful in suppressing plant defenses and/or releasing nutrients. PMID:25520727

Molecular mimicry in Helicobacter pylori infections

PubMed Central

Chmiela, Magdalena; Gonciarz, Weronika

2017-01-01

Gram-negative bacteria Helicobacter pylori (H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tissue lymphoma. The role of H. pylori infection in the pathogenesis of several extragastric diseases has been suggested including immune thrombocytopenic purpura, iron deficiency anemia, vitamin D deficiency, cardiovascular diseases, diabetes mellitus and dermatological disorders. Also neurological diseases and even lung cancer have attracted researchers concern. The relation between H. pylori infection and a growth retardation in children has also been suggested. Many mechanisms of molecular mimicry between H. pylori and the host have been proposed as a pathogen strategy to manipulate the immune system of the host in order to remain unrecognized and avoid eradication. A lot of effort has been put into the demonstration of homologous sequences between H. pylori and host compounds. However, knowledge about how often autoantibodies or autoreactive T lymphocytes induced during H. pylori infections cause pathological disorders is insufficient. This review provides data on H. pylori antigenic mimicry and possible deleterious effects due to the induction of immune response to the components common to these bacteria and the host. PMID:28652651

The Vibrio cholerae VprA-VprB Two-Component System Controls Virulence Through Endotoxin Modification

DTIC Science & Technology

2014-12-23

antimicrobial peptides of the innate immune system bind to the membrane of Gram-negative pathogens via conserved, surface-exposed lipopolysaccharide (LPS... antimicrobial peptide polymyxin. However, the regulatory mechanisms of lipid A modification in V. 1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE...12211 Research Triangle Park, NC 27709-2211 bacterial cell surface, host immune system, cationic antimicrobial peptides , lipid A, LPS REPORT

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

Autophagy as a macrophage response to bacterial infection.

PubMed

Gong, Lan; Devenish, Rodney J; Prescott, Mark

2012-09-01

The macrophage is a key component of host defense mechanisms against pathogens. In addition to the phagocytosis of bacteria and secretion of proinflammatory mediators by macrophages, autophagy, a process involved in turnover of cellular material, is a recently identified component of the immune response to bacterial infection. Despite the bactericidal effect of autophagy, some species of intracellular bacteria are able to survive by using one or more strategies to avoid host autophagic attack. Here, we review the latest findings on the interactions between bacteria and autophagy in macrophages. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Deep sequencing-based transcriptome profiling analysis of bacteria-challenged Lateolabrax japonicus reveals insight into the immune-relevant genes in marine fish

PubMed Central

2010-01-01

Background Systematic research on fish immunogenetics is indispensable in understanding the origin and evolution of immune systems. This has long been a challenging task because of the limited number of deep sequencing technologies and genome backgrounds of non-model fish available. The newly developed Solexa/Illumina RNA-seq and Digital gene expression (DGE) are high-throughput sequencing approaches and are powerful tools for genomic studies at the transcriptome level. This study reports the transcriptome profiling analysis of bacteria-challenged Lateolabrax japonicus using RNA-seq and DGE in an attempt to gain insights into the immunogenetics of marine fish. Results RNA-seq analysis generated 169,950 non-redundant consensus sequences, among which 48,987 functional transcripts with complete or various length encoding regions were identified. More than 52% of these transcripts are possibly involved in approximately 219 known metabolic or signalling pathways, while 2,673 transcripts were associated with immune-relevant genes. In addition, approximately 8% of the transcripts appeared to be fish-specific genes that have never been described before. DGE analysis revealed that the host transcriptome profile of Vibrio harveyi-challenged L. japonicus is considerably altered, as indicated by the significant up- or down-regulation of 1,224 strong infection-responsive transcripts. Results indicated an overall conservation of the components and transcriptome alterations underlying innate and adaptive immunity in fish and other vertebrate models. Analysis suggested the acquisition of numerous fish-specific immune system components during early vertebrate evolution. Conclusion This study provided a global survey of host defence gene activities against bacterial challenge in a non-model marine fish. Results can contribute to the in-depth study of candidate genes in marine fish immunity, and help improve current understanding of host-pathogen interactions and evolutionary history of immunogenetics from fish to mammals. PMID:20707909

Hiding in plain sight: immune evasion by the staphylococcal protein SdrE.

PubMed

Herr, Andrew B; Thorman, Alexander W

2017-05-10

The human immune system is responsible for identification and destruction of invader cells, such as the bacterial pathogen Staphylococcus aureus In response, S. aureus brings to the fight a large number of virulence factors, including several that allow it to evade the host immune response. The staphylococcal surface protein SdrE was recently reported to bind to complement Factor H, an important regulator of complement activation. Factor H attaches to the surface of host cells to inhibit complement activation and amplification, preventing the destruction of the host cell. SdrE binding to Factor H allows S. aureus to mimic a host cell and reduces bacterial killing by granulocytes. In a new study published in Biochemical Journal , Zhang et al. describe crystal structures of SdrE and its complex with the C-terminal portion of Factor H. The structure of SdrE and its interaction with the Factor H peptide closely resemble a family of surface proteins that recognize extracellular matrix components such as fibrinogen. However, unbound SdrE forms a novel 'Closed' conformation with an occluded peptide-binding groove. These structures reveal a fascinating mechanism for immune evasion and provide a potential avenue for the development of novel antimicrobial agents to target SdrE. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Evasion of host immune defenses by human papillomavirus.

PubMed

Westrich, Joseph A; Warren, Cody J; Pyeon, Dohun

2017-03-02

A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Evasion of Host Immune Defenses by Human Papillomavirus

PubMed Central

Westrich, Joseph A.; Warren, Cody J.; Pyeon, Dohun

2016-01-01

A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses. PMID:27890631

Tick-borne encephalitis virus and the immune response of the mammalian host.

PubMed

Dörrbecker, Bastian; Dobler, Gerhard; Spiegel, Martin; Hufert, Frank T

2010-07-01

Tick-borne encephalitis (TBE) is caused by Tick-borne encephalitis virus (TBEV), one of the most prevalent arboviruses in Europe and in many parts of Asia. Transmission of TBEV to humans usually occurs by bite of an infected tick or rarely by ingestion of unpasteurized milk products of infected livestock. TBEV infection induces an innate and adaptive immune response, nevertheless it is able to replicate in several cell types of the immune system at the same time which probably contributes to the spread of the virus in the human host. Furthermore, TBEV can enter the central nervous system (CNS) by yet not well understood mechanisms via the blood brain barrier (BBB) or the olfactory neurons which leads to serious neurological disorders like meningitis, encephalitis or even meningoencephalitis. In this article we review the known facts and possible hypotheses of interaction of TBEV with components of the mammalian immune system and their implications for TBEV-mediated pathogenesis. Copyright © 2010 Elsevier Ltd. All rights reserved.

Viral evasion of intracellular DNA and RNA sensing

PubMed Central

Chan, Ying Kai; Gack, Michaela U.

2016-01-01

The co-evolution of viruses with their hosts has led to the emergence of viral pathogens that are adept at evading or actively suppressing host immunity. Pattern recognition receptors (PRRs) are key components of antiviral immunity that detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, we discuss the strategies that viruses use to escape immune surveillance by key intracellular sensors of viral RNA or DNA, with a focus on RIG-I-like receptors (RLRs), cyclic GMP–AMP synthase (cGAS) and interferon-γ (IFNγ)-inducible protein 16 (IFI16). Such viral strategies include the sequestration or modification of viral nucleic acids, interference with specific post-translational modifications of PRRs or their adaptor proteins, the degradation or cleavage of PRRs or their adaptors, and the sequestration or relocalization of PRRs. An understanding of viral immune-evasion mechanisms at the molecular level may guide the development of vaccines and antivirals. PMID:27174148

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococci

PubMed Central

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2013-01-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 may disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococci, especially Staphylococcus aureus. Here, we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococci. PMID:23040277

The innate immune response during urinary tract infection and pyelonephritis

PubMed Central

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

2013-01-01

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

The innate immune response during urinary tract infection and pyelonephritis.

PubMed

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

2014-07-01

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

Tissue-enriched expression profiles in Aedes aegypti identify hemocyte-specific transcriptome responses to infection

PubMed Central

Choi, Young-Jun; Fuchs, Jeremy F.; Mayhew, George F.; Yu, Helen E.; Christensen, Bruce M.

2012-01-01

Hemocytes are integral components of mosquito immune mechanisms such as phagocytosis, melanization, and production of antimicrobial peptides. However, our understanding of hemocyte-specific molecular processes and their contribution to shaping the host immune response remains limited. To better understand the immunophysiological features distinctive of hemocytes, we conducted genome-wide analysis of hemocyte-enriched transcripts, and examined how tissue-enriched expression patterns change with the immune status of the host. Our microarray data indicate that the hemocyte-enriched trascriptome is dynamic and context-dependent. Analysis of transcripts enriched after bacterial challenge in circulating hemocytes with respect to carcass added a dimension to evaluating infection-responsive genes and immune-related gene families. We resolved patterns of transcriptional change unique to hemocytes from those that are likely shared by other immune responsive tissues, and identified clusters of genes preferentially induced in hemocytes, likely reflecting their involvement in cell type specific functions. In addition, the study revealed conserved hemocyte-enriched molecular repertoires which might be implicated in core hemocyte function by cross-species meta-analysis of microarray expression data from Anopheles gambiae and Drosophila melanogaster. PMID:22796331

Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy.

PubMed

Zhao, Limei; Shao, Shuai; Chen, Yi; Sun, Ximeng; Sun, Ran; Huang, Jingjing; Zhan, Bin; Zhu, Xinping

2017-01-01

As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin ( Ts -CRT), a Ca 2+ -binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts -CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts -CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts -CRT (r Ts -CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte-macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts -CRT on the surface of newborn larvae (NBL) of T. spiralis with anti- Ts -CRT antibody increased the C1q-mediated adherence of monocyte-macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis -expressed Ts -CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages.

Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy

PubMed Central

Zhao, Limei; Shao, Shuai; Chen, Yi; Sun, Ximeng; Sun, Ran; Huang, Jingjing; Zhan, Bin; Zhu, Xinping

2017-01-01

As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin (Ts-CRT), a Ca2+-binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts-CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts-CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts-CRT (rTs-CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte–macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts-CRT on the surface of newborn larvae (NBL) of T. spiralis with anti-Ts-CRT antibody increased the C1q-mediated adherence of monocyte–macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis-expressed Ts-CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages. PMID:28620388

Identifying Bacterial Immune Evasion Proteins Using Phage Display.

PubMed

Fevre, Cindy; Scheepmaker, Lisette; Haas, Pieter-Jan

2017-01-01

Methods aimed at identification of immune evasion proteins are mainly rely on in silico prediction of sequence, structural homology to known evasion proteins or use a proteomics driven approach. Although proven successful these methods are limited by a low efficiency and or lack of functional identification. Here we describe a high-throughput genomic strategy to functionally identify bacterial immune evasion proteins using phage display technology. Genomic bacterial DNA is randomly fragmented and ligated into a phage display vector that is used to create a phage display library expressing bacterial secreted and membrane bound proteins. This library is used to select displayed bacterial secretome proteins that interact with host immune components.

Mechanism of immune evasion in breast cancer

PubMed Central

Wang, Mozhi; Zhang, Changwang; Song, Yongxi; Wang, Zhenning; Wang, Yaojia; Luo, Fang; Xu, Yujie; Zhao, Yi; Wu, Zhonghua; Xu, Yingying

2017-01-01

Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail. PMID:28352189

Variability of whipworm infection and humoral immune response in a wild population of mole voles (Ellobius talpinus Pall.).

PubMed

Novikov, Eugene; Petrovski, Dmitry; Mak, Viktoria; Kondratuk, Ekaterina; Krivopalov, Anton; Moshkin, Mikhail

2016-08-01

Restricted mobility and spatial isolation of social units in gregarious subterranean mammals ensure good defence mechanisms against parasites, which in turn allows for a reduction of immunity components. In contrast, a parasite invasion may cause an increased adaptive immune response. Therefore, it can be expected that spatial and temporal distribution of parasites within a population will correlate with the local variability in the host's immunocompetence. To test this hypothesis, the intra-population variability of a whipworm infestation and the humoral immune response to non-replicated antigens in mole voles (Ellobius talpinus Pall.), social subterranean rodents, was estimated. Whipworm prevalence in mole voles increased from spring to autumn, and this tendency was more pronounced in settlements living in natural meadows compared to settlements in man-made meadows. However, humoral immune response was lowest in animals from natural meadows trapped in autumn. Since whipworm infestation does not directly affect the immunity of mole voles, the reciprocal tendencies in seasonal dynamics and spatial distribution of whipworm abundance and host immunocompetence may be explained by local deterioration of habitat conditions, which increases the probability of an infestation.

The immunological contribution of NF-κB within the tumor microenvironment: A potential protective role of zinc as an anti-tumor agent

PubMed Central

Bao, Bin; Thakur, Archana; Li, Yiwei; Ahmad, Aamir; Azmi, Asfar S.; Banerjee, Sanjeev; Kong, Dejuan; Ali, Shadan; Lum, Lawrence G.; Sarkar, Fazlul H.

2013-01-01

Over decades, cancer treatment has been mainly focused on targeting cancer cells and not much attention to host tumor microenvironment. Recent advances suggest that the tumor microenvironment requires in-depth investigation for understanding the interactions between tumor cell biology and immunobiology in order to optimize therapeutic approaches. Tumor microenvironment consists of cancer cells and tumor associated reactive fibroblasts, infiltrating non-cancer cells, secreted soluble factors or molecules, and non-cellular support materials. Tumor associated host immune cells such as Th1, Th2, Th17, regulatory cells, dendritic cells, macrophages, and myeloid-derived suppressor cells are major components of the tumor microenvironment. Accumulating evidence suggests that these tumor associated immune cells may play important roles in cancer development and progression. However, the exact functions of these cells in the tumor microenvironment are poorly understood. In the tumor microenvironment, NF-κB plays an important role in cancer development and progression because this is a major transcription factor which regulates immune functions within the tumor microenvironment. In this review, we will focus our discussion on the immunological contribution of NF-κB in tumor associated host immune cells within the tumor microenvironment. We will also discuss the potential protective role of zinc, a well-known immune response mediator, in the regulation of these immune cells and cancer cells in the tumor microenvironment especially because zinc could be useful for conditioning the tumor microenvironment toward innovative cancer therapy. PMID:22155217

Group B Streptococcal Maternal Colonization and Neonatal Disease: Molecular Mechanisms and Preventative Approaches

PubMed Central

Patras, Kathryn A.; Nizet, Victor

2018-01-01

Group B Streptococcus (GBS) colonizes the gastrointestinal and vaginal epithelium of a significant percentage of healthy women, with potential for ascending intrauterine infection or transmission during parturition, creating a risk of serious disease in the vulnerable newborn. This review highlights new insights on the bacterial virulence determinants, host immune responses, and microbiome interactions that underpin GBS vaginal colonization, the proximal step in newborn infectious disease pathogenesis. From the pathogen perspective, the function GBS adhesins and biofilms, β-hemolysin/cytolysin toxin, immune resistance factors, sialic acid mimicry, and two-component transcriptional regulatory systems are reviewed. From the host standpoint, pathogen recognition, cytokine responses, and the vaginal mucosal and placental immunity to the pathogen are detailed. Finally, the rationale, efficacy, and potential unintended consequences of current universal recommended intrapartum antibiotic prophylaxis are considered, with updates on new developments toward a GBS vaccine or alternative approaches to reducing vaginal colonization. PMID:29520354

The innate immune response to Aspergillus fumigatus at the alveolar surface.

PubMed

Margalit, Anatte; Kavanagh, Kevin

2015-09-01

Aspergillus fumigatus is an ubiquitous, saprophytic mould that forms and releases airborne conidia which are inhaled by humans on a daily basis. When the immune system is compromised (e.g. immunosuppressive therapy prior to organ transplantation) or there is pre-existing pulmonary malfunction (e.g. asthma, cystic fibrosis, TB lesions), A. fumigatus exploits weaknesses in the host defenses which can result in the development of saphrophytic, allergic or invasive aspergillosis. If not effectively eliminated by the innate immune response, conidia germinate and form invasive hyphae which can penetrate pulmonary tissues. The innate immune response to A. fumigatus is stage-specific and various components of the host's defenses are recruited to challenge the different cellular forms of the pathogen. In immunocompetent hosts, anatomical barriers (e.g. the mucociliary elevator) and professional phagocytes such as alveolar macrophages (AM) and neutrophils prevent the development of aspergillosis by inhibiting the growth of conidia and hyphae. The recognition of inhaled conidia by AM leads to the intracellular degradation of the spores and the secretion of proinflammatory mediators which recruit neutrophils to assist in fungal clearance. During the later stages of infection, dendritic cells activate a protective A. fumigatus-specific adaptive immune response which is driven by Th1 CD4(+) T cells. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

DNA Tumor Virus Regulation of Host DNA Methylation and Its Implications for Immune Evasion and Oncogenesis

PubMed Central

Kuss-Duerkop, Sharon K.; Westrich, Joseph A.

2018-01-01

Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. Several DNA tumor viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in antitumor immune responses. Here, we describe viral mechanisms and virus–host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity, which may contribute to the generation of an immunosuppressive microenvironment during cancer development. Recent trials of immunotherapies have shown promising results to treat multiple cancers; however, a significant number of non-responders necessitate identifying additional targets for cancer immunotherapies. Thus, understanding immune evasion mechanisms of cancer-causing viruses may provide great insights for reversing immune suppression to prevent and treat associated cancers. PMID:29438328

Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity.

PubMed

Murphy, J E; Robert, C; Kupper, T S

2000-03-01

As our primary interface with the environment, the skin is constantly subjected to injury and invasion by pathogens. The fundamental force driving the evolution of the immune system has been the need to protect the host against overwhelming infection. The ability of T and B cells to recombine antigen receptor genes during development provides an efficient, flexible, and powerful immune system with nearly unlimited specificity for antigen. The capacity to expand subsets of antigen-specific lymphocytes that become activated by environmental antigens (memory response) is termed "acquired" immunity. Immunologic memory, although a fundamental aspect of mammalian biology, is a relatively recent evolutionary event that permits organisms to live for years to decades. "Innate" immunity, mediated by genes that remain in germ line conformation and encode for proteins that recognize conserved structural patterns on microorganisms, is a much more ancient system of host defense. Defensins and other antimicrobial peptides, complement and opsonins, and endocytic receptors are all considered components of the innate immune system. None of these, however, are signal-transducing receptors. Most recently, a large family of cell surface receptors that mediate signaling through the NF-kappaB transcription factor has been identified. This family of proteins shares striking homology with plant and Drosophila genes that mediate innate immunity. In mammals, this family includes the type I interleukin-1 receptor, the interleukin-18 receptor, and a growing family of Toll-like receptors, two of which were recently identified as signal-transducing receptors for bacterial endotoxin. In this review, we discuss how interleukin-1 links the innate and acquired immune systems to provide synergistic host defense activities in skin.

Bench-to-bedside review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis

PubMed Central

Opal, Steven M; Esmon, Charles T

2003-01-01

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review. PMID:12617738

Natural selection on immune defense: A field experiment.

PubMed

Langeloh, Laura; Behrmann-Godel, Jasminca; Seppälä, Otto

2017-02-01

Predicting the evolution of phenotypic traits requires an understanding of natural selection on them. Despite its indispensability in the fight against parasites, selection on host immune defense has remained understudied. Theory predicts immune traits to be under stabilizing selection due to associated trade-offs with other fitness-related traits. Empirical studies, however, report mainly positive directional selection. This discrepancy could be caused by low phenotypic variation in the examined individuals and/or variation in host resource level that confounds trade-offs in empirical studies. In a field experiment where we maintained Lymnaea stagnalis snails individually in cages in a lake, we investigated phenotypic selection on two immune defense traits, phenoloxidase (PO)-like activity and antibacterial activity, in hemolymph. We used a diverse laboratory population and manipulated snail resource level by limiting their food supply. For six weeks, we followed immune activity, growth, and two fitness components, survival and fecundity of snails. We found that PO-like activity and growth were under stabilizing selection, while antibacterial activity was under positive directional selection. Selection on immune traits was mainly driven by variation in survival. The form of selection on immune defense apparently depends on the particular trait, possibly due to its importance for countering the present parasite community. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

Host genetics affect microbial ecosystems via host immunity.

PubMed

El Kafsi, Hela; Gorochov, Guy; Larsen, Martin

2016-10-01

Genetic evolution of multicellular organisms has occurred in response to environmental challenges, including competition for nutrients, climate change, physical and chemical stressors, and pathogens. However, fitness of an organism is dependent not only on defense efficacy, but also on the ability to take advantage of symbiotic organisms. Indeed, microbes not only encompass pathogenicity, but also enable efficient nutrient uptake from diets nondegradable by the host itself. Moreover, microbes play important roles in the development of host immunity. Here we review associations between specific host genes and variance in microbiota composition and compare with interactions between microbes and host immunity. Recent genome-wide association studies reveal that symbiosis between host and microbiota is the exquisite result of genetic coevolution. Moreover, a subset of microbes from human and mouse microbiota have been identified to interact with humoral and cellular immunity. Interestingly, microbes associated with both host genetics and host immunity are taxonomically related. Most involved are Bifidobacterium, Lactobacillus, and Akkermansia, which are dually associated with both host immunity and host genetics. We conclude that future therapeutics targeting microbiota in the context of chronic inflammatory diseases need to consider both immune and genetic host features associated with microbiota homeostasis.

Viral ancestors of antiviral systems.

PubMed

Villarreal, Luis P

2011-10-01

All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the 'Big Bang' theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features.

Viral Ancestors of Antiviral Systems

PubMed Central

Villarreal, Luis P.

2011-01-01

All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the ‘Big Bang’ theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features. PMID:22069523

IgE and mast cells in host defense against parasites and venoms

PubMed Central

Mukai, Kaori; Tsai, Mindy; Galli, Stephen J.

2016-01-01

IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly “maladaptive” immune response develop in evolution, and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms. PMID:27225312

IgE and mast cells in host defense against parasites and venoms.

PubMed

Mukai, Kaori; Tsai, Mindy; Starkl, Philipp; Marichal, Thomas; Galli, Stephen J

2016-09-01

IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly "maladaptive" immune response develop in evolution and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms.

Evasion and Interactions of the Humoral Innate Immune Response in Pathogen Invasion, Autoimmune Disease, and Cancer

PubMed Central

Rettig, Trisha A.; Harbin, Julie N.; Harrington, Adelaide; Dohmen, Leonie; Fleming, Sherry D.

2015-01-01

The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how gram positive bacteria, viruses, cancer, and the autoimmune conditions Systemic Lupus Erythematosus and Anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development. PMID:26145788

Living off a fish: a trade-off between parasites and the immune system.

PubMed

Sitjà-Bobadilla, A

2008-10-01

Research in fish immune system and parasite invasion mechanisms has advanced the knowledge of the mechanisms whereby parasites evade or cope with fish immune response. The main mechanisms of immune evasion employed by fish parasites are reviewed and considered under ten headings. 1) Parasite isolation: parasites develop in immuno-privileged host tissues, such as brain, gonads, or eyes, where host barriers prevent or limit the immune response. 2) Host isolation: the host cellular immune response isolates and encapsulates the parasites in a dormant stage without killing them. 3) Intracellular disguise: typical of intracellular microsporidians, coccidians and some myxosporeans. 4) Parasite migration, behavioural and environmental strategies: parasites migrate to host sites the immune response has not yet reached or where it is not strong enough to kill them, or they accommodate their life cycles to the season or the age in which the host immune system is down-regulated. 5) Antigen-based strategies such as mimicry or masking, variation and sharing of parasite antigens. 6) Anti-immune mechanisms: these allow parasites to resist innate humoral factors, to neutralize host antibodies or to scavenge reactive oxygen species within macrophages. 7) Immunodepression: parasites either suppress the fish immune systems by reducing the proliferative capacity of lymphocytes or the phagocytic activity of macrophages, or they induce apoptosis of host leucocytes. 8) Immunomodulation: parasites secrete or excrete substances which modulate the secretion of host immune factors, such as cytokines, to their own benefit. 9) Fast development: parasites proliferate faster than the ability of the host to mount a defence response. 10) Exploitation of the host immune reaction. Knowledge of the evasion strategies adopted by parasites will help us to understand host-parasite interactions and may therefore help in the discovery of novel immunotherapeutic agents or targeted vaccines, and permit the selection of host-resistant strains.

Histopathology of a mesoparasitic hatschekiid copepod in hospite: does Mihbaicola sakamakii (Copepoda: Siphonostomatoida: Hatschekiidae) fast within the host fish tissue?

PubMed

Hirose, Euichi; Uyeno, Daisuke

2014-08-01

Mihbaicola sakamakii is a mesoparasitic copepod that infests the branchiostegal membranes of groupers (Perciformes: Serranidae). In this study, we observed M. sakamakii within host tissue. Histologically, copepods were found enclosed inside a pouch composed of the thickened epidermis of the host, tightly encased on all sides by the host epidermal pouch wall. There were no host blood cells or other food resources in the pouch lumen. Since the host epidermis was intact and continuous, even in the vicinity of the oral region of the parasite, the copepod would not have access to the host blood in this state. However, the stomach (ampullary part of the mid gut) was filled with granular components, the majority of which were crystalloids that likely originated from fish erythrocyte hemoglobin. We supposed that the parasite drinks blood exuded from the lesion in the fish caused by copepod entry into the host tissue. Invasion of the parasite may elicit immune responses in the host, but there were no traces on the copepod of any cellular immune reactions, such as encapsulation. The array of minute protuberances on the copepod cuticle surface may be involved in avoidance of cell adhesion. After the lesion has healed, the copepod is enclosed in a tough epidermal pouch, in which it gradually digests the contents of its stomach and continues egg production.

B cell function in the immune response to helminths

PubMed Central

Harris, Nicola

2010-01-01

Similar T helper (Th)2-type immune responses are generated against different helminths parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important during the Th2-type immune response to helminths, and B cell activation might be a target for effective vaccine development. Antibody production is a function of B cells during helminth infection and understanding how polyclonal and antigen-specific antibodies contribute should provide important insights into how protective immunity develops. In addition, B cells might also contribute to the host response against helminths through antibody-independent functions including, antigen-presentation, as well as regulatory and effector activity. In this review, we examine the role of B cells during Th2-type immune response to these multicellular parasites. PMID:21159556

Host-Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response.

PubMed

Brasil, Thaís Rigueti; Freire-de-Lima, Celio Geraldo; Morrot, Alexandre; Vetö Arnholdt, Andrea Cristina

2017-01-01

Toxoplasma gondii has successfully developed strategies to evade host's immune response and reach immune privileged sites, which remains in a controlled environment inside quiescent tissue cysts. In this review, we will approach several known mechanisms used by the parasite to modulate mainly the murine immune system at its favor. In what follows, we review recent findings revealing interference of host's cell autonomous immunity and cell signaling, gene expression, apoptosis, and production of microbicide molecules such as nitric oxide and oxygen reactive species during parasite infection. Modulation of host's metalloproteinases of extracellular matrix is also discussed. These immune evasion strategies are determinant to parasite dissemination throughout the host taking advantage of cells from the immune system to reach brain and retina, crossing crucial hosts' barriers.

Probiotics: beneficial factors of the defence system.

PubMed

Antoine, Jean Michel

2010-08-01

Probiotics, defined as living micro-organisms that provide a health benefit to the host when ingested in adequate amounts, have been used traditionally as food components to help the body to recover from diarrhoea. They are commonly ingested as part of fermented foods, mostly in fresh fermented dairy products. They can interact with the host through different components of the gut defence systems. There is mounting clinical evidence that some probiotics, but not all, help the defence of the host as demonstrated by either a shorter duration of infections or a decrease in the host's susceptibility to pathogens. Different components of the gut barrier can be involved in the strengthening of the body's defences: the gut microbiota, the gut epithelial barrier and the immune system. Many studies have been conducted in normal free-living subjects or in subjects during common infections like the common cold and show that some probiotic-containing foods can improve the functioning of or strengthen the body's defence. Specific probiotic foods can be included in the usual balanced diet of consumers to help them to better cope with the daily challenges of their environment.

Immune evasion strategies of ranaviruses and innate immune responses to these emerging pathogens.

PubMed

Grayfer, Leon; Andino, Francisco De Jesús; Chen, Guangchun; Chinchar, Gregory V; Robert, Jacques

2012-07-01

Ranaviruses (RV, Iridoviridae) are large double-stranded DNA viruses that infect fish, amphibians and reptiles. For ecological and commercial reasons, considerable attention has been drawn to the increasing prevalence of ranaviral infections of wild populations and in aquacultural settings. Importantly, RVs appear to be capable of crossing species barriers of numerous poikilotherms, suggesting that these pathogens possess a broad host range and potent immune evasion mechanisms. Indeed, while some of the 95-100 predicted ranavirus genes encode putative evasion proteins (e.g., vIFα, vCARD), roughly two-thirds of them do not share significant sequence identity with known viral or eukaryotic genes. Accordingly, the investigation of ranaviral virulence and immune evasion strategies is promising for elucidating potential antiviral targets. In this regard, recombination-based technologies are being employed to knock out gene candidates in the best-characterized RV member, Frog Virus (FV3). Concurrently, by using animal infection models with extensively characterized immune systems, such as the African clawed frog, Xenopus laevis, it is becoming evident that components of innate immunity are at the forefront of virus-host interactions. For example, cells of the macrophage lineage represent important combatants of RV infections while themselves serving as targets for viral infection, maintenance and possibly dissemination. This review focuses on the recent advances in the understanding of the RV immune evasion strategies with emphasis on the roles of the innate immune system in ranaviral infections.

The Plant Actin Cytoskeleton Responds to Signals from Microbe-Associated Molecular Patterns

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henty-Ridilla, Jessica L.; Shimono, Masaki; Li, Jiejie

2013-04-04

Plants are constantly exposed to a large and diverse array of microbes; however, most plants are immune to the majority of potential invaders and susceptible to only a small subset of pathogens. The cytoskeleton comprises a dynamic intracellular framework that responds rapidly to biotic stresses and supports numerous fundamental cellular processes including vesicle trafficking, endocytosis and the spatial distribution of organelles and protein complexes. For years, the actin cytoskeleton has been assumed to play a role in plant innate immunity against fungi and oomycetes, based largely on static images and pharmacological studies. To date, however, there is little evidence thatmore » the host-cell actin cytoskeleton participates in responses to phytopathogenic bacteria. Here, we quantified the spatiotemporal changes in host-cell cytoskeletal architecture during the immune response to pathogenic and non-pathogenic strains of Pseudomonas syringae pv. tomato DC3000. Two distinct changes to host cytoskeletal arrays were observed that correspond to distinct phases of plant-bacterial interactions i.e. the perception of microbe-associated molecular patterns (MAMPs) during pattern-triggered immunity (PTI) and perturbations by effector proteins during effector-triggered susceptibility (ETS). We demonstrate that an immediate increase in actin filament abundance is a conserved and novel component of PTI. Notably, treatment of leaves with a MAMP peptide mimic was sufficient to elicit a rapid change in actin organization in epidermal cells, and this actin response required the host-cell MAMP receptor kinase complex, including FLS2, BAK1 and BIK1. Finally, we found that actin polymerization is necessary for the increase in actin filament density and that blocking this increase with the actin-disrupting drug latrunculin B leads to enhanced susceptibility of host plants to pathogenic and non-pathogenic bacteria.« less

Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation.

PubMed

Ost, Kyla S; Esher, Shannon K; Leopold Wager, Chrissy M; Walker, Louise; Wagener, Jeanette; Munro, Carol; Wormley, Floyd L; Alspaugh, J Andrew

2017-01-31

Compared to other fungal pathogens, Cryptococcus neoformans is particularly adept at avoiding detection by innate immune cells. To explore fungal cellular features involved in immune avoidance, we characterized cell surface changes of the C. neoformans rim101Δ mutant, a strain that fails to organize and shield immunogenic epitopes from host detection. These cell surface changes are associated with an exaggerated, detrimental inflammatory response in mouse models of infection. We determined that the disorganized strain rim101Δ cell wall increases macrophage detection in a contact-dependent manner. Using biochemical and microscopy methods, we demonstrated that the rim101Δ strain shows a modest increase in the levels of both cell wall chitin and chitosan but that it shows a more dramatic increase in chito-oligomer exposure, as measured by wheat germ agglutinin staining. We also created a series of mutants with various levels of cell wall wheat germ agglutinin staining, and we demonstrated that the staining intensity correlates with the degree of macrophage activation in response to each strain. To explore the host receptors responsible for recognizing the rim101Δ mutant, we determined that both the MyD88 and CARD9 innate immune signaling proteins are involved. Finally, we characterized the immune response to the rim101Δ mutant in vivo, documenting a dramatic and sustained increase in Th1 and Th17 cytokine responses. These results suggest that the Rim101 transcription factor actively regulates the C. neoformans cell wall to prevent the exposure of immune stimulatory molecules within the host. These studies further explored the ways in which immune cells detect C. neoformans and other fungal pathogens by mechanisms that include sensing N-acetylglucosamine-containing structures, such as chitin and chitosan. Infectious microorganisms have developed many ways to avoid recognition by the host immune system. For example, pathogenic fungi alter their cell surfaces to mask immunogenic epitopes. We have created a fungal strain with a targeted mutation in a pH response pathway that is unable to properly organize its cell wall, resulting in a dramatic immune reaction during infection. This mutant cell wall is defective in hiding important cell wall components, such as the chito-oligomers chitin and chitosan. By creating a series of cell wall mutants, we demonstrated that the degree of chito-oligomer exposure correlates with the intensity of innate immune cell activation. This activation requires a combination of host receptors to recognize and respond to these infecting microorganisms. Therefore, these experiments explored host-pathogen interactions that determine the degree of the subsequent inflammatory response and the likely outcome of infection. Copyright © 2017 Ost et al.

Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8*

PubMed Central

Ireland, Robin; Wang, Rong; Alinger, Joshua B.; Small, Pamela; Bosio, Catharine M.

2013-01-01

Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity is a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. Here, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated Live Vaccine Strain (LVS), inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα independent inhibition of NF-κBp65 activation and selective inhibition of activation of Interferon Regulatory Factors (IRFs). Interference with NF-κBp65 and IRFs is also observed following infection with viable SchuS4. Together these data provide novel insight as to how highly virulent bacteria selectively modulate the host to interfere innate immune responses required for survival of infection. PMID:23817430

Analysis of Thioester-Containing Proteins during the Innate Immune Response of Drosophila melanogaster

PubMed Central

Bou Aoun, Richard; Hetru, Charles; Troxler, Laurent; Doucet, Daniel; Ferrandon, Dominique; Matt, Nicolas

2010-01-01

Thioester-containing proteins (TEPs) are conserved proteins among insects that are thought to be involved in innate immunity. In Drosophila, the Tep family is composed of 6 genes named Tep1–Tep6. In this study, we investigated the phylogeny, expression pattern and roles of these genes in the host defense of Drosophila. Protostomian Tep genes are clustered in 3 distinct branches, 1 of which is specific to mosquitoes. Most D. melanogaster Tep genes are expressed in hemocytes, can be induced in the fat body, and are expressed in specific regions of the hypodermis. This expression pattern is consistent with a role in innate immunity. However, we find that TEP1, TEP2, and TEP4 are not strictly required in the body cavity to fight several bacterial and fungal infections. One possibility is that Drosophila TEPs act redundantly or that their absence can be compensated by other components of the immune response. TEPs may thus provide a subtle selective advantage during evolution. Alternatively, they may be required in host defense against specific as yet unidentified natural pathogens of Drosophila. PMID:21063077

The Phagocyte, Metchnikoff, and the Foundation of Immunology.

PubMed

Teti, Giuseppe; Biondo, Carmelo; Beninati, Concetta

2016-04-01

Since the ability of some cells to engulf particulate material was observed before Metchnikoff, he did not "discover" phagocytosis, as is sometimes mentioned in textbooks. Rather, he assigned to particle internalization the role of defending the host against noxious stimuli, which represented a new function relative to the previously recognized task of intracellular digestion. With this proposal, Metchnikoff built the conceptual framework within which immunity could finally be seen as an active host function triggered by noxious stimuli. In this sense, Metchnikoff can be rightly regarded as the father of all immunological sciences and not only of innate immunity or myeloid cell biology. Moreover, the recognition properties of his phagocyte fit surprisingly well with recent discoveries and modern models of immune sensing. For example, rather than assigning to immune recognition exclusively the function of eliminating nonself components (as others did after him), Metchnikoff viewed phagocytes as homeostatic agents capable of monitoring the internal environment and promoting tissue remodeling, thereby continuously defining the identity of the organism. No doubt, Metchnikoff's life and creativity can provide, still today, a rich source of inspiration.

Metal acquisition and virulence in Brucella

PubMed Central

Roop, R. Martin

2013-01-01

Similar to other bacteria, Brucella strains require several biologically essential metals for their survival in vitro and in vivo. Acquiring sufficient levels of some of these metals, particularly iron, manganese and zinc, is especially challenging in the mammalian host, where sequestration of these micronutrients is a well-documented component of both the innate and acquired immune responses. This review describes the Brucella metal transporters that have been shown to play critical roles in the virulence of these bacteria in experimental and natural hosts. PMID:22632611

Covariance in species diversity and facilitation among non-interactive parasite taxa: all against the host.

PubMed

Krasnov, B R; Mouillot, D; Khokhlova, I S; Shenbrot, G I; Poulin, R

2005-10-01

Different parasite taxa exploit different host resources and are often unlikely to interact directly. It is unclear, however, whether the diversity of any given parasite taxon is indirectly influenced by that of other parasite taxa on the same host. Some components of host immune defences may operate simultaneously against all kinds of parasites, whereas investment by the host in specific defences against one type of parasite may come at the expense of defence against other parasites. We investigated the relationships between the species diversity of 4 higher taxa of ectoparasites (fleas, sucking lice, mesostigmatid mites, and ixodid ticks), and between the species richness of ectoparasites and endoparasitic helminths, across different species of rodent hosts. Our analyses used 2 measures of species diversity, species richness and taxonomic distinctness, and controlled for the potentially confounding effects of sampling effort and phylogenetic relationships among host species. We found positive pairwise correlations between the species richness of fleas, mites and ticks; however, there was no association between species richness of any of these 3 groups and that of lice. We also found a strong positive relationship between the taxonomic distinctness of ecto- and endoparasite assemblages across host species. These results suggest the existence of a process of apparent facilitation among unrelated taxa in the organization of parasite communities. We propose explanations based on host immune responses, involving acquired cross-resistance to infection and interspecific variation in immunocompetence among hosts, to account for these patterns.

The role of lipids in host microbe interactions.

PubMed

Lang, Roland; Mattner, Jochen

2017-06-01

Lipids are one of the major subcellular constituents and serve as signal molecules, energy sources, metabolic precursors and structural membrane components in various organisms. The function of lipids can be modified by multiple biochemical processes such as (de-)phosphorylation or (de-)glycosylation, and the organization of fatty acids into distinct cellular pools and subcellular compartments plays a pivotal role for the morphology and function of various cell populations. Thus, lipids regulate, for example, phagosome formation and maturation within host cells and thus, are critical for the elimination of microbial pathogens. Vice versa, microbial pathogens can manipulate the lipid composition of phagosomal membranes in host cells, and thus avoid their delivery to phagolysosomes. Lipids of microbial origin belong also to the strongest and most versatile inducers of mammalian immune responses upon engagement of distinct receptors on myeloid and lymphoid cells. Furthermore, microbial lipid toxins can induce membrane injuries and cell death. Thus, we will review here selected examples for mutual host-microbe interactions within the broad and divergent universe of lipids in microbial defense, tissue injury and immune evasion.

A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development.

PubMed

Makthal, Nishanth; Nguyen, Kimberly; Do, Hackwon; Gavagan, Maire; Chandrangsu, Pete; Helmann, John D; Olsen, Randall J; Kumaraswami, Muthiah

2017-07-01

Bacterial pathogens must overcome host immune mechanisms to acquire micronutrients for successful replication and infection. Streptococcus pyogenes, also known as group A streptococcus (GAS), is a human pathogen that causes a variety of clinical manifestations, and disease prevention is hampered by lack of a human GAS vaccine. Herein, we report that the mammalian host recruits calprotectin (CP) to GAS infection sites and retards bacterial growth by zinc limitation. However, a GAS-encoded zinc importer and a nuanced zinc sensor aid bacterial defense against CP-mediated growth inhibition and contribute to GAS virulence. Immunization of mice with the extracellular component of the zinc importer confers protection against systemic GAS challenge. Together, we identified a key early stage host-GAS interaction and translated that knowledge into a novel vaccine strategy against GAS infection. Furthermore, we provided evidence that a similar struggle for zinc may occur during other streptococcal infections, which raises the possibility of a broad-spectrum prophylactic strategy against multiple streptococcal pathogens. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells

PubMed Central

Pachathundikandi, Suneesh Kumar; Tegtmeyer, Nicole; Backert, Steffen

2013-01-01

Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α5β1 receptor. Other targeted membrane-based receptors include the integrins αvβ3, αvβ5, and β2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed. PMID:24280762

Emerging Role of D-Amino Acid Metabolism in the Innate Defense.

PubMed

Sasabe, Jumpei; Suzuki, Masataka

2018-01-01

Mammalian innate and adaptive immune systems use the pattern recognition receptors, such as toll-like receptors, to detect conserved bacterial and viral components. Bacteria synthesize diverse D-amino acids while eukaryotes and archaea generally produce two D-amino acids, raising the possibility that many of bacterial D-amino acids are bacteria-specific metabolites. Although D-amino acids have not been identified to bind to any known pattern recognition receptors, D-amino acids are enantioselectively recognized by some other receptors and enzymes including a flavoenzyme D-amino acid oxidase (DAO) in mammals. At host-microbe interfaces in the neutrophils and intestinal mucosa, DAO catalyzes oxidation of bacterial D-amino acids, such as D-alanine, and generates H 2 O 2 , which is linked to antimicrobial activity. Intestinal DAO also modifies the composition of microbiota through modulation of growth for some bacteria that are dependent on host nutrition. Furthermore, regulation and recognition of D-amino acids in mammals have additional meanings at various host-microbe interfaces; D-phenylalanine and D-tryptophan regulate chemotaxis of neutrophils through a G-coupled protein receptor, D-serine has a bacteriostatic role in the urinary tract, D-phenylalanine and D-leucine inhibit innate immunity through the sweet taste receptor in the upper airway, and D-tryptophan modulates immune tolerance in the lower airway. This mini-review highlights recent evidence supporting the hypothesis that D-amino acids are utilized as inter-kingdom communication at host-microbe interface to modulate bacterial colonization and host defense.

Group B Streptococcus CovR regulation modulates host immune signaling pathways to promote vaginal colonization

PubMed Central

Patras, Kathryn A.; Wang, Nai-Yu; Fletcher, Erin M.; Cavaco, Courtney K.; Jimenez, Alyssa; Garg, Mansi; Fierer, Joshua; Sheen, Tamsin R.; Rajagopal, Lakshmi; Doran, Kelly S.

2013-01-01

Summary Streptococcus agalactiae (Group B Streptococcus, GBS) is a frequent commensal organism of the vaginal tract of healthy women. However, GBS can transition to a pathogen in susceptible hosts, but host and microbial factors that contribute to this conversion are not well understood. GBS CovR/S (CsrR/S) is a two component regulatory system that regulates key virulence elements including adherence and toxin production. We performed global transcription profiling of human vaginal epithelial cells exposed to WT, CovR deficient, and toxin deficient strains, and observed that insufficient regulation by CovR and subsequent increased toxin production results in a drastic increase in host inflammatory responses, particularly in cytokine signaling pathways promoted by IL-8 and CXCL2. Additionally, we observed that CovR regulation impacts epithelial cell attachment and intracellular invasion. In our mouse model of GBS vaginal colonization, we further demonstrated that CovR regulation promotes vaginal persistence, as infection with a CovR deficient strain resulted in a heightened host immune response as measured by cytokine production and neutrophil activation. Using CXCr2 KO mice, we determined that this immune alteration occurs, at least in part, via signaling through the CXCL2 receptor. Taken together, we conclude that CovR is an important regulator of GBS vaginal colonization and loss of this regulatory function may contribute to the inflammatory havoc seen during the course of infection. PMID:23298320

Immunology and Immunotherapy of Head and Neck Cancer

PubMed Central

Ferris, Robert L.

2015-01-01

The immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. HNSCC cells evade the host immune system through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented. PMID:26351330

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species.

PubMed

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2012-11-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Translating insights from persistent LCMV infection into anti-HIV immunity.

PubMed

Wilson, Elizabeth B; Brooks, David G

2010-12-01

Human immunodeficiency virus (HIV) is a major global health concern with more than 30 million individuals currently infected worldwide. To date, attempts to stimulate protective immunity to viral components of HIV have been unsuccessful in preventing or clearing infection. Lymphocytic choriomeningitis virus (LCMV) is an established murine model of persistent viral infection that has been instrumental in illuminating several critical aspects of antiviral immunity. Although virologically the course of LCMV infection differs significantly from HIV, the immune responses and regulatory mechanisms elicited by these two viruses are markedly similar. In this review we discuss important recent findings in the LCMV model, highlighting the role of host-derived proteins in shaping immune responses to persistent infections, and explore the therapeutic potential of manipulating these pathways to enhance HIV vaccination strategies.

Subverting Toll-Like Receptor Signaling by Bacterial Pathogens

PubMed Central

McGuire, Victoria A.; Arthur, J. Simon C.

2015-01-01

Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection. PMID:26648936

Anaemia, iron deficiency and susceptibility to infections.

PubMed

Jonker, Femke A M; Boele van Hensbroek, Michaël

2014-11-01

Anaemia, iron deficiency and infections are three major causes of childhood morbidity and mortality throughout the world, although they predominantly occur in resource limited settings. As the three conditions may have the same underlying aetiologies, they often occur simultaneously and may interact. Being an essential component in erythropoiesis, iron is also essential for proper functioning of the host immune system as well as an essential nutrient for growth of various pathogens, including non-typhoid salmonella. This has resulted in a treatment dilemma in which iron is needed to treat the iron deficient anaemia and improve the immune system of the host (child), but the same treatment may also put the child at an increased, potentially fatal, infection risk. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Geographical variation in parasitism shapes larval immune function in a phytophagous insect

NASA Astrophysics Data System (ADS)

Vogelweith, Fanny; Dourneau, Morgane; Thiéry, Denis; Moret, Yannick; Moreau, Jérôme

2013-12-01

Two of the central goals of immunoecology are to understand natural variation in the immune system among populations and to identify those selection pressures that shape immune traits. Maintenance of the immune system can be costly, and both food quality and parasitism selection pressure are factors potentially driving immunocompetence. In tritrophic interactions involving phytophagous insects, host plants, and natural enemies, the immunocompetence of phytophagous insects is constrained by selective forces from both the host plants and the natural enemies. Here, we assessed the roles of host plants and natural enemies as selective pressures on immune variation among natural populations of Lobesia botrana. Our results showed marked geographical variation in immune defenses and parasitism among different natural populations. Larval immune functions were dependent of the host plant quality and were positively correlated to parasitism, suggesting that parasitoids select for greater investment into immunity in moth. Furthermore, investment in immune defense was negatively correlated with body size, suggesting that it is metabolically expensive. The findings emphasize the roles of host plants and parasitoids as selective forces shaping host immune functions in natural conditions. We argue that kinds of study are central to understanding natural variations in immune functions, and the selective forces beyond.

A Framework for Understanding the Evasion of Host Immunity by Candida Biofilms

PubMed Central

Garcia-Perez, Josselyn E.; Mathé, Lotte; Humblet-Baron, Stephanie; Braem, Annabel; Lagrou, Katrien; Van Dijck, Patrick; Liston, Adrian

2018-01-01

Candida biofilms are a major cause of nosocomial morbidity and mortality. The mechanism by which Candida biofilms evade the immune system remains unknown. In this perspective, we develop a theoretical framework of the three, not mutually exclusive, models, which could explain biofilm evasion of host immunity. First, biofilms may exhibit properties of immunological silence, preventing immune activation. Second, biofilms may produce immune-deviating factors, converting effective immunity into ineffective immunity. Third, biofilms may resist host immunity, which would otherwise be effective. Using a murine subcutaneous biofilm model, we found that mice infected with biofilms developed sterilizing immunity effective when challenged with yeast form Candida. Despite the induction of effective anti-Candida immunity, no spontaneous clearance of the biofilm was observed. These results support the immune resistance model of biofilm immune evasion and demonstrate an asymmetric relationship between the host and biofilms, with biofilms eliciting effective immune responses yet being resistant to immunological clearance. PMID:29616035

Spreading of multiple epidemics with cross immunization.

PubMed

Uekermann, Florian; Sneppen, Kim

2012-09-01

Pathogen-host relationships are the result of an ongoing coevolutionary race where the immune system of the host attempts to eliminate the pathogen, while the successful pathogen mutates to become invisible for the host's immune system. We here propose a minimal pathogen-host evolution model that takes into account cross immunization and allows for evolution of a spatially heterogeneous immune status of a population of hosts. With only the mutation rate as a determining parameter, the model allows us to produce an evolutionary tree of diseases which is highly branched, but hardly ever splits into separate long-lived trunks. Side branches remain short lived and seldom diverge to the extent of losing all cross immunizations.

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components

PubMed Central

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-01-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity. PMID:29682500

Specific β-turns precede PPIIL structures binding to allele-specific HLA-DRβ1* PBRs in fully-protective malaria vaccine components

NASA Astrophysics Data System (ADS)

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-04-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

Molecular Profiling of Phagocytic Immune Cells in Anopheles gambiae Reveals Integral Roles for Hemocytes in Mosquito Innate Immunity*

PubMed Central

Smith, Ryan C.; King, Jonas G.; Tao, Dingyin; Zeleznik, Oana A.; Brando, Clara; Thallinger, Gerhard G.; Dinglasan, Rhoel R.

2016-01-01

The innate immune response is highly conserved across all eukaryotes and has been studied in great detail in several model organisms. Hemocytes, the primary immune cell population in mosquitoes, are important components of the mosquito innate immune response, yet critical aspects of their biology have remained uncharacterized. Using a novel method of enrichment, we isolated phagocytic granulocytes and quantified their proteomes by mass spectrometry. The data demonstrate that phagocytosis, blood-feeding, and Plasmodium falciparum infection promote dramatic shifts in the proteomic profiles of An. gambiae granulocyte populations. Of interest, large numbers of immune proteins were induced in response to blood feeding alone, suggesting that granulocytes have an integral role in priming the mosquito immune system for pathogen challenge. In addition, we identify several granulocyte proteins with putative roles as membrane receptors, cell signaling, or immune components that when silenced, have either positive or negative effects on malaria parasite survival. Integrating existing hemocyte transcriptional profiles, we also compare differences in hemocyte transcript and protein expression to provide new insight into hemocyte gene regulation and discuss the potential that post-transcriptional regulation may be an important component of hemocyte gene expression. These data represent a significant advancement in mosquito hemocyte biology, providing the first comprehensive proteomic profiling of mosquito phagocytic granulocytes during homeostasis blood-feeding, and pathogen challenge. Together, these findings extend current knowledge to further illustrate the importance of hemocytes in shaping mosquito innate immunity and their principal role in defining malaria parasite survival in the mosquito host. PMID:27624304

Structural diversity of Burkholderia pseudomallei lipopolysaccharides affects innate immune signaling

PubMed Central

Norris, Michael H.; Schweizer, Herbert P.

2017-01-01

Burkholderia pseudomallei (Bp) causes the disease melioidosis. The main cause of mortality in this disease is septic shock triggered by the host responding to lipopolysaccharide (LPS) components of the Gram-negative outer membrane. Bp LPS is thought to be a weak inducer of the host immune system. LPS from several strains of Bp were purified and their ability to induce the inflammatory mediators TNF-α and iNOS in murine macrophages at low concentrations was investigated. Innate and adaptive immunity qPCR arrays were used to profile expression patterns of 84 gene targets in response to the different LPS types. Additional qPCR validation confirmed large differences in macrophage response. LPS from a high-virulence serotype B strain 576a and a virulent rough central nervous system tropic strain MSHR435 greatly induced the innate immune response indicating that the immunopathogenesis of these strains is different than in infections with strains similar to the prototype strain 1026b. The accumulation of autophagic vesicles was also increased in macrophages challenged with highly immunogenic Bp LPS. Gene induction and concomitant cytokine secretion profiles of human PBMCs in response to the various LPS were also investigated. MALDI-TOF/TOF was used to probe the lipid A portions of the LPS, indicating substantial structural differences that likely play a role in host response to LPS. These findings add to the evolving knowledge of host-response to bacterial LPS, which can be used to better understand septic shock in melioidosis patients and in the rational design of vaccines. PMID:28453531

Immunopathology of inflammatory bowel disease

PubMed Central

Wallace, Kori L; Zheng, Li-Bo; Kanazawa, Yoshitake; Shih, David Q

2014-01-01

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. The host microbiome, as well as viruses and fungi, play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system. New technologies have allowed researchers to be able to quantify the various components of the microbiome, which will allow for future developments in the etiology of IBD. Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells, innate lymphoid cells, cells of the innate (macrophages/monocytes, neutrophils, and dendritic cells) and adaptive (T-cells and B-cells) immune system, and their secreted mediators (cytokines and chemokines). Either a mucosal susceptibility or defect in sampling of gut luminal antigen, possibly through the process of autophagy, leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity. The antigen presenting cells then mediate the differentiation of naïve T-cells into effector T helper (Th) cells, including Th1, Th2, and Th17, which alter gut homeostasis and lead to IBD. In this review, the effects of these components in the immunopathogenesis of IBD will be discussed. PMID:24415853

Immunopathology of inflammatory bowel disease.

PubMed

Wallace, Kori L; Zheng, Li-Bo; Kanazawa, Yoshitake; Shih, David Q

2014-01-07

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. The host microbiome, as well as viruses and fungi, play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system. New technologies have allowed researchers to be able to quantify the various components of the microbiome, which will allow for future developments in the etiology of IBD. Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells, innate lymphoid cells, cells of the innate (macrophages/monocytes, neutrophils, and dendritic cells) and adaptive (T-cells and B-cells) immune system, and their secreted mediators (cytokines and chemokines). Either a mucosal susceptibility or defect in sampling of gut luminal antigen, possibly through the process of autophagy, leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity. The antigen presenting cells then mediate the differentiation of naïve T-cells into effector T helper (Th) cells, including Th1, Th2, and Th17, which alter gut homeostasis and lead to IBD. In this review, the effects of these components in the immunopathogenesis of IBD will be discussed.

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

Contextual control of skin immunity and inflammation by Corynebacterium.

PubMed

Ridaura, Vanessa K; Bouladoux, Nicolas; Claesen, Jan; Chen, Y Erin; Byrd, Allyson L; Constantinides, Michael G; Merrill, Eric D; Tamoutounour, Samira; Fischbach, Michael A; Belkaid, Yasmine

2018-03-05

How defined microbes influence the skin immune system remains poorly understood. Here we demonstrate that Corynebacteria , dominant members of the skin microbiota, promote a dramatic increase in the number and activation of a defined subset of γδ T cells. This effect is long-lasting, occurs independently of other microbes, and is, in part, mediated by interleukin (IL)-23. Under steady-state conditions, the impact of Corynebacterium is discrete and noninflammatory. However, when applied to the skin of a host fed a high-fat diet, Corynebacterium accolens alone promotes inflammation in an IL-23-dependent manner. Such effect is highly conserved among species of Corynebacterium and dependent on the expression of a dominant component of the cell envelope, mycolic acid. Our data uncover a mode of communication between the immune system and a dominant genus of the skin microbiota and reveal that the functional impact of canonical skin microbial determinants is contextually controlled by the inflammatory and metabolic state of the host. © 2018 Ridaura et al.

Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition

PubMed Central

Kurz, C Leopold; Charroux, Bernard; Chaduli, Delphine; Viallat-Lieutaud, Annelise; Royet, Julien

2017-01-01

As infectious diseases pose a threat to host integrity, eukaryotes have evolved mechanisms to eliminate pathogens. In addition to develop strategies reducing infection, animals can engage in behaviors that lower the impact of the infection. The molecular mechanisms by which microbes impact host behavior are not well understood. We demonstrate that bacterial infection of Drosophila females reduces oviposition and that peptidoglycan, the component that activates Drosophila antibacterial response, is also the elicitor of this behavioral change. We show that peptidoglycan regulates egg-laying rate by activating NF-κB signaling pathway in octopaminergic neurons and that, a dedicated peptidoglycan degrading enzyme acts in these neurons to buffer this behavioral response. This study shows that a unique ligand and signaling cascade are used in immune cells to mount an immune response and in neurons to control fly behavior following infection. This may represent a case of behavioral immunity. DOI: http://dx.doi.org/10.7554/eLife.21937.001 PMID:28264763

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

PubMed Central

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

2014-01-01

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

Molecular recognition of microbial lipid-based antigens by T cells.

PubMed

Gras, Stephanie; Van Rhijn, Ildiko; Shahine, Adam; Le Nours, Jérôme

2018-05-01

The immune system has evolved to protect hosts from pathogens. T cells represent a critical component of the immune system by their engagement in host defence mechanisms against microbial infections. Our knowledge of the molecular recognition by T cells of pathogen-derived peptidic antigens that are presented by the major histocompatibility complex glycoproteins is now well established. However, lipids represent an additional, distinct chemical class of molecules that when presented by the family of CD1 antigen-presenting molecules can serve as antigens, and be recognized by specialized subsets of T cells leading to antigen-specific activation. Over the past decades, numerous CD1-presented self- and bacterial lipid-based antigens have been isolated and characterized. However, our understanding at the molecular level of T cell immunity to CD1 molecules presenting microbial lipid-based antigens is still largely unexplored. Here, we review the insights and the molecular basis underpinning the recognition of microbial lipid-based antigens by T cells.

Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity

PubMed Central

Thomas, David C.; Clare, Simon; Sowerby, John M.; Juss, Jatinder K.; Goulding, David A.; van der Weyden, Louise; Prakash, Ananth; Harcourt, Katherine; Mukhopadhyay, Subhankar; Antrobus, Robin; Bateman, Alex

2017-01-01

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox. Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense. PMID:28351984

Novel disease susceptibility factors for fungal necrotrophic pathogens in Arabidopsis.

PubMed

Dobón, Albor; Canet, Juan Vicente; García-Andrade, Javier; Angulo, Carlos; Neumetzler, Lutz; Persson, Staffan; Vera, Pablo

2015-04-01

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens.

Uncovering the components of the Francisella tularensis virulence stealth strategy

PubMed Central

Jones, Bradley D.; Faron, Matthew; Rasmussen, Jed A.; Fletcher, Joshua R.

2014-01-01

Over the last decade, studies on the virulence of the highly pathogenic intracellular bacterial pathogen Francisella tularensis have increased dramatically. The organism produces an inert LPS, a capsule, escapes the phagosome to grow in the cytosol (FPI genes mediate phagosomal escape) of a variety of host cell types that include epithelial, endothelial, dendritic, macrophage, and neutrophil. This review focuses on the work that has identified and characterized individual virulence factors of this organism and we hope to highlight how these factors collectively function to produce the pathogenic strategy of this pathogen. In addition, several recent studies have been published characterizing F. tularensis mutants that induce host immune responses not observed in wild type F. tularensis strains that can induce protection against challenge with virulent F. tularensis. As more detailed studies with attenuated strains are performed, it will be possible to see how host models develop acquired immunity to Francisella. Collectively, detailed insights into the mechanisms of virulence of this pathogen are emerging that will allow the design of anti-infective strategies. PMID:24639953

Five Xanthomonas type III effectors suppress cell death induced by components of immunity-associated MAP kinase cascades

PubMed Central

Teper, Doron; Sunitha, Sukumaran; Martin, Gregory B; Sessa, Guido

2015-01-01

Mitogen-activated protein kinase (MAPK) cascades play a fundamental role in signaling of plant immunity and mediate elicitation of cell death. Xanthomonas spp. manipulate plant signaling by using a type III secretion system to deliver effector proteins into host cells. We examined the ability of 33 Xanthomonas effectors to inhibit cell death induced by overexpression of components of MAPK cascades in Nicotiana benthamiana plants. Five effectors inhibited cell death induced by overexpression of MAPKKKα and MEK2, but not of MAP3Kϵ. In addition, expression of AvrBs1 in yeast suppressed activation of the high osmolarity glycerol MAPK pathway, suggesting that the target of this effector is conserved in eukaryotic organisms. These results indicate that Xanthomonas employs several type III effectors to suppress immunity-associated cell death mediated by MAPK cascades. PMID:26237448

Drosophila melanogaster as a High-Throughput Model for Host-Microbiota Interactions.

PubMed

Trinder, Mark; Daisley, Brendan A; Dube, Josh S; Reid, Gregor

2017-01-01

Microbiota research often assumes that differences in abundance and identity of microorganisms have unique influences on host physiology. To test this concept mechanistically, germ-free mice are colonized with microbial communities to assess causation. Due to the cost, infrastructure challenges, and time-consuming nature of germ-free mouse models, an alternative approach is needed to investigate host-microbial interactions. Drosophila melanogaster (fruit flies) can be used as a high throughput in vivo screening model of host-microbiome interactions as they are affordable, convenient, and replicable. D. melanogaster were essential in discovering components of the innate immune response to pathogens. However, axenic D. melanogaster can easily be generated for microbiome studies without the need for ethical considerations. The simplified microbiota structure enables researchers to evaluate permutations of how each microbial species within the microbiota contribute to host phenotypes of interest. This enables the possibility of thorough strain-level analysis of host and microbial properties relevant to physiological outcomes. Moreover, a wide range of mutant D. melanogaster strains can be affordably obtained from public stock centers. Given this, D. melanogaster can be used to identify candidate mechanisms of host-microbe symbioses relevant to pathogen exclusion, innate immunity modulation, diet, xenobiotics, and probiotic/prebiotic properties in a high throughput manner. This perspective comments on the most promising areas of microbiota research that could immediately benefit from using the D. melanogaster model.

Characterization of the effect of Cr(VI) on humoral innate immunity using Drosophila melanogaster.

PubMed

Pragya, P; Shukla, A K; Murthy, R C; Abdin, M Z; Kar Chowdhuri, D

2015-11-01

With the advancement of human race, different anthropogenic activities have heaped the environment with chemicals that can cause alteration in the immune system of exposed organism. As a first line of barrier, the evolutionary conserved innate immunity is crucial for the health of an organism. However, there is paucity of information regarding in vivo assessment of the effect of environmental chemicals on innate immunity. Therefore, we examined the effect of a widely used environmental chemical, Cr(VI), on humoral innate immune response using Drosophila melanogaster. The adverse effect of Cr(VI) on host humoral response was characterized by decreased gene expression of antimicrobial peptides (AMPs) in the exposed organism. Concurrently, a significantly decreased transcription of humoral pathway receptors (Toll and PGRP) and triglyceride level along with inhibition of antioxidant enzyme activities were observed in exposed organism. This in turn weakened the immune response of exposed organism that was manifested by their reduced resistance against bacterial infection. In addition, overexpression of the components of humoral immunity particularly Diptericin benefits Drosophila from Cr(VI)-induced humoral immune-suppressive effect. To our knowledge, this is the first report regarding negative impact of an environmental chemical on humoral innate immune response of Drosophila along with subsequent protection by AMPs, which may provide novel insight into host-chemical interactions. Also, our data validate the utility and sensitivity of Drosophila as a model that could be used for screening the possible risk of environmental chemicals on innate immunity with minimum ethical concern that can be further extrapolated to higher organisms. © 2014 Wiley Periodicals, Inc.

Development and characterization of a bovine monocyte-derived macrophage cell line

USDA-ARS?s Scientific Manuscript database

Monocytes circulate in the blood, and later differentiate into macrophages in the tissues. They are components of the innate arm of the immune response and are one of the first lines of defense again invading pathogens. However, they also serve as host cells for intracellular pathogens such as Mycob...

Characterization of a double WAP domain-containing protein from the red swamp crayfish Procambarus clarkii

USDA-ARS?s Scientific Manuscript database

Crustaceans express multiple whey acidic protein (WAP) domain containing proteins which are components of host immunity. In the present study, a new double WAP domain containing protein was identified from red swamp crayfish Procambarus clarkii, designated Pc-DWD. The ORF is 387 bp, encoding 128 ami...

Understanding regulation of the host-mediated gut symbiont population and the symbiont-mediated host immunity in the Riptortus-Burkholderia symbiosis system.

PubMed

Kim, Jiyeun Kate; Lee, Jun Beom; Jang, Ho Am; Han, Yeon Soo; Fukatsu, Takema; Lee, Bok Luel

2016-11-01

Valuable insect models have tremendously contributed to our understanding of innate immunity and symbiosis. Bean bug, Riptortus pedestris, is a useful insect symbiosis model due to harboring cultivable monospecific gut symbiont, genus Burkholderia. Bean bug is a hemimetabolous insect whose immunity is not well-understood. However, we recently identified three major antimicrobial peptides of Riptortus and examined the relationship between gut symbiosis and host immunity. We found that the presence of Burkholderia gut symbiont positively affects Riptortus immunity. From studying host regulation mechanisms of symbiont population, we revealed that the symbiotic Burkholderia cells are much more susceptible to Riptortus immune responses than the cultured cells. We further elucidated that the immune-susceptibility of the Burkholderia gut symbionts is due to the drastic change of bacterial cell envelope. Finally, we show that the immune-susceptible Burkholderia symbionts are able to prosper in host owing to the suppression of immune responses of the symbiotic midgut. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mechanisms of nuclear suppression of host immunity by effectors from the Arabidopsis downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa).

PubMed

Caillaud, M-C; Wirthmueller, L; Fabro, G; Piquerez, S J M; Asai, S; Ishaque, N; Jones, J D G

2012-01-01

Filamentous phytopathogens form sophisticated intracellular feeding structures called haustoria in plant cells. Pathogen effectors are likely to play a role in the establishment and maintenance of haustoria additional to their more characterized role of suppressing plant defense. Recent studies suggest that effectors may manipulate host transcription or other nuclear regulatory components for the benefit of pathogen development. However, the specific mechanisms by which these effectors promote susceptibility remain unclear. Of two recent screenings, we identified 15 nuclear-localized Hpa effectors (HaRxLs) that interact directly or indirectly with host nuclear components. When stably expressed in planta, nuclear HaRxLs cause diverse developmental phenotypes highlighting that nuclear effectors might interfere with fundamental plant regulatory mechanisms. Here, we report recent advances in understanding how a pathogen can manipulate nuclear processes in order to cause disease.

A minimal model for multiple epidemics and immunity spreading.

PubMed

Sneppen, Kim; Trusina, Ala; Jensen, Mogens H; Bornholdt, Stefan

2010-10-18

Pathogens and parasites are ubiquitous in the living world, being limited only by availability of suitable hosts. The ability to transmit a particular disease depends on competing infections as well as on the status of host immunity. Multiple diseases compete for the same resource and their fate is coupled to each other. Such couplings have many facets, for example cross-immunization between related influenza strains, mutual inhibition by killing the host, or possible even a mutual catalytic effect if host immunity is impaired. We here introduce a minimal model for an unlimited number of unrelated pathogens whose interaction is simplified to simple mutual exclusion. The model incorporates an ongoing development of host immunity to past diseases, while leaving the system open for emergence of new diseases. The model exhibits a rich dynamical behavior with interacting infection waves, leaving broad trails of immunization in the host population. This obtained immunization pattern depends only on the system size and on the mutation rate that initiates new diseases.

Worming Their Way into the Picture: Microbiota Help Helminths Modulate Host Immunity.

PubMed

Reynolds, Lisa A; Finlay, B Brett

2015-11-17

Parasitic helminths are potent regulators of host immunity, including inhibition of allergic inflammation. In this issue of Immunity, Zaiss et al. (2015) reveal that microbiota compositional shifts during helminth infection contribute to the multifaceted ways that helminths modulate host immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

Immunology and Immunotherapy of Head and Neck Cancer.

PubMed

Ferris, Robert L

2015-10-10

The immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. HNSCC cells evade the host immune system through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented. © 2015 by American Society of Clinical Oncology.

Dual RNA-seq reveals no plastic transcriptional response of the coccidian parasite Eimeria falciformis to host immune defenses.

PubMed

Ehret, Totta; Spork, Simone; Dieterich, Christoph; Lucius, Richard; Heitlinger, Emanuel

2017-09-05

Parasites can either respond to differences in immune defenses that exist between individual hosts plastically or, alternatively, follow a genetically canalized ("hard wired") program of infection. Assuming that large-scale functional plasticity would be discernible in the parasite transcriptome we have performed a dual RNA-seq study of the lifecycle of Eimeria falciformis using infected mice with different immune status as models for coccidian infections. We compared parasite and host transcriptomes (dual transcriptome) between naïve and challenge infected mice, as well as between immune competent and immune deficient ones. Mice with different immune competence show transcriptional differences as well as differences in parasite reproduction (oocyst shedding). Broad gene categories represented by differently abundant host genes indicate enrichments for immune reaction and tissue repair functions. More specifically, TGF-beta, EGF, TNF and IL-1 and IL-6 are examples of functional annotations represented differently depending on host immune status. Much in contrast, parasite transcriptomes were neither different between Coccidia isolated from immune competent and immune deficient mice, nor between those harvested from naïve and challenge infected mice. Instead, parasite transcriptomes have distinct profiles early and late in infection, characterized largely by biosynthesis or motility associated functional gene groups, respectively. Extracellular sporozoite and oocyst stages showed distinct transcriptional profiles and sporozoite transcriptomes were found enriched for species specific genes and likely pathogenicity factors. We propose that the niche and host-specific parasite E. falciformis uses a genetically canalized program of infection. This program is likely fixed in an evolutionary process rather than employing phenotypic plasticity to interact with its host. This in turn might limit the potential of the parasite to adapt to new host species or niches, forcing it to coevolve with its host.

Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model

PubMed Central

Limmer, Stefanie; Haller, Samantha; Drenkard, Eliana; Lee, Janice; Yu, Shen; Kocks, Christine; Ausubel, Frederick M.; Ferrandon, Dominique

2011-01-01

An in-depth mechanistic understanding of microbial infection necessitates a molecular dissection of host–pathogen relationships. Both Drosophila melanogaster and Pseudomonas aeruginosa have been intensively studied. Here, we analyze the infection of D. melanogaster by P. aeruginosa by using mutants in both host and pathogen. We show that orally ingested P. aeruginosa crosses the intestinal barrier and then proliferates in the hemolymph, thereby causing the infected flies to die of bacteremia. Host defenses against ingested P. aeruginosa included an immune deficiency (IMD) response in the intestinal epithelium, systemic Toll and IMD pathway responses, and a cellular immune response controlling bacteria in the hemocoel. Although the observed cellular and intestinal immune responses appeared to act throughout the course of the infection, there was a late onset of the systemic IMD and Toll responses. In this oral infection model, P. aeruginosa PA14 did not require its type III secretion system or other well-studied virulence factors such as the two-component response regulator GacA or the protease AprA for virulence. In contrast, the quorum-sensing transcription factor RhlR, but surprisingly not LasR, played a key role in counteracting the cellular immune response against PA14, possibly at an early stage when only a few bacteria are present in the hemocoel. These results illustrate the power of studying infection from the dual perspective of host and pathogen by revealing that RhlR plays a more complex role during pathogenesis than previously appreciated. PMID:21987808

Stress responses in Streptococcus species and their effects on the host.

PubMed

Nguyen, Cuong Thach; Park, Sang-Sang; Rhee, Dong-Kwon

2015-11-01

Streptococci cause a variety of diseases, such as dental caries, pharyngitis, meningitis, pneumonia, bacteremia, endocarditis, erysipelas, and necrotizing fasciitis. The natural niche of this genus of bacteria ranges from the mouth and nasopharynx to the skin, indicating that the bacteria will inevitably be subjected to environmental changes during invasion into the host, where it is exposed to the host immune system. Thus, the Streptococcus-host interaction determines whether bacteria are cleared by the host's defenses or whether they survive after invasion to cause serious diseases. If this interaction was to be deciphered, it could aid in the development of novel preventive and therapeutic agents. Streptococcus species possess many virulent factors, such as peroxidases and heat-shock proteins (HSPs), which play key roles in protecting the bacteria from hostile host environments. This review will discuss insights into the mechanism(s) by which streptococci adapt to host environments. Additionally, we will address how streptococcal infections trigger host stress responses; however, the mechanism by which bacterial components modulate host stress responses remains largely unknown.

Immunity against Helminths: Interactions with the Host and the Intercurrent Infections

PubMed Central

Moreau, Emmanuelle; Chauvin, Alain

2010-01-01

Helminth parasites are of considerable medical and economic importance. Studies of the immune response against helminths are of great interest in understanding interactions between the host immune system and parasites. Effector immune mechanisms against tissue-dwelling helminths and helminths localized in the lumen of organs, and their regulation, are reviewed. Helminth infections are characterized by an association of Th2-like and Treg responses. Worms are able to persist in the host and are mainly responsible for chronic infection despite a strong immune response developed by the parasitized host. Two types of protection against the parasite, namely, premune and partial immunities, have been described. Immune responses against helminths can also participate in pathogenesis. Th2/Treg-like immunomodulation allows the survival of both host and parasite by controlling immunopathologic disorders and parasite persistence. Consequences of the modified Th2-like responses on co-infection, vaccination, and inflammatory diseases are discussed. PMID:20150967

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

PubMed Central

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

2013-01-01

Mycoplasma hominis is a facultative human pathogen primarily associated with bacterial vaginosis and pelvic inflammatory disease, but it is also able to spread to other sites, leading to arthritis or, in neonates, meningitis. With a minimal set of 537 annotated genes, M. hominis is the second smallest self-replicating mycoplasma and thus an ideal model organism for studying the effects of an infectious agent on its host more closely. M. hominis adherence, colonisation and invasion of HeLa cells were characterised in a time-course study using scanning electron microscopy, confocal microscopy and microarray-based analysis of the HeLa cell transcriptome. At 4 h post infection, cytoadherence of M. hominis to the HeLa cell surface was accompanied by differential regulation of 723 host genes (>2 fold change in expression). Genes associated with immune responses and signal transduction pathways were mainly affected and components involved in cell-cycle regulation, growth and death were highly upregulated. At 48 h post infection, when mycoplasma invasion started, 1588 host genes were differentially expressed and expression of genes for lysosome-specific proteins associated with bacterial lysis was detected. In a chronically infected HeLa cell line (2 weeks), the proportion of intracellular mycoplasmas reached a maximum of 10% and M. hominis-filled protrusions of the host cell membrane were seen by confocal microscopy, suggesting exocytotic dissemination. Of the 1972 regulated host genes, components of the ECM-receptor interaction pathway and phagosome-related integrins were markedly increased. The immune response was quite different to that at the beginning of infection, with a prominent induction of IL1B gene expression, affecting pathways of MAPK signalling, and genes connected with cytokine-cytokine interactions and apoptosis. These data show for the first time the complex, time-dependent reaction of the host directed at mycoplasmal clearance and the counter measures of this pestering pathogen. PMID:23326599

A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS)

PubMed Central

Mahdavinia, Mahboobeh; Keshavarzian, Ali; Tobin, Mary C; Landay, Alan; Schleimer, Robert P.

2015-01-01

Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying chronic rhinosinusitis. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison to healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS. PMID:26510171

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

Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions

PubMed Central

Kravchenko, Julia; Corsini, Emanuela; Williams, Marc A.; Decker, William; Manjili, Masoud H.; Otsuki, Takemi; Singh, Neetu; Al-Mulla, Faha; Al-Temaimi, Rabeah; Amedei, Amedeo; Colacci, Anna Maria; Vaccari, Monica; Mondello, Chiara; Scovassi, A. Ivana; Raju, Jayadev; Hamid, Roslida A.; Memeo, Lorenzo; Forte, Stefano; Roy, Rabindra; Woodrick, Jordan; Salem, Hosni K.; Ryan, Elizabeth P.; Brown, Dustin G.; Lowe, Leroy; Lyerly, H.Kim

2015-01-01

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression. PMID:26002081

[Riddles in human tuberculous infection].

PubMed

Tsuyuguchi, I

2000-10-01

Tuberculosis is indeed an infectious disease caused by Mycobacterium tuberculosis. However, only a small percentage of individuals infected develops overt disease, tuberculosis whereas the infected bacilli persist alive years long within the vast majority of persons infected but remained healthy. There are several riddles or enigmas in the natural history of M. tuberculosis infection in humans. Some of them are as follows: 1. What is the virulence of M. tuberculosis? 2. How does M. tuberculosis persist dormant within the host? 3. What determines the development of disease from remaining healthy after infection with M. tuberculosis? 4. What is the mechanism of "endogenous reactivation" of dormant M. tuberculosis within the host? 5. Can we expect more potent anti-TB vaccine than BCG in near future? Most of these issues cited above remain unsolved. What is urgently needed today to answer correctly to these questions is the production of appropriate animal model of tuberculosis infection which mimics human tuberculosis. Murine TB does not reflect human TB at all. What characterizes the mycobacterial organism is its armour-plated unique cell wall structure which is rich in lipid and carbohydrate. Cord factor or trehalose dimycolate (TDM), the main component of cell wall, has once been regarded as the virulence factor of mycobacteria. Cord factor is responsible for the pathogenesis of TB and cachexia or even death of the patients infected. However, cord factor in itself is not toxic but exerts its detrimental effect to the host through the excessive stimulation of the host's immune system to produce abundant varied cytokines including TNF-alpha. How to evade this embarrassing effect of mycobacterial cell wall component on the host immune system seems very important for the future development of better TB vaccine than the currently used BCG.

Recognition between symbiotic Vibrio fischeri and the haemocytes of Euprymna scolopes.

PubMed

Nyholm, Spencer V; Stewart, Jennifer J; Ruby, Edward G; McFall-Ngai, Margaret J

2009-02-01

The light organ crypts of the squid Euprymna scolopes permit colonization exclusively by the luminous bacterium Vibrio fischeri. Because the crypt interior remains in contact with seawater, the squid must not only foster the specific symbiosis, but also continue to exclude other bacteria. Investigation of the role of the innate immune system in these processes revealed that macrophage-like haemocytes isolated from E. scolopes recognized and phagocytosed V. fischeri less than other closely related bacterial species common to the host's environment. Interestingly, phagocytes isolated from hosts that had been cured of their symbionts bound five times more V. fischeri cells than those from uncured hosts. No such change in the ability to bind other species of bacteria was observed, suggesting that the host adapts specifically to V. fischeri. Deletion of the gene encoding OmpU, the major outer membrane protein of V. fischeri, increased binding by haemocytes from uncured animals to the level observed for haemocytes from cured animals. Co-incubation with wild-type V. fischeri reduced this binding, suggesting that they produce a factor that complements the mutant's defect. Analyses of the phagocytosis of bound cells by fluorescence-activated cell sorting indicated that once binding to haemocytes had occurred, V. fischeri cells are phagocytosed as effectively as other bacteria. Thus, discrimination by this component of the squid immune system occurs at the level of haemocyte binding, and this response: (i) is modified by previous exposure to the symbiont and (ii) relies on outer membrane and/or secreted components of the symbionts. These data suggest that regulation of host haemocyte binding by the symbiont may be one of many factors that contribute to specificity in this association.

Parasitic Nematode Immunomodulatory Strategies: Recent Advances and Perspectives

PubMed Central

Cooper, Dustin; Eleftherianos, Ioannis

2016-01-01

More than half of the described species of the phylum Nematoda are considered parasitic, making them one of the most successful groups of parasites. Nematodes are capable of inhabiting a wide variety of niches. A vast array of vertebrate animals, insects, and plants are all identified as potential hosts for nematode parasitization. To invade these hosts successfully, parasitic nematodes must be able to protect themselves from the efficiency and potency of the host immune system. Innate immunity comprises the first wave of the host immune response, and in vertebrate animals it leads to the induction of the adaptive immune response. Nematodes have evolved elegant strategies that allow them to evade, suppress, or modulate host immune responses in order to persist and spread in the host. Nematode immunomodulation involves the secretion of molecules that are capable of suppressing various aspects of the host immune response in order to promote nematode invasion. Immunomodulatory mechanisms can be identified in parasitic nematodes infecting insects, plants, and mammals and vary greatly in the specific tactics by which the parasites modify the host immune response. Nematode-derived immunomodulatory effects have also been shown to affect, negatively or positively, the outcome of some concurrent diseases suffered by the host. Understanding nematode immunomodulatory actions will potentially reveal novel targets that will in turn lead to the development of effective means for the control of destructive nematode parasites. PMID:27649248

Parasitic Nematode Immunomodulatory Strategies: Recent Advances and Perspectives.

PubMed

Cooper, Dustin; Eleftherianos, Ioannis

2016-09-14

More than half of the described species of the phylum Nematoda are considered parasitic, making them one of the most successful groups of parasites. Nematodes are capable of inhabiting a wide variety of niches. A vast array of vertebrate animals, insects, and plants are all identified as potential hosts for nematode parasitization. To invade these hosts successfully, parasitic nematodes must be able to protect themselves from the efficiency and potency of the host immune system. Innate immunity comprises the first wave of the host immune response, and in vertebrate animals it leads to the induction of the adaptive immune response. Nematodes have evolved elegant strategies that allow them to evade, suppress, or modulate host immune responses in order to persist and spread in the host. Nematode immunomodulation involves the secretion of molecules that are capable of suppressing various aspects of the host immune response in order to promote nematode invasion. Immunomodulatory mechanisms can be identified in parasitic nematodes infecting insects, plants, and mammals and vary greatly in the specific tactics by which the parasites modify the host immune response. Nematode-derived immunomodulatory effects have also been shown to affect, negatively or positively, the outcome of some concurrent diseases suffered by the host. Understanding nematode immunomodulatory actions will potentially reveal novel targets that will in turn lead to the development of effective means for the control of destructive nematode parasites.

Interactions of Cryptococcus with Dendritic Cells

PubMed Central

Wozniak, Karen L.

2018-01-01

The fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening infections in immune compromised and immune competent hosts. These pathogens enter the host via inhalation, and respiratory tract innate immune cells such as dendritic cells (DCs) are one of the first host cells they encounter. The interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease in the host. This review will focus specifically on the interactions between Cryptococcus and dendritic cells (DCs), including recognition/processing by DCs, effects of immune mediators on DC recruitment and activity, and the potential for DC vaccination against cryptococcosis. PMID:29543719

Interactions of Cryptococcus with Dendritic Cells.

PubMed

Wozniak, Karen L

2018-03-15

The fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening infections in immune compromised and immune competent hosts. These pathogens enter the host via inhalation, and respiratory tract innate immune cells such as dendritic cells (DCs) are one of the first host cells they encounter. The interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease in the host. This review will focus specifically on the interactions between Cryptococcus and dendritic cells (DCs), including recognition/processing by DCs, effects of immune mediators on DC recruitment and activity, and the potential for DC vaccination against cryptococcosis.

Interaction of entomopathogenic fungi with the host immune system.

PubMed

Qu, Shuang; Wang, Sibao

2018-06-01

Entomopathogenic fungi can invade wide range of insect hosts in the natural world and have been used as environmentally friendly alternatives to chemical insecticides for pest control. Studies of host-pathogen interactions provide valuable insights into the coevolutionay arms race between fungal pathogens and their hosts. Entomopathogenic fungi have evolved a series of sophisticated strategies to counter insect immune defenses. In response to fungal infection, insect hosts rely on behavior avoidance, physical barrier and innate immune defenses in the fight against invading pathogens. The insect cuticle acts as the first physical barrier against pathogens. It is an inhospitable physiological environment that contains chemicals (e.g., antimicrobial peptides and reactive oxygen species), which inhibit fungal growth. In addition, innate immune responses, including cellular immunity and humoral immunity, play critical roles in preventing fungal infection. In this review, we outline the current state of our knowledge of insect defenses to fungal infection and discuss the strategies by which entomopathogenic fungi counter the host immune system. Increased knowledge regarding the molecular interactions between entomopathogenic fungi and the insect host could provide new strategies for pest management. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Cell Wall of the Human Fungal Pathogen Aspergillus fumigatus: Biosynthesis, Organization, Immune Response, and Virulence.

PubMed

Latgé, Jean-Paul; Beauvais, Anne; Chamilos, Georgios

2017-09-08

More than 90% of the cell wall of the filamentous fungus Aspergillus fumigatus comprises polysaccharides. Biosynthesis of the cell wall polysaccharides is under the control of three types of enzymes: transmembrane synthases, which are anchored to the plasma membrane and use nucleotide sugars as substrates, and cell wall-associated transglycosidases and glycosyl hydrolases, which are responsible for remodeling the de novo synthesized polysaccharides and establishing the three-dimensional structure of the cell wall. For years, the cell wall was considered an inert exoskeleton of the fungal cell. The cell wall is now recognized as a living organelle, since the composition and cellular localization of the different constitutive cell wall components (especially of the outer layers) vary when the fungus senses changes in the external environment. The cell wall plays a major role during infection. The recognition of the fungal cell wall by the host is essential in the initiation of the immune response. The interactions between the different pattern-recognition receptors (PRRs) and cell wall pathogen-associated molecular patterns (PAMPs) orientate the host response toward either fungal death or growth, which would then lead to disease development. Understanding the molecular determinants of the interplay between the cell wall and host immunity is fundamental to combatting Aspergillus diseases.

γ-Oryzanol-Rich Black Rice Bran Extract Enhances the Innate Immune Response.

PubMed

Shin, Soon Young; Kim, Heon-Woong; Jang, Hwan-Hee; Hwang, Yu-Jin; Choe, Jeong-Sook; Lim, Yoongho; Kim, Jung-Bong; Lee, Young Han

2017-09-01

The innate immune response is an important host primary defense system against pathogens. γ-Oryzanol is one of the nutritionally important phytoceutical components in rice bran oil. The goal of this study was to investigate the effect of γ-oryzanol-rich extract from black rice bran (γORE) on the activation of the innate immune system. In this study, we show that γORE increased the expression of CD14 and Toll-like receptor 4 and enhanced the phagocytic activity of RAW264.7 macrophages. Furthermore, γORE and its active ingredient γ-oryzanol promoted the secretion of innate cytokines, interleukin-8, and CCL2, which facilitate phagocytosis by RAW264.7 cells. These findings suggest that γ-oryzanol in the γORE enhances innate immune responses.

Xanthomonas campestris cell-cell signalling molecule DSF (diffusible signal factor) elicits innate immunity in plants and is suppressed by the exopolysaccharide xanthan.

PubMed

Kakkar, Akanksha; Nizampatnam, Narasimha Rao; Kondreddy, Anil; Pradhan, Binod Bihari; Chatterjee, Subhadeep

2015-11-01

Several secreted and surface-associated conserved microbial molecules are recognized by the host to mount the defence response. One such evolutionarily well-conserved bacterial process is the production of cell-cell signalling molecules which regulate production of multiple virulence functions by a process known as quorum sensing. Here it is shown that a bacterial fatty acid cell-cell signalling molecule, DSF (diffusible signal factor), elicits innate immunity in plants. The DSF family of signalling molecules are highly conserved among many phytopathogenic bacteria belonging to the genus Xanthomonas as well as in opportunistic animal pathogens. Using Arabidopsis, Nicotiana benthamiana, and rice as model systems, it is shown that DSF induces a hypersensitivity reaction (HR)-like response, programmed cell death, the accumulation of autofluorescent compounds, hydrogen peroxide production, and the expression of the PATHOGENESIS-RELATED1 (PR-1) gene. Furthermore, production of the DSF signalling molecule in Pseudomonas syringae, a non-DSF-producing plant pathogen, induces the innate immune response in the N. benthamiana host plant and also affects pathogen growth. By pre- and co-inoculation of DSF, it was demonstrated that the DSF-induced plant defence reduces disease severity and pathogen growth in the host plant. In this study, it was further demonstrated that wild-type Xanthomonas campestris suppresses the DSF-induced innate immunity by secreting xanthan, the main component of extracellular polysaccharide. The results indicate that plants have evolved to recognize a widely conserved bacterial communication system and may have played a role in the co-evolution of host recognition of the pathogen and the communication machinery. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Xanthomonas campestris cell–cell signalling molecule DSF (diffusible signal factor) elicits innate immunity in plants and is suppressed by the exopolysaccharide xanthan

PubMed Central

Kakkar, Akanksha; Nizampatnam, Narasimha Rao; Kondreddy, Anil; Pradhan, Binod Bihari; Chatterjee, Subhadeep

2015-01-01

Several secreted and surface-associated conserved microbial molecules are recognized by the host to mount the defence response. One such evolutionarily well-conserved bacterial process is the production of cell–cell signalling molecules which regulate production of multiple virulence functions by a process known as quorum sensing. Here it is shown that a bacterial fatty acid cell–cell signalling molecule, DSF (diffusible signal factor), elicits innate immunity in plants. The DSF family of signalling molecules are highly conserved among many phytopathogenic bacteria belonging to the genus Xanthomonas as well as in opportunistic animal pathogens. Using Arabidopsis, Nicotiana benthamiana, and rice as model systems, it is shown that DSF induces a hypersensitivity reaction (HR)-like response, programmed cell death, the accumulation of autofluorescent compounds, hydrogen peroxide production, and the expression of the PATHOGENESIS-RELATED1 (PR-1) gene. Furthermore, production of the DSF signalling molecule in Pseudomonas syringae, a non-DSF-producing plant pathogen, induces the innate immune response in the N. benthamiana host plant and also affects pathogen growth. By pre- and co-inoculation of DSF, it was demonstrated that the DSF-induced plant defence reduces disease severity and pathogen growth in the host plant. In this study, it was further demonstrated that wild-type Xanthomonas campestris suppresses the DSF-induced innate immunity by secreting xanthan, the main component of extracellular polysaccharide. The results indicate that plants have evolved to recognize a widely conserved bacterial communication system and may have played a role in the co-evolution of host recognition of the pathogen and the communication machinery. PMID:26248667

Comparison of the surface coat proteins of the pine wood nematode appeared during host pine infection and in vitro culture by a proteomic approach.

PubMed

Shinya, Ryoji; Morisaka, Hironobu; Takeuchi, Yuko; Ueda, Mitsuyoshi; Futai, Kazuyoshi

2010-12-01

Pine wilt disease, caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus, has become of worldwide quarantine concern in recent years. Here, we disclosed the surface coat (SC) proteins of the PWN which are thought to be one of the key components in pine wilt development. This is the first report that focused on the SC proteins and thoroughly identified those proteins of a plant-parasitic nematode using the proteomic approach. In this study, SC protein profiles were compared for PWNs grown on the fungus Botrytis cinerea and in host pine seedlings. The results demonstrated that the gross amount of PWN SC proteins drastically increased during infection of the host pine. Thirty-seven protein bands showed significant quantity differences between fungus-grown and host-origin PWNs, and were used for identification by matrix-assisted laser desorption ionization time of flight mass spectrometry analysis. These included several proteins that are presumed to be involved in the host immune response; for example, regulators of reactive oxygen species (ROS) and a ROS scavenger. These results might suggest that the PWN SC proteins are crucial in modulating or evading host immune response. Our data provide a new insight into the mechanism of pine wilt disease and the biological role of the SC proteins of plant-parasitic nematodes.

Interplay between Bladder Microbiota and Urinary Antimicrobial Peptides: Mechanisms for Human Urinary Tract Infection Risk and Symptom Severity

PubMed Central

Nienhouse, Vanessa; Gao, Xiang; Dong, Qunfeng; Nelson, David E.; Toh, Evelyn; McKinley, Kathleen; Schreckenberger, Paul; Shibata, Noriko; Fok, Cynthia S.; Mueller, Elizabeth R.; Brubaker, Linda; Wolfe, Alan J.; Radek, Katherine A.

2014-01-01

Resident bacterial communities (microbiota) and host antimicrobial peptides (AMPs) are both essential components of normal host innate immune responses that limit infection and pathogen induced inflammation. However, their interdependence has not been investigated in the context of urinary tract infection (UTI) susceptibility. Here, we explored the interrelationship between the urinary microbiota and host AMP responses as mechanisms for UTI risk. Using prospectively collected day of surgery (DOS) urine specimens from female pelvic floor surgery participants, we report that the relative abundance and/or frequency of specific urinary microbiota distinguished between participants who did or did not develop a post-operative UTI. Furthermore, UTI risk significantly correlated with both specific urinary microbiota and β-defensin AMP levels. Finally, urinary AMP hydrophobicity and protease activity were greater in participants who developed UTI, and correlated positively with both UTI risk and pelvic floor symptoms. These data demonstrate an interdependency between the urinary microbiota, AMP responses and symptoms, and identify a potential mechanism for UTI risk. Assessment of bacterial microbiota and host innate immune AMP responses in parallel may identify increased risk of UTI in certain populations. PMID:25486068

Monitoring Extracellular Vesicle Cargo Active Uptake by Imaging Flow Cytometry.

PubMed

Ofir-Birin, Yifat; Abou Karam, Paula; Rudik, Ariel; Giladi, Tal; Porat, Ziv; Regev-Rudzki, Neta

2018-01-01

Extracellular vesicles are essential for long distance cell-cell communication. They function as carriers of different compounds, including proteins, lipids and nucleic acids. Pathogens, like malaria parasites ( Plasmodium falciparum, Pf ), excel in employing vesicle release to mediate cell communication in diverse processes, particularly in manipulating the host response. Establishing research tools to study the interface between pathogen-derived vesicles and their host recipient cells will greatly benefit the scientific community. Here, we present an imaging flow cytometry (IFC) method for monitoring the uptake of malaria-derived vesicles by host immune cells. By staining different cargo components, we were able to directly track the cargo's internalization over time and measure the kinetics of its delivery. Impressively, we demonstrate that this method can be used to specifically monitor the translocation of a specific protein within the cellular milieu upon internalization of parasitic cargo; namely, we were able to visually observe how uptaken parasitic Pf -DNA cargo leads to translocation of transcription factor IRF3 from the cytosol to the nucleus within the recipient immune cell. Our findings demonstrate that our method can be used to study cellular dynamics upon vesicle uptake in different host-pathogen and pathogen-pathogen systems.

Transcription expression of immune-related genes from Caligus rogercresseyi evidences host-dependent patterns on Atlantic and coho salmon.

PubMed

Vera-Bizama, Fredy; Valenzuela-Muñoz, Valentina; Gonçalves, Ana Teresa; Marambio, Jorge Pino; Hawes, Christopher; Wadsworth, Simon; Gallardo-Escárate, Cristian

2015-12-01

The transcriptomic response of the sea louse Caligus rogercresseyi during the infestation on Atlantic salmon (Salmo salar) and coho salmon (Oncorhynchus kisutch) was evaluated using 27 genes related to immune response, antioxidant system and secretome. Results showed early responses of TLR/IMD signaling pathway in sea lice infesting Atlantic salmon. Overall, genes associated with oxidative stress responses were upregulated in both host species. This pattern suggests that reactive oxygen species emitted by the host as a response to the infestation, could modulate the sea louse antioxidant system. Secretome-related transcripts evidenced upregulation of trypsins and serpins, mainly associated to Atlantic salmon than coho salmon. Interestingly, cathepsins and trypsin2 were downregulated at 7 days post-infection (dpi) in coho salmon. The principal component analysis revealed an inverse time-dependent pattern based on the different responses of C. rogercresseyi infecting both salmon species. Here, Atlantic salmon strongly modulates the transcriptome responses at earlier infection stages; meanwhile coho salmon reveals a less marked modulation, increasing the transcription activity during the infection process. This study evidences transcriptome differences between two salmon host species and provides pivotal knowledge towards elaborating future control strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Induction of innate host responses characterized by production of interleukin (IL)-1β and recruitment of macrophages to the respiratory tract of chickens following infection with infectious bronchitis virus (IBV).

PubMed

Amarasinghe, Aruna; Abdul-Cader, Mohamed Sarjoon; Almatrouk, Zahraa; van der Meer, Frank; Cork, Susan C; Gomis, Susantha; Abdul-Careem, Mohamed Faizal

2018-02-01

Infectious bronchitis virus (IBV) infection is a major cause of economic losses to the poultry industry. Due to limitations in current control measures, alternative approaches, based on thorough understanding of the host responses are required. As one of the key component of the avian immune system, the innate immune system has a crucial role in limiting virus replication at the initial stage of the infection. As parts of the innate host response, macrophages and cytokines, such as interleukin (IL)-1β, are critical components as shown in other host-virus infection models. Since information on the importance of macrophages and IL-1β in IBV infection in chickens is limited, our objective was to determine the association of IL-1β, originating from avian macrophages and IBV infection in the trachea and lung. Following experimental IBV infection in 6 days old chickens, we found increased production of IL-1β and increased recruitment of macrophages in the respiratory tract. Towards the end of the study (5 and 7 days following the IBV infection), the recruited macrophages appear to be a significant source IL-1β. However, only the recruitment of macrophages in the lung correlated with IBV genome loads in this tissue. In conclusion, the present study demonstrates that recruitment of macrophages and the production of IL-1β originating from macrophages, as well as other sources, occur following IBV infection in the respiratory tract suggesting potential roles of these mediators in the host responses to IBV infection. However, further studies are warranted to elucidate whether macrophages and IL-1β are the causes of reduced IBV genome loads in the respiratory tract and also to investigate whether immune mediators that were not measured in the current study were involved in reducing IBV genome load in the respiratory tract towards the end of the study. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Pickle Flavors Relish in Drosophila Immunity.

PubMed

Salminen, Tiina Susanna; Rämet, Mika

2016-09-14

Immune responses must be tightly controlled to avoid host damage. In Drosophila, two NF-κB signaling pathways, Toll and Imd, mediate host immune responses. In this issue of Cell Host & Microbe, Morris et al. (2016) introduce Pickle, a nuclear IκB that inhibits Drosophila immune signaling by modulating the NF-κB Relish. Copyright © 2016 Elsevier Inc. All rights reserved.

Immune Cells and Microbiota Response to Iron Starvation.

PubMed

Chieppa, Marcello; Giannelli, Gianluigi

2018-01-01

Metal ions are essential for life on Earth, mostly as crucial components of all living organisms; indeed, they are necessary for bioenergetics functions as crucial redox catalysts. Due to the essential role of iron in biological processes, body iron content is finely regulated and is the battlefield of a tug-of-war between the host and the microbiota.

Macrophage Migration Inhibitory Factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken

USDA-ARS?s Scientific Manuscript database

Macrophage migration inhibitory factor (MIF) is a soluble factor produced by sensitized T lymphocytes that inhibits the random migration of macrophages. Homologues of MIF from invertebrates have been identified making it an interesting molecule from a functional perspective. In the present study, ...

An Arabidopsis lipid flippase is required for timely recruitment of defenses to the host-pathogen interface at the plant cell surface

USDA-ARS?s Scientific Manuscript database

Deposition of cell wall-reinforcing papillae is an integral component of the plant immune response. The Arabidopsis PENETRATION 3 (PEN3) ATP binding cassette (ABC) transporter plays a role in defense against numerous pathogens and is recruited to sites of pathogen detection where it accumulates with...

Mast cells and IgE in defense against venoms: Possible "good side" of allergy?

PubMed

Galli, Stephen J; Starkl, Philipp; Marichal, Thomas; Tsai, Mindy

2016-01-01

Physicians think of mast cells and IgE primarily in the context of allergic disorders, including fatal anaphylaxis. This 'bad side' of mast cells and IgE is so well accepted that it can be difficult to think of them in other contexts, particularly those in which they may have beneficial functions. However, there is evidence that mast cells and IgE, as well as basophils (circulating granulocytes whose functions partially overlap with those of mast cells), can contribute to host defense as components of adaptive type 2 immune responses to helminths, ticks and certain other parasites. Accordingly, allergies often are conceptualized as "misdirected" type 2 immune responses, in which IgE antibodies are produced against any of a diverse group of apparently harmless antigens, as well as against components of animal venoms. Indeed, certain unfortunate patients who have become sensitized to venoms develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. In this review, we will describe evidence that mast cells can enhance innate resistance to reptile or arthropod venoms during a first exposure to such venoms. We also will discuss findings indicating that, in mice which survive an initial encounter with venom, acquired type 2 immune responses, IgE antibodies, the high affinity IgE receptor (FcɛRI), and mast cells can contribute to acquired resistance to the lethal effects of both honeybee venom and Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against venoms and perhaps other noxious substances. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Role of toll-like receptors in cardiovascular diseases.

PubMed

Vallejo, Jesus G

2011-07-01

The discovery and characterization of the TLR (Toll-like receptor) family has led to a better understanding of the innate immune system. The strategy of innate immune recognition is based on the detection of constitutive and conserved products of micro-organisms. However, host molecules that are released during injury can also activate TLRs. Engagement of TLRs by microbial or host-derived molecules induces the expression of pro-inflammatory cytokines, which may have both beneficial and detrimental effects on the host. In addition to being expressed in immune cells, TLRs are expressed in other tissues such as those of the cardiovascular system. In the present review, the role of TLRs in septic cardiomyopathy, viral myocarditis, atherosclerosis, ischaemia/reperfusion injury and cardiac remodelling after myocardial infarction are outlined, with attention paid to genetically modified murine models. Although much has been learned about stress-induced TLR activation in the tissues of the cardiovascular system, the role of individual TLRs in initiating and integrating homoeostatic responses within the heart remains to be defined. Accumulating evidence indicates that TLRs may play an important role in the pathogenesis of atherosclerosis, viral myocarditis, dilated cardiomyopathy, cardiac allograft rejection and sepsis-induced left ventricular dysfunction. Moreover, heart failure of diverse aetiology is also now recognized to have an important immune component, with TLR signalling influencing the process of cardiac remodelling and prognosis. In the present review, we outline the biology of TLRs as well as the current experimental and clinical evidence for the role of TLRs in cardiovascular diseases.

Two-Component Elements Mediate Interactions between Cytokinin and Salicylic Acid in Plant Immunity

PubMed Central

Argueso, Cristiana T.; Ferreira, Fernando J.; Epple, Petra; To, Jennifer P. C.; Hutchison, Claire E.; Schaller, G. Eric; Dangl, Jeffery L.; Kieber, Joseph J.

2012-01-01

Recent studies have revealed an important role for hormones in plant immunity. We are now beginning to understand the contribution of crosstalk among different hormone signaling networks to the outcome of plant–pathogen interactions. Cytokinins are plant hormones that regulate development and responses to the environment. Cytokinin signaling involves a phosphorelay circuitry similar to two-component systems used by bacteria and fungi to perceive and react to various environmental stimuli. In this study, we asked whether cytokinin and components of cytokinin signaling contribute to plant immunity. We demonstrate that cytokinin levels in Arabidopsis are important in determining the amplitude of immune responses, ultimately influencing the outcome of plant–pathogen interactions. We show that high concentrations of cytokinin lead to increased defense responses to a virulent oomycete pathogen, through a process that is dependent on salicylic acid (SA) accumulation and activation of defense gene expression. Surprisingly, treatment with lower concentrations of cytokinin results in increased susceptibility. These functions for cytokinin in plant immunity require a host phosphorelay system and are mediated in part by type-A response regulators, which act as negative regulators of basal and pathogen-induced SA–dependent gene expression. Our results support a model in which cytokinin up-regulates plant immunity via an elevation of SA–dependent defense responses and in which SA in turn feedback-inhibits cytokinin signaling. The crosstalk between cytokinin and SA signaling networks may help plants fine-tune defense responses against pathogens. PMID:22291601

The bifacial role of helminths in cancer: involvement of immune and non-immune mechanisms.

PubMed

Oikonomopoulou, Katerina; Brinc, Davor; Hadjisavvas, Andreas; Christofi, Georgios; Kyriacou, Kyriacos; Diamandis, Eleftherios P

2014-06-01

Infectious agents have been associated with cancer due to activation of pro-carcinogenic inflammatory processes within their host. Several reports, however, indicate that specific pathogens may be able to elicit anti-tumor immune responses that can lead to protection from tumorigenesis or cancer regression. Amongst these "beneficial" pathogens are some helminthic parasites that have already been connected with prevention of autoimmune diseases and allergies, immune conditions increasingly associated with cancer. Even though helminths have co-existed with humans and their ancestors for millions of years, investigations of their impact on human (patho)physiology are relatively new and the functions of components that can explain the helminth bi-directional influence on carcinogenesis are not well understood. This review aims to discuss evidence for the helminth-induced immune, genetic, epigenetic, proteomic, hormonal and metabolic changes that may ultimately mediate the potential pro- or anti-carcinogenic role of helminths. This overview may serve future investigations in clarifying the tumorigenic role of the most common helminthic parasites. It may also inspire the development of anti-cancer regimens and vaccines, in parallel to ongoing efforts of using helminth-based components for the prevention and/or treatment of autoimmune diseases and allergies.

Host Defense Versus Immunosuppression: Unisexual Infection With Male or Female Schistosoma mansoni Differentially Impacts the Immune Response Against Invading Cercariae.

PubMed

Sombetzki, Martina; Koslowski, Nicole; Rabes, Anne; Seneberg, Sonja; Winkelmann, Franziska; Fritzsche, Carlos; Loebermann, Micha; Reisinger, Emil C

2018-01-01

Infection with the intravascular diecious trematode Schistosoma spp . remains a serious tropical disease and public health problem in the developing world, affecting over 258 million people worldwide. During chronic Schistosoma mansoni infection, complex immune responses to tissue-entrapped parasite eggs provoke granulomatous inflammation which leads to serious damage of the liver and intestine. The suppression of protective host immune mechanisms by helminths promotes parasite survival and benefits the host by reducing tissue damage. However, immune-suppressive cytokines may reduce vaccine-induced immune responses. By combining a single-sex infection system with a murine air pouch model, we were able to demonstrate that male and female schistosomes play opposing roles in modulating the host's immune response. Female schistosomes suppress early innate immune responses to invading cercariae in the skin and upregulate anergy-associated genes. In contrast, male schistosomes trigger strong innate immune reactions which lead to a reduction in worm and egg burden in the liver. Our data suggest that the female worm is a neglected player in the dampening of the host's immune defense system and is therefore a promising target for new immune modulatory therapies.

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses.

PubMed

Boro, Monoranjan; Singh, Vikas; Balaji, Kithiganahalli Narayanaswamy

2016-11-24

Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20-like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

Complement Activation in Inflammatory Skin Diseases

PubMed Central

Giang, Jenny; Seelen, Marc A. J.; van Doorn, Martijn B. A.; Rissmann, Robert; Prens, Errol P.; Damman, Jeffrey

2018-01-01

The complement system is a fundamental part of the innate immune system, playing a crucial role in host defense against various pathogens, such as bacteria, viruses, and fungi. Activation of complement results in production of several molecules mediating chemotaxis, opsonization, and mast cell degranulation, which can contribute to the elimination of pathogenic organisms and inflammation. Furthermore, the complement system also has regulating properties in inflammatory and immune responses. Complement activity in diseases is rather complex and may involve both aberrant expression of complement and genetic deficiencies of complement components or regulators. The skin represents an active immune organ with complex interactions between cellular components and various mediators. Complement involvement has been associated with several skin diseases, such as psoriasis, lupus erythematosus, cutaneous vasculitis, urticaria, and bullous dermatoses. Several triggers including auto-antibodies and micro-organisms can activate complement, while on the other hand complement deficiencies can contribute to impaired immune complex clearance, leading to disease. This review provides an overview of the role of complement in inflammatory skin diseases and discusses complement factors as potential new targets for therapeutic intervention. PMID:29713318

ChIP-seq reveals broad roles of SARD1 and CBP60g in regulating plant immunity.

PubMed

Sun, Tongjun; Zhang, Yaxi; Li, Yan; Zhang, Qian; Ding, Yuli; Zhang, Yuelin

2015-12-18

Recognition of pathogens by host plants leads to rapid transcriptional reprogramming and activation of defence responses. The expression of many defence regulators is induced in this process, but the mechanisms of how they are controlled transcriptionally are largely unknown. Here we use chromatin immunoprecipitation sequencing to show that the transcription factors SARD1 and CBP60g bind to the promoter regions of a large number of genes encoding key regulators of plant immunity. Among them are positive regulators of systemic immunity and signalling components for effector-triggered immunity and PAMP-triggered immunity, which is consistent with the critical roles of SARD1 and CBP60g in these processes. In addition, SARD1 and CBP60g target a number of genes encoding negative regulators of plant immunity, suggesting that they are also involved in negative feedback regulation of defence responses. Based on these findings we propose that SARD1 and CBP60g function as master regulators of plant immune responses.

In vivo Ebola virus infection leads to a strong innate response in circulating immune cells.

PubMed

Caballero, Ignacio S; Honko, Anna N; Gire, Stephen K; Winnicki, Sarah M; Melé, Marta; Gerhardinger, Chiara; Lin, Aaron E; Rinn, John L; Sabeti, Pardis C; Hensley, Lisa E; Connor, John H

2016-09-05

Ebola virus is the causative agent of a severe syndrome in humans with a fatality rate that can approach 90 %. During infection, the host immune response is thought to become dysregulated, but the mechanisms through which this happens are not entirely understood. In this study, we analyze RNA sequencing data to determine the host response to Ebola virus infection in circulating immune cells. Approximately half of the 100 genes with the strongest early increases in expression were interferon-stimulated genes, such as ISG15, OAS1, IFIT2, HERC5, MX1 and DHX58. Other highly upregulated genes included cytokines CXCL11, CCL7, IL2RA, IL2R1, IL15RA, and CSF2RB, which have not been previously reported to change during Ebola virus infection. Comparing this response in two different models of exposure (intramuscular and aerosol) revealed a similar signature of infection. The strong innate response in the aerosol model was seen not only in circulating cells, but also in primary and secondary target tissues. Conversely, the innate immune response of vaccinated macaques was almost non-existent. This suggests that the innate response is a major aspect of the cellular response to Ebola virus infection in multiple tissues. Ebola virus causes a severe infection in humans that is associated with high mortality. The host immune response to virus infection is thought to be an important aspect leading to severe pathology, but the components of this overactive response are not well characterized. Here, we analyzed how circulating immune cells respond to the virus and found that there is a strong innate response dependent on active virus replication. This finding is in stark contrast to in vitro evidence showing a suppression of innate immune signaling, and it suggests that the strong innate response we observe in infected animals may be an important contributor to pathogenesis.

Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during Francisella infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakayasu, Ernesto S.; Tempel, Rebecca; Cambronne, Xiaolu A.

2013-09-22

Francisella tularensis is a facultative intracellular bacterium that causes the deadly disease tularemia. Most evidence suggests that Francisella is not well recognized by the innate immune system that normally leads to cytokine expression and cell death. In previous work, we identified new bacterial factors that were hyper-cytotoxic to macrophages. Four of the identified hyper-cytotoxic strains (lpcC, manB, manC and kdtA) had an impaired lipopolysaccharide (LPS) synthesis and produced an exposed lipid A lacking the O-antigen. These mutants were not only hyper-cytotoxic but also were phagocytosed at much higher rates compared to the wild type parent strain. To elucidate the cellularmore » signaling underlying this enhanced phagocytosis and cell death, we performed a large-scale comparative phosphoproteomic analysis of cells infected with wild-type and delta-lpcC F. novicida. Our data suggest that not only actin but also intermediate filaments and microtubules are important for F. novicida entry into the host cells. In addition, we observed differential phosphorylation of tristetraprolin (TTP), a key component of the mRNA-degrading machinery that controls the expression of a variety of genes including many cytokines. Infection with the delta-lpcC mutant induced the hyper-phosphorylation and inhibition of TTP, leading to the production of cytokines such as IL-1beta and TNF-alpha which may kill the host cells by triggering apoptosis. Together, our data provide new insights for Francisella invasion and a post-transcriptional mechanism that prevents the expression of host immune response factors that controls infection by this pathogen.« less

Social Immunity: Emergence and Evolution of Colony-Level Disease Protection.

PubMed

Cremer, Sylvia; Pull, Christopher D; Fürst, Matthias A

2018-01-07

Social insect colonies have evolved many collectively performed adaptations that reduce the impact of infectious disease and that are expected to maximize their fitness. This colony-level protection is termed social immunity, and it enhances the health and survival of the colony. In this review, we address how social immunity emerges from its mechanistic components to produce colony-level disease avoidance, resistance, and tolerance. To understand the evolutionary causes and consequences of social immunity, we highlight the need for studies that evaluate the effects of social immunity on colony fitness. We discuss the roles that host life history and ecology have on predicted eco-evolutionary dynamics, which differ among the social insect lineages. Throughout the review, we highlight current gaps in our knowledge and promising avenues for future research, which we hope will bring us closer to an integrated understanding of socio-eco-evo-immunology.

Understanding the immune response to seasonal influenza vaccination in older adults: a systems biology approach.

PubMed

Lambert, Nathaniel D; Ovsyannikova, Inna G; Pankratz, V Shane; Jacobson, Robert M; Poland, Gregory A

2012-08-01

Annual vaccination against seasonal influenza is recommended to decrease disease-related mortality and morbidity. However, one population that responds suboptimally to influenza vaccine is adults over the age of 65 years. The natural aging process is associated with a complex deterioration of multiple components of the host immune system. Research into this phenomenon, known as immunosenescence, has shown that aging alters both the innate and adaptive branches of the immune system. The intricate mechanisms involved in immune response to influenza vaccine, and how these responses are altered with age, have led us to adopt a more encompassing systems biology approach to understand exactly why the response to vaccination diminishes with age. Here, the authors review what changes occur with immunosenescence, and some immunogenetic factors that influence response, and outline the systems biology approach to understand the immune response to seasonal influenza vaccination in older adults.

Innate Immune Cells in Liver Inflammation

PubMed Central

Liaskou, Evaggelia; Wilson, Daisy V.; Oo, Ye H.

2012-01-01

Innate immune system is the first line of defence against invading pathogens that is critical for the overall survival of the host. Human liver is characterised by a dual blood supply, with 80% of blood entering through the portal vein carrying nutrients and bacterial endotoxin from the gastrointestinal tract. The liver is thus constantly exposed to antigenic loads. Therefore, pathogenic microorganism must be efficiently eliminated whilst harmless antigens derived from the gastrointestinal tract need to be tolerized in the liver. In order to achieve this, the liver innate immune system is equipped with multiple cellular components; monocytes, macrophages, granulocytes, natural killer cells, and dendritic cells which coordinate to exert tolerogenic environment at the same time detect, respond, and eliminate invading pathogens, infected or transformed self to mount immunity. This paper will discuss the innate immune cells that take part in human liver inflammation, and their roles in both resolution of inflammation and tissue repair. PMID:22933833

Immune response of T cells during herpes simplex virus type 1 (HSV-1) infection.

PubMed

Zhang, Jie; Liu, Huan; Wei, Bin

Herpes simplex virus type 1 (HSV-1), a neurotropic member of the alphaherpes virus family, is among the most prevalent and successful human pathogens. HSV-1 can cause serious diseases at every stage of life including fatal disseminated disease in newborns, cold sores, eye disease, and fatal encephalitis in adults. HSV-1 infection can trigger rapid immune responses, and efficient inhibition and clearance of HSV-1 infection rely on both the innate and adaptive immune responses of the host. Multiple strategies have been used to restrict host innate immune responses by HSV-1 to facilitate its infection in host cells. The adaptive immunity of the host plays an important role in inhibiting HSV-1 infections. The activation and regulation of T cells are the important aspects of the adaptive immunity. They play a crucial role in host-mediated immunity and are important for clearing HSV-1. In this review, we examine the findings on T cell immune responses during HSV-1 infection, which hold promise in the design of new vaccine candidates for HSV-1.

Immune response of T cells during herpes simplex virus type 1 (HSV-1) infection*

PubMed Central

Zhang, Jie; Liu, Huan; Wei, Bin

2017-01-01

Herpes simplex virus type 1 (HSV-1), a neurotropic member of the alphaherpes virus family, is among the most prevalent and successful human pathogens. HSV-1 can cause serious diseases at every stage of life including fatal disseminated disease in newborns, cold sores, eye disease, and fatal encephalitis in adults. HSV-1 infection can trigger rapid immune responses, and efficient inhibition and clearance of HSV-1 infection rely on both the innate and adaptive immune responses of the host. Multiple strategies have been used to restrict host innate immune responses by HSV-1 to facilitate its infection in host cells. The adaptive immunity of the host plays an important role in inhibiting HSV-1 infections. The activation and regulation of T cells are the important aspects of the adaptive immunity. They play a crucial role in host-mediated immunity and are important for clearing HSV-1. In this review, we examine the findings on T cell immune responses during HSV-1 infection, which hold promise in the design of new vaccine candidates for HSV-1. PMID:28378566

SUMO-Enriched Proteome for Drosophila Innate Immune Response

PubMed Central

Handu, Mithila; Kaduskar, Bhagyashree; Ravindranathan, Ramya; Soory, Amarendranath; Giri, Ritika; Elango, Vijay Barathi; Gowda, Harsha; Ratnaparkhi, Girish S.

2015-01-01

Small ubiquitin-like modifier (SUMO) modification modulates the expression of defense genes in Drosophila, activated by the Toll/nuclear factor-κB and immune-deficient/nuclear factor-κB signaling networks. We have, however, limited understanding of the SUMO-modulated regulation of the immune response and lack information on SUMO targets in the immune system. In this study, we measured the changes to the SUMO proteome in S2 cells in response to a lipopolysaccharide challenge and identified 1619 unique proteins in SUMO-enriched lysates. A confident set of 710 proteins represents the immune-induced SUMO proteome and analysis suggests that specific protein domains, cellular pathways, and protein complexes respond to immune stress. A small subset of the confident set was validated by in-bacto SUMOylation and shown to be bona-fide SUMO targets. These include components of immune signaling pathways such as Caspar, Jra, Kay, cdc42, p38b, 14-3-3ε, as well as cellular proteins with diverse functions, many being components of protein complexes, such as prosß4, Rps10b, SmD3, Tango7, and Aats-arg. Caspar, a human FAF1 ortholog that negatively regulates immune-deficient signaling, is SUMOylated at K551 and responds to treatment with lipopolysaccharide in cultured cells. Our study is one of the first to describe SUMO proteome for the Drosophila immune response. Our data and analysis provide a global framework for the understanding of SUMO modification in the host response to pathogens. PMID:26290570

SUMO-Enriched Proteome for Drosophila Innate Immune Response.

PubMed

Handu, Mithila; Kaduskar, Bhagyashree; Ravindranathan, Ramya; Soory, Amarendranath; Giri, Ritika; Elango, Vijay Barathi; Gowda, Harsha; Ratnaparkhi, Girish S

2015-08-18

Small ubiquitin-like modifier (SUMO) modification modulates the expression of defense genes in Drosophila, activated by the Toll/nuclear factor-κB and immune-deficient/nuclear factor-κB signaling networks. We have, however, limited understanding of the SUMO-modulated regulation of the immune response and lack information on SUMO targets in the immune system. In this study, we measured the changes to the SUMO proteome in S2 cells in response to a lipopolysaccharide challenge and identified 1619 unique proteins in SUMO-enriched lysates. A confident set of 710 proteins represents the immune-induced SUMO proteome and analysis suggests that specific protein domains, cellular pathways, and protein complexes respond to immune stress. A small subset of the confident set was validated by in-bacto SUMOylation and shown to be bona-fide SUMO targets. These include components of immune signaling pathways such as Caspar, Jra, Kay, cdc42, p38b, 14-3-3ε, as well as cellular proteins with diverse functions, many being components of protein complexes, such as prosß4, Rps10b, SmD3, Tango7, and Aats-arg. Caspar, a human FAF1 ortholog that negatively regulates immune-deficient signaling, is SUMOylated at K551 and responds to treatment with lipopolysaccharide in cultured cells. Our study is one of the first to describe SUMO proteome for the Drosophila immune response. Our data and analysis provide a global framework for the understanding of SUMO modification in the host response to pathogens. Copyright © 2015 Handu et al.

Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity.

PubMed

Thomas, David C; Clare, Simon; Sowerby, John M; Pardo, Mercedes; Juss, Jatinder K; Goulding, David A; van der Weyden, Louise; Storisteanu, Daniel; Prakash, Ananth; Espéli, Marion; Flint, Shaun; Lee, James C; Hoenderdos, Kim; Kane, Leanne; Harcourt, Katherine; Mukhopadhyay, Subhankar; Umrania, Yagnesh; Antrobus, Robin; Nathan, James A; Adams, David J; Bateman, Alex; Choudhary, Jyoti S; Lyons, Paul A; Condliffe, Alison M; Chilvers, Edwin R; Dougan, Gordon; Smith, Kenneth G C

2017-04-03

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91 phox and p22 phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643 , and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91 phox and p22 phox Consequently, Eros -deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense. © 2017 Thomas et al.

Novel Disease Susceptibility Factors for Fungal Necrotrophic Pathogens in Arabidopsis

PubMed Central

García-Andrade, Javier; Angulo, Carlos; Neumetzler, Lutz; Persson, Staffan; Vera, Pablo

2015-01-01

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens. PMID:25830627

Modulating airway defenses against microbes.

PubMed

Reynolds, Herbert Y

2002-05-01

Prevention and treatment of respiratory infections remain an important health care challenge as the US population ages, contains more susceptible or high-risk people, and encounters new pathogens or antibiotic resistant bacteria. Reasonably protective vaccines against very common microbes are available for childhood and adult immunization, but, generally, these are underutilized. A broader definition of higher risk individuals is evolving, which will include more for immunization. Different approaches to vaccine development through design of new component vaccines are necessary. This review has updated host defense mechanisms at three levels in the human respiratory tract: naso-oropharynx (upper airways), conducting airways, and alveolar space. Examples of representative pathogenic microbes have been inserted at the respective airway segment where they may colonize or create infection (influenza, measles virus, Porphyromonas gingivalis causing periodontitis, Bordetella pertussis, Chlamydia pneumoniae, Streptococcus pneumoniae, and Bacillus anthracis ). Hopefully, microbe-host interactions will suggest new approaches for preventing these kinds of infections.

Influenza A virus-induced degradation of eukaryotic translation initiation factor 4B contributes to viral replication by suppressing IFITM3 protein expression.

PubMed

Wang, Song; Chi, Xiaojuan; Wei, Haitao; Chen, Yuhai; Chen, Zhilong; Huang, Shile; Chen, Ji-Long

2014-08-01

Although alteration in host cellular translation machinery occurs in virus-infected cells, the role of such alteration and the precise pathogenic processes are not well understood. Influenza A virus (IAV) infection shuts off host cell gene expression at transcriptional and translational levels. Here, we found that the protein level of eukaryotic translation initiation factor 4B (eIF4B), an integral component of the translation initiation apparatus, was dramatically reduced in A549 cells as well as in the lung, spleen, and thymus of mice infected with IAV. The decrease in eIF4B level was attributed to lysosomal degradation of eIF4B, which was induced by viral NS1 protein. Silencing eIF4B expression in A549 cells significantly promoted IAV replication, and conversely, overexpression of eIF4B markedly inhibited the viral replication. Importantly, we observed that eIF4B knockdown transgenic mice were more susceptible to IAV infection, exhibiting faster weight loss, shorter survival time, and more-severe organ damage. Furthermore, we demonstrated that eIF4B regulated the expression of interferon-induced transmembrane protein 3 (IFITM3), a critical protein involved in immune defense against a variety of RNA viruses, including influenza virus. Taken together, our findings reveal that eIF4B plays an important role in host defense against IAV infection at least by regulating the expression of IFITM3, which restricts viral entry and thereby blocks early stages of viral production. These data also indicate that influenza virus has evolved a strategy to overcome host innate immunity by downregulating eIF4B protein. Influenza A virus (IAV) infection stimulates the host innate immune system, in part, by inducing interferons (IFNs). Secreted IFNs activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, leading to elevated transcription of a large group of IFN-stimulated genes that have antiviral function. To circumvent the host innate immune response, influenza virus has evolved multiple strategies for suppressing the production of IFNs. Here, we show that IAV infection induces lysosomal degradation of eIF4B protein; and eIF4B inhibits IAV replication by upregulating expression of interferon-induced transmembrane protein 3 (IFITM3), a key protein that protects the host from virus infection. Our finding illustrates a critical role of eIF4B in the host innate immune response and provides novel insights into the complex mechanisms by which influenza virus interacts with its host. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The Role of the Polymeric Immunoglobulin Receptor and Secretory Immunoglobulins during Mucosal Infection and Immunity.

PubMed

Turula, Holly; Wobus, Christiane E

2018-05-03

The gastrointestinal tract houses millions of microbes, and thus has evolved several host defense mechanisms to keep them at bay, and prevent their entry into the host. One such mucosal surface defense is the secretion of secretory immunoglobulins (SIg). Secretion of SIg depends on the polymeric immunoglobulin receptor (pIgR), which transports polymeric Ig (IgA or IgM) from the basolateral surface of the epithelium to the apical side. Upon reaching the luminal side, a portion of pIgR, called secretory component (SC) is cleaved off to release Ig, forming SIg. Through antigen-specific and non-specific binding, SIg can modulate microbial communities and pathogenic microbes via several mechanisms: agglutination and exclusion from the epithelial surface, neutralization, or via host immunity and complement activation. Given the crucial role of SIg as a microbial scavenger, some pathogens also evolved ways to modulate and utilize pIgR and SIg to facilitate infection. This review will cover the regulation of the pIgR/SIg cycle, mechanisms of SIg-mediated mucosal protection as well as pathogen utilization of SIg.

Cross-reactive acquired immunity influences transmission success of the Lyme disease pathogen, Borrelia afzelii.

PubMed

Jacquet, Maxime; Durand, Jonas; Rais, Olivier; Voordouw, Maarten J

2015-12-01

Cross-reactive acquired immunity in the vertebrate host induces indirect competition between strains of a given pathogen species and is critical for understanding the ecology of mixed infections. In vector-borne diseases, cross-reactive antibodies can reduce pathogen transmission at the vector-to-host and the host-to-vector lifecycle transition. The highly polymorphic, immunodominant, outer surface protein C (OspC) of the tick-borne spirochete bacterium Borrelia afzelii induces a strong antibody response in the vertebrate host. To test how cross-immunity in the vertebrate host influences tick-to-host and host-to-tick transmission, mice were immunized with one of two strain-specific recombinant OspC proteins (A3, A10), challenged via tick bite with one of the two B. afzelii ospC strains (A3, A10), and infested with xenodiagnostic ticks. Immunization with a given rOspC antigen protected mice against homologous strains carrying the same major ospC group allele but provided little or no cross-protection against heterologous strains carrying a different major ospC group allele. There were cross-immunity effects on the tick spirochete load but not on the probability of host-to-tick transmission. The spirochete load in ticks that had fed on mice with cross-immune experience was reduced by a factor of two compared to ticks that had fed on naive control mice. In addition, strain-specific differences in mouse spirochete load, host-to-tick transmission, tick spirochete load, and the OspC-specific IgG response revealed the mechanisms that determine variation in transmission success between strains of B. afzelii. This study shows that cross-immunity in infected vertebrate hosts can reduce pathogen load in the arthropod vector with potential consequences for vector-to-host pathogen transmission. Copyright © 2015 Elsevier B.V. All rights reserved.

Interchromosomal Transfer of Immune Regulation During Infection of Barley with the Powdery Mildew Pathogen

PubMed Central

Surana, Priyanka; Xu, Ruo; Fuerst, Gregory; Chapman, Antony V. E.; Nettleton, Dan; Wise, Roger P.

2017-01-01

Powdery mildew pathogens colonize over 9500 plant species, causing critical yield loss. The Ascomycete fungus, Blumeria graminis f. sp. hordei (Bgh), causes powdery mildew disease in barley (Hordeum vulgare L.). Successful infection begins with penetration of host epidermal cells, culminating in haustorial feeding structures, facilitating delivery of fungal effectors to the plant and exchange of nutrients from host to pathogen. We used expression Quantitative Trait Locus (eQTL) analysis to dissect the temporal control of immunity-associated gene expression in a doubled haploid barley population challenged with Bgh. Two highly significant regions possessing trans eQTL were identified near the telomeric ends of chromosomes (Chr) 2HL and 1HS. Within these regions reside diverse resistance loci derived from barley landrace H. laevigatum (MlLa) and H. vulgare cv. Algerian (Mla1), which associate with the altered expression of 961 and 3296 genes during fungal penetration of the host and haustorial development, respectively. Regulatory control of transcript levels for 299 of the 961 genes is reprioritized from MlLa on 2HL to Mla1 on 1HS as infection progresses, with 292 of the 299 alternating the allele responsible for higher expression, including Adaptin Protein-2 subunit μ AP2M and Vesicle Associated Membrane Protein VAMP72 subfamily members VAMP721/722. AP2M mediates effector-triggered immunity (ETI) via endocytosis of plasma membrane receptor components. VAMP721/722 and SNAP33 form a Soluble N-ethylmaleimide-sensitive factor Attachment Protein REceptor (SNARE) complex with SYP121 (PEN1), which is engaged in pathogen associated molecular pattern (PAMP)-triggered immunity via exocytosis. We postulate that genes regulated by alternate chromosomal positions are repurposed as part of a conserved immune complex to respond to different pathogen attack scenarios. PMID:28790145

Spiroplasma and host immunity: activation of humoral immune responses increases endosymbiont load and susceptibility to certain Gram-negative bacterial pathogens in Drosophila melanogaster.

PubMed

Herren, Jeremy K; Lemaitre, Bruno

2011-09-01

Spiroplasma poulsonii and its relatives are facultative, vertically transmitted endosymbionts harboured by several Drosophila species. Their long-term survival requires not only evasion of host immunity, but also that Spiroplasma does not have a net detrimental effect on host fitness. These requirements provide the central framework for interactions between host and endosymbiont. We use Drosophila melaogaster as a model to unravel aspects of the mechanistic basis of endosymbiont-host immune interactions. Here we show that Spiroplasma does not activate an immune response in Drosophila and is not susceptible to either the cellular or humoral arms of the Drosophila immune system. We gain unexpected insight into host factors that can promote Spiroplasma growth by showing that activation of Toll and Imd immune pathways actually increases Sprioplasma titre. Spiroplasma-mediated protection is not observed for variety of fungal and bacterial pathogens and Spiroplasma actually increases susceptibility of Drosophila to certain Gram-negative pathogens. Finally, we show that the growth of endosymbiotic Spiroplasma is apparently self-regulated, as suggested by the unhindered proliferation of non-endosymbiotic Spiroplasma citri in fly haemolymph. © 2011 Blackwell Publishing Ltd.

Comparison of O-Antigen gene clusters of all O-Serogroups of Escherichia coli and proposal for adopting a new nomenclature for O-Typing

USDA-ARS?s Scientific Manuscript database

Escherichia coli strains are classified based on O-antigens that are components of the lipopolysaccharide (LPS) in the cell envelope. O-antigens are important virulence factors, targets of both the innate and adaptive immune system, and play a role in host-pathogen interaction. Because they are hi...

Up in Arms: Immune and Nervous System Response to Sea Star Wasting Disease.

PubMed

Fuess, Lauren E; Eisenlord, Morgan E; Closek, Collin J; Tracy, Allison M; Mauntz, Ruth; Gignoux-Wolfsohn, Sarah; Moritsch, Monica M; Yoshioka, Reyn; Burge, Colleen A; Harvell, C Drew; Friedman, Carolyn S; Hewson, Ian; Hershberger, Paul K; Roberts, Steven B

2015-01-01

Echinoderms, positioned taxonomically at the base of deuterostomes, provide an important system for the study of the evolution of the immune system. However, there is little known about the cellular components and genes associated with echinoderm immunity. The 2013-2014 sea star wasting disease outbreak is an emergent, rapidly spreading disease, which has led to large population declines of asteroids in the North American Pacific. While evidence suggests that the signs of this disease, twisting arms and lesions, may be attributed to a viral infection, the host response to infection is still poorly understood. In order to examine transcriptional responses of the sea star Pycnopodia helianthoides to sea star wasting disease, we injected a viral sized fraction (0.2 μm) homogenate prepared from symptomatic P. helianthoides into apparently healthy stars. Nine days following injection, when all stars were displaying signs of the disease, specimens were sacrificed and coelomocytes were extracted for RNA-seq analyses. A number of immune genes, including those involved in Toll signaling pathways, complement cascade, melanization response, and arachidonic acid metabolism, were differentially expressed. Furthermore, genes involved in nervous system processes and tissue remodeling were also differentially expressed, pointing to transcriptional changes underlying the signs of sea star wasting disease. The genomic resources presented here not only increase understanding of host response to sea star wasting disease, but also provide greater insight into the mechanisms underlying immune function in echinoderms.

A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs.

PubMed

Gordon, Y Jerold; Romanowski, Eric G; McDermott, Alison M

2005-07-01

Antimicrobial peptides (AMPs) are an essential part of innate immunity that evolved in most living organisms over 2.6 billion years to combat microbial challenge. These small cationic peptides are multifunctional as effectors of innate immunity on skin and mucosal surfaces and have demonstrated direct antimicrobial activity against various bacteria, viruses, fungi, and parasites. This review summarizes their progress to date as commercial antimicrobial drugs for topical and systemic indications. Literature review. Despite numerous clinical trials, no modified AMP has obtained Food & Drug Administration approval yet for any topical or systemic medical indications. While AMPs are recognized as essential components of natural host innate immunity against microbial challenge, their usefulness as a new class of antimicrobial drugs still remains to be proven.

T-cell selection and intestinal homeostasis

PubMed Central

Ai, Teresa L.; Solomon, Benjamin D.; Hsieh, Chyi-Song

2014-01-01

Summary Although intestinal bacteria live deep within the body, they are topographically on the exterior surface and thus outside the host. According to the classic notion that the immune system targets non-self rather than self, these intestinal bacteria should be considered foreign and therefore attacked and eliminated. While this appears to be true for some commensal bacterial species, recent data suggests that the immune system actively becomes tolerant to many bacterial organisms. The induction or activation of regulatory T (Treg) cells that inhibit, rather than promote, inflammatory responses to commensal bacteria appears to be a central component of mucosal tolerance. Loss of this mechanism can lead to inappropriate immune reactivity toward commensal organisms, perhaps contributing to mucosal inflammation characteristic of disorders such as inflammatory bowel disease. PMID:24712459

Sexual dimorphism in immune function changes during the annual cycle in house sparrows

NASA Astrophysics Data System (ADS)

Pap, Péter László; Czirják, Gábor Árpád; Vágási, Csongor István; Barta, Zoltán; Hasselquist, Dennis

2010-10-01

Difference between sexes in parasitism is a common phenomenon among birds, which may be related to differences between males and females in their investment into immune functions or as a consequence of differential exposure to parasites. Because life-history strategies change sex specifically during the annual cycle, immunological responses of the host aiming to reduce the impact of parasites may be sexually dimorphic. Despite the great complexity of the immune system, studies on immunoecology generally characterise the immune status through a few variables, often overlooking potentially important seasonal and gender effects. However, because of the differences in physiological and defence mechanisms among different arms of the immune system, we expect divergent responses of immune components to environmental seasonality. In male and female house sparrows ( Passer domesticus), we measured the major components of the immune system (innate, acquired, cellular and humoral) during four important life-history stages across the year: (1) mating, (2) breeding, (3) moulting and (4) during the winter capture and also following introduction to captivity in aviary. Different individuals were sampled from the same population during the four life cycle stages. We found that three out of eight immune variables showed a significant life cycle stage × sex interaction. The difference in immune response between the sexes was significant in five immune variables during the mating stage, when females had consistently stronger immune function than males, while variables varied generally non-significantly with sex during the remaining three life cycle stages. Our results show that the immune system is highly variable between life cycle stages and sexes, highlighting the potential fine tuning of the immune system to specific physiological states and environmental conditions.

Contribution of advances in immunology to vaccine development.

PubMed

Morrison, W I; Taylor, G; Gaddum, R M; Ellis, S A

1999-01-01

During the last 10 years, investigation of the bovine immune system has generated knowledge and reagents that can now be applied to study the mechanisms of immunity to disease and the identity of antigens recognized by protective immune responses. Such studies can indicate which antigens are likely to be effective in subunit vaccines and also highlight the type of antigen delivery system that will be required for a vaccine to induce a protective immune response. In the case of bovine RSV, studies of immune responses in the target host have demonstrated that both antibody and CTL responses play an important role in immunity. Both the F and G glycoproteins have been identified as targets of protective antibodies, and systems have been established that will allow the identification of the viral antigens recognized by CTL. Further studies of CD4+ T-cell responses to the virus are required to determine whether or not components of the response have the potential to enhance disease and, therefore, need to be avoided in vaccination strategies.

Statistical Physics of T-Cell Development and Pathogen Specificity

NASA Astrophysics Data System (ADS)

Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

2013-04-01

In addition to an innate immune system that battles pathogens in a nonspecific fashion, higher organisms, such as humans, possess an adaptive immune system to combat diverse (and evolving) microbial pathogens. Remarkably, the adaptive immune system mounts pathogen-specific responses, which can be recalled upon reinfection with the same pathogen. It is difficult to see how the adaptive immune system can be preprogrammed to respond specifically to a vast and unknown set of pathogens. Although major advances have been made in understanding pertinent molecular and cellular phenomena, the precise principles that govern many aspects of an immune response are largely unknown. We discuss complementary approaches from statistical mechanics and cell biology that can shed light on how key components of the adaptive immune system, T cells, develop to enable pathogen-specific responses against many diverse pathogens. The mechanistic understanding that emerges has implications for how host genetics may influence the development of T cells with differing responses to the human immunodeficiency virus (HIV) infection.

Experimental demonstration of a parasite-induced immune response in wild birds: Darwin's finches and introduced nest flies.

PubMed

Koop, Jennifer A H; Owen, Jeb P; Knutie, Sarah A; Aguilar, Maria A; Clayton, Dale H

2013-08-01

Ecological immunology aims to explain variation among hosts in the strength and efficacy of immunological defenses. However, a shortcoming has been the failure to link host immune responses to actual parasites under natural conditions. Here, we present one of the first experimental demonstrations of a parasite-induced immune response in a wild bird population. The recently introduced ectoparasitic nest fly Philornis downsi severely impacts the fitness of Darwin's finches and other land birds in the Galápagos Islands. An earlier study showed that female medium ground finches (Geospiza fortis) had P. downsi-binding antibodies correlating with presumed variation in fly exposure over time. In the current study, we experimentally manipulated fly abundance to test whether the fly does, in fact, cause changes in antibody levels. We manipulated P. downsi abundance in nests and quantified P. downsi-binding antibody levels of medium ground finch mothers, fathers, and nestlings. We also quantified host behaviors, such as preening, which can integrate with antibody-mediated defenses against ectoparasites. Philornis downsi-binding antibody levels were significantly higher among mothers at parasitized nests, compared to mothers at (fumigated) nonparasitized nests. Mothers with higher antibody levels tended to have fewer parasites in their nests, suggesting that antibodies play a role in defense against parasites. Mothers showed no behavioral changes that would enhance the effectiveness of the immune response. Neither adult males, nor nestlings, had P. downsi-induced immunological or behavioral responses that would enhance defense against flies. None of the parasitized nests fledged any offspring, despite the immune response by mothers. Thus, this study shows that, while the immune response of mothers appeared to be defensive, it was not sufficient to rescue current reproductive fitness. This study further shows the importance of testing the fitness consequences of immune defenses, rather than assuming that such responses increase host fitness. Host immune responses can protect against the negative fitness consequences of parasitism; however, the strength and effectiveness of these responses vary among hosts. Strong host immune responses are often assumed to correlate with greater host fitness. This study investigates the relationship between host immune response, parasite load, and host fitness using Darwin's finches and an invasive nest parasite. We found that while the immune response of mothers appeared defensive, it did not rescue current reproductive fitness.

Common themes in microbial pathogenicity revisited.

PubMed Central

Finlay, B B; Falkow, S

1997-01-01

Bacterial pathogens employ a number of genetic strategies to cause infection and, occasionally, disease in their hosts. Many of these virulence factors and their regulatory elements can be divided into a smaller number of groups based on the conservation of similar mechanisms. These common themes are found throughout bacterial virulence factors. For example, there are only a few general types of toxins, despite a large number of host targets. Similarly, there are only a few conserved ways to build the bacterial pilus and nonpilus adhesins used by pathogens to adhere to host substrates. Bacterial entry into host cells (invasion) is a complex mechanism. However, several common invasion themes exist in diverse microorganisms. Similarly, once inside a host cell, pathogens have a limited number of ways to ensure their survival, whether remaining within a host vacuole or by escaping into the cytoplasm. Avoidance of the host immune defenses is key to the success of a pathogen. Several common themes again are employed, including antigenic variation, camouflage by binding host molecules, and enzymatic degradation of host immune components. Most virulence factors are found on the bacterial surface or secreted into their immediate environment, yet virulence factors operate through a relatively small number of microbial secretion systems. The expression of bacterial pathogenicity is dependent upon complex regulatory circuits. However, pathogens use only a small number of biochemical families to express distinct functional factors at the appropriate time that causes infection. Finally, virulence factors maintained on mobile genetic elements and pathogenicity islands ensure that new strains of pathogens evolve constantly. Comprehension of these common themes in microbial pathogenicity is critical to the understanding and study of bacterial virulence mechanisms and to the development of new "anti-virulence" agents, which are so desperately needed to replace antibiotics. PMID:9184008

Fungal effector Ecp6 outcompetes host immune receptor for chitin binding through intrachain LysM dimerization

PubMed Central

Kombrink, Anja; Hansen, Guido; Valkenburg, Dirk-Jan

2013-01-01

While host immune receptors detect pathogen-associated molecular patterns to activate immunity, pathogens attempt to deregulate host immunity through secreted effectors. Fungi employ LysM effectors to prevent recognition of cell wall-derived chitin by host immune receptors, although the mechanism to compete for chitin binding remained unclear. Structural analysis of the LysM effector Ecp6 of the fungal tomato pathogen Cladosporium fulvum reveals a novel mechanism for chitin binding, mediated by intrachain LysM dimerization, leading to a chitin-binding groove that is deeply buried in the effector protein. This composite binding site involves two of the three LysMs of Ecp6 and mediates chitin binding with ultra-high (pM) affinity. Intriguingly, the remaining singular LysM domain of Ecp6 binds chitin with low micromolar affinity but can nevertheless still perturb chitin-triggered immunity. Conceivably, the perturbation by this LysM domain is not established through chitin sequestration but possibly through interference with the host immune receptor complex. DOI: http://dx.doi.org/10.7554/eLife.00790.001 PMID:23840930

Escaping Deleterious Immune Response in Their Hosts: Lessons from Trypanosomatids

PubMed Central

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

2016-01-01

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

Local and Long-Distance Calling: Conversations between the Gut Microbiota and Intra- and Extra-Gastrointestinal Tract Infections.

PubMed

Denny, Joshua E; Powell, Whitney L; Schmidt, Nathan W

2016-01-01

Preservation of health from infectious diseases depends upon both mucosal and systemic immunity via the collaborative effort of innate and adaptive immune responses. The proficiency of host immunity stems from robust defense mechanisms--physical barriers and specialized immune cells--and a failure of these mechanisms leads to pathology. Intriguingly, immunocompetence to pathogens can be shaped by the gut microbiome as recent publications highlight a dynamic interplay between the gut microbiome and host susceptibility to infection. Modulation of host immunity to enteric pathogens has long been studied where gut bacteria shape multiple facts of both innate and adaptive immunity. Conversely, the impact of gut commensals on host immunity to extra-gastrointestinal (GI) tract infections has only recently been recognized. In this context, the gut microbiome can augment host immunity to extra-GI tract bacterial, viral, and parasitic pathogens. This review explores the research that affords insight into the role of the gut microbiome in various infectious diseases, with a particular emphasis on extra-GI tract infections. A better understanding of the link between the gut microbiome and infectious disease will be critical for improving global health in the years ahead.

A Plethora of Virulence Strategies Hidden Behind Nuclear Targeting of Microbial Effectors

PubMed Central

Rivas, Susana; Genin, Stéphane

2011-01-01

Plant immune responses depend on the ability to couple rapid recognition of the invading microbe to an efficient response. During evolution, plant pathogens have acquired the ability to deliver effector molecules inside host cells in order to manipulate cellular and molecular processes and establish pathogenicity. Following translocation into plant cells, microbial effectors may be addressed to different subcellular compartments. Intriguingly, a significant number of effector proteins from different pathogenic microorganisms, including viruses, oomycetes, fungi, nematodes, and bacteria, is targeted to the nucleus of host cells. In agreement with this observation, increasing evidence highlights the crucial role played by nuclear dynamics, and nucleocytoplasmic protein trafficking during a great variety of analyzed plant–pathogen interactions. Once in the nucleus, effector proteins are able to manipulate host transcription or directly subvert essential host components to promote virulence. Along these lines, it has been suggested that some effectors may affect histone packing and, thereby, chromatin configuration. In addition, microbial effectors may either directly activate transcription or target host transcription factors to alter their regular molecular functions. Alternatively, nuclear translocation of effectors may affect subcellular localization of their cognate resistance proteins in a process that is essential for resistance protein-mediated plant immunity. Here, we review recent progress in our field on the identification of microbial effectors that are targeted to the nucleus of host plant cells. In addition, we discuss different virulence strategies deployed by microbes, which have been uncovered through examination of the mechanisms that guide nuclear localization of effector proteins. PMID:22639625

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.…

Drosophila Pkaap regulates Rab4/Rab11-dependent traffic and Rab11 exocytosis of innate immune cargo

PubMed Central

Sorvina, Alexandra; Shandala, Tetyana; Brooks, Douglas A.

2016-01-01

ABSTRACT The secretion of immune-mediators is a critical step in the host innate immune response to pathogen invasion, and Rab GTPases have an important role in the regulation of this process. Rab4/Rab11 recycling endosomes are involved in the sorting of immune-mediators into specialist Rab11 vesicles that can traffic this cargo to the plasma membrane; however, how this sequential delivery process is regulated has yet to be fully defined. Here, we report that Drosophila Pkaap, an orthologue of the human dual-specific A-kinase-anchoring protein 2 or D-AKAP2 (also called AKAP10), appeared to have a nucleotide-dependent localisation to Rab4 and Rab11 endosomes. RNAi silencing of pkaap altered Rab4/Rab11 recycling endosome morphology, suggesting that Pkaap functions in cargo sorting and delivery in the secretory pathway. The depletion of pkaap also had a direct effect on Rab11 vesicle exocytosis and the secretion of the antimicrobial peptide Drosomycin at the plasma membrane. We propose that Pkaap has a dual role in antimicrobial peptide traffic and exocytosis, making it an essential component for the secretion of inflammatory mediators and the defence of the host against pathogens. PMID:27190105

The VraSR regulatory system contributes to virulence in Streptococcus suis via resistance to innate immune defenses

PubMed Central

Chang, Peixi; Li, Weitian; Shi, Guolin; Li, Huan; Yang, Xiaoqing; Xia, Zechen; Ren, Yuan; Li, Zhiwei; Chen, Huanchun; Bei, Weicheng

2018-01-01

ABSTRACT Streptococcus suis is a highly invasive pathogen that can cause sepsis and meningitis in pigs and humans. However, we have limited understanding of the mechanisms S. suis uses to evade innate immunity. To investigate the involvement of the two-component signal transduction system of S. suis in host immune defense, we examined the expression of 15 response regulators of S. suis following stimulation with polymorphonuclear leukocytes (PMNs). We found that several response regulators were significantly up-regulated including vraR. Thus, we constructed an isogenic deletion mutant of vraSR genes in S. suis and demonstrated VraSR promotes both bacterial survival in human blood and resistance to human PMN-mediated killing. The VraSR mutant was more susceptible to phagocytosis by human PMNs and had greater sensitivity to oxidant and lysozyme than wild-type S. suis. Furthermore, in vitro findings and in vivo evidence from a mouse infection model together strongly demonstrate that ΔvraSR had greatly attenuated virulence compared with wild-type S. suis. Collectively, our data reveal that VraSR is a critical regulatory system that contributes to the survival of S. suis and its ability to defend against host innate immunity. PMID:29471718

Bombyx mori and Aedes aegypti form multi-functional immune complexes that integrate pattern recognition, melanization, coagulants, and hemocyte recruitment

PubMed Central

Phillips, Dennis R.

2017-01-01

The innate immune system of insects responds to wounding and pathogens by mobilizing multiple pathways that provide both systemic and localized protection. Key localized responses in hemolymph include melanization, coagulation, and hemocyte encapsulation, which synergistically seal wounds and envelop and destroy pathogens. To be effective, these pathways require a targeted deposition of their components to provide protection without compromising the host. Extensive research has identified a large number of the effectors that comprise these responses, but questions remain regarding their post-translational processing, function, and targeting. Here, we used mass spectrometry to demonstrate the integration of pathogen recognition proteins, coagulants, and melanization components into stable, high-mass, multi-functional Immune Complexes (ICs) in Bombyx mori and Aedes aegypti. Essential proteins common to both include phenoloxidases, apolipophorins, serine protease homologs, and a serine protease that promotes hemocyte recruitment through cytokine activation. Pattern recognition proteins included C-type Lectins in B. mori, while A. aegypti contained a protein homologous to Plasmodium-resistant LRIM1 from Anopheles gambiae. We also found that the B. mori IC is stabilized by extensive transglutaminase-catalyzed cross-linking of multiple components. The melanization inhibitor Egf1.0, from the parasitoid wasp Microplitis demolitor, blocked inclusion of specific components into the IC and also inhibited transglutaminase activity. Our results show how coagulants, melanization components, and hemocytes can be recruited to a wound surface or pathogen, provide insight into the mechanism by which a parasitoid evades this immune response, and suggest that insects as diverse as Lepidoptera and Diptera utilize similar defensive mechanisms. PMID:28199361

Bombyx mori and Aedes aegypti form multi-functional immune complexes that integrate pattern recognition, melanization, coagulants, and hemocyte recruitment.

PubMed

Phillips, Dennis R; Clark, Kevin D

2017-01-01

The innate immune system of insects responds to wounding and pathogens by mobilizing multiple pathways that provide both systemic and localized protection. Key localized responses in hemolymph include melanization, coagulation, and hemocyte encapsulation, which synergistically seal wounds and envelop and destroy pathogens. To be effective, these pathways require a targeted deposition of their components to provide protection without compromising the host. Extensive research has identified a large number of the effectors that comprise these responses, but questions remain regarding their post-translational processing, function, and targeting. Here, we used mass spectrometry to demonstrate the integration of pathogen recognition proteins, coagulants, and melanization components into stable, high-mass, multi-functional Immune Complexes (ICs) in Bombyx mori and Aedes aegypti. Essential proteins common to both include phenoloxidases, apolipophorins, serine protease homologs, and a serine protease that promotes hemocyte recruitment through cytokine activation. Pattern recognition proteins included C-type Lectins in B. mori, while A. aegypti contained a protein homologous to Plasmodium-resistant LRIM1 from Anopheles gambiae. We also found that the B. mori IC is stabilized by extensive transglutaminase-catalyzed cross-linking of multiple components. The melanization inhibitor Egf1.0, from the parasitoid wasp Microplitis demolitor, blocked inclusion of specific components into the IC and also inhibited transglutaminase activity. Our results show how coagulants, melanization components, and hemocytes can be recruited to a wound surface or pathogen, provide insight into the mechanism by which a parasitoid evades this immune response, and suggest that insects as diverse as Lepidoptera and Diptera utilize similar defensive mechanisms.

SELENIUM-DEFICIENCY MODIFIES INFLUENZA INFECTION OF DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL CELLS

EPA Science Inventory

The nutritional status of the host is important in the defense against invading pathogens. Many studies regarding the effects of host nutritional status on the immune response have demonstrated that suboptimal host nutrition results in impaired host immunity and increased suscept...

Ectromelia virus inhibitor of complement enzymes protects intracellular mature virus and infected cells from mouse complement.

PubMed

Moulton, Elizabeth A; Bertram, Paula; Chen, Nanhai; Buller, R Mark L; Atkinson, John P

2010-09-01

Poxviruses produce complement regulatory proteins to subvert the host's immune response. Similar to the human pathogen variola virus, ectromelia virus has a limited host range and provides a mouse model where the virus and the host's immune response have coevolved. We previously demonstrated that multiple components (C3, C4, and factor B) of the classical and alternative pathways are required to survive ectromelia virus infection. Complement's role in the innate and adaptive immune responses likely drove the evolution of a virus-encoded virulence factor that regulates complement activation. In this study, we characterized the ectromelia virus inhibitor of complement enzymes (EMICE). Recombinant EMICE regulated complement activation on the surface of CHO cells, and it protected complement-sensitive intracellular mature virions (IMV) from neutralization in vitro. It accomplished this by serving as a cofactor for the inactivation of C3b and C4b and by dissociating the catalytic domain of the classical pathway C3 convertase. Infected murine cells initiated synthesis of EMICE within 4 to 6 h postinoculation. The levels were sufficient in the supernatant to protect the IMV, upon release, from complement-mediated neutralization. EMICE on the surface of infected murine cells also reduced complement activation by the alternative pathway. In contrast, classical pathway activation by high-titer antibody overwhelmed EMICE's regulatory capacity. These results suggest that EMICE's role is early during infection when it counteracts the innate immune response. In summary, ectromelia virus produced EMICE within a few hours of an infection, and EMICE in turn decreased complement activation on IMV and infected cells.

Leishmania Hijacks Myeloid Cells for Immune Escape

PubMed Central

Martínez-López, María; Soto, Manuel; Iborra, Salvador; Sancho, David

2018-01-01

Protozoan parasites of the Leishmania genus are the causative agents of leishmaniasis, a group of neglected tropical diseases whose clinical manifestations vary depending on the infectious Leishmania species but also on host factors. Recognition of the parasite by host myeloid immune cells is a key to trigger an effective Leishmania-specific immunity. However, the parasite is able to persist in host myeloid cells by evading, delaying and manipulating host immunity in order to escape host resistance and ensure its transmission. Neutrophils are first in infiltrating infection sites and could act either favoring or protecting against infection, depending on factors such as the genetic background of the host or the parasite species. Macrophages are the main host cells where the parasites grow and divide. However, macrophages are also the main effector population involved in parasite clearance. Parasite elimination by macrophages requires the priming and development of an effector Th1 adaptive immunity driven by specific subtypes of dendritic cells. Herein, we will provide a comprehensive outline of how myeloid cells regulate innate and adaptive immunity against Leishmania, and the mechanisms used by the parasites to promote their evasion and sabotage. Understanding the interactions between Leishmania and the host myeloid cells may lead to the development of new therapeutic approaches and improved vaccination to leishmaniases, an important worldwide health problem in which current therapeutic or preventive approaches are limited. PMID:29867798

The cGAS-STING Defense Pathway and Its Counteraction by Viruses.

PubMed

Ma, Zhe; Damania, Blossom

2016-02-10

Upon virus infection, host cells mount a concerted innate immune response involving type I interferon and pro-inflammatory cytokines to enable elimination of the pathogen. Recently, cGAS and STING have been identified as intracellular sensors that activate the interferon pathway in response to virus infection and thus mediate host defense against a range of DNA and RNA viruses. Here we review how viruses are sensed by the cGAS-STING signaling pathway as well as how viruses modulate this pathway. Mechanisms utilized by viral proteins to inhibit cGAS and/or STING are also discussed. On the flip side, host cells have also evolved strategies to thwart viral immune escape. The balance between host immune control and viral immune evasion is pivotal to viral pathogenesis, and we discuss this virus-host stand-off in the context of the cGAS-STING innate immune pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Infectious diseases of marine molluscs and host responses as revealed by genomic tools

PubMed Central

Ford, Susan E.

2016-01-01

More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc's defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance. PMID:26880838

Fungal melanin stimulates surfactant protein D-mediated opsonization of and host immune response to Aspergillus fumigatus spores.

PubMed

Wong, Sarah Sze Wah; Rani, Manjusha; Dodagatta-Marri, Eswari; Ibrahim-Granet, Oumaima; Kishore, Uday; Bayry, Jagadeesh; Latgé, Jean-Paul; Sahu, Arvind; Madan, Taruna; Aimanianda, Vishukumar

2018-03-30

Surfactant protein D (SP-D), a C-type lectin and pattern-recognition soluble factor, plays an important role in immune surveillance to detect and eliminate human pulmonary pathogens. SP-D has been shown to protect against infections with the most ubiquitous airborne fungal pathogen, Aspergillus fumigatus , but the fungal surface component(s) interacting with SP-D is unknown. Here, we show that SP-D binds to melanin pigment on the surface of A. fumigatus dormant spores (conidia). SP-D also exhibited an affinity to two cell-wall polysaccharides of A. fumigatus , galactomannan (GM) and galactosaminogalactan (GAG). The immunolabeling pattern of SP-D was punctate on the conidial surface and was uniform on germinating conidia, in accordance with the localization of melanin, GM, and GAG. We also found that the collagen-like domain of SP-D is involved in its interaction with melanin, whereas its carbohydrate-recognition domain recognized GM and GAG. Unlike un-opsonized conidia, SP-D-opsonized conidia were phagocytosed more efficiently and stimulated the secretion of proinflammatory cytokines by human monocyte-derived macrophages. Furthermore, SP-D -/- mice challenged intranasally with wildtype conidia or melanin ghosts ( i.e. hollow melanin spheres) displayed significantly reduced proinflammatory cytokines in the lung compared with wildtype mice. In summary, SP-D binds to melanin present on the dormant A. fumigatus conidial surface, facilitates conidial phagocytosis, and stimulates the host immune response. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport

PubMed Central

Kumaraswamy, Monika; Kousha, Armin; Nizet, Victor

2017-01-01

ABSTRACT This study examines the pharmacodynamics of antimicrobials that are used to treat Salmonella with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic in vitro against Salmonella enterica serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing Salmonella. Exposure of Salmonella to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics in vivo against Salmonella may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat Salmonella with each other and with components of innate immunity warrant further study in light of recent findings showing in vivo selection of antimicrobial resistance by single agents in this pathogen. IMPORTANCE It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo. PMID:29242830

Die another day: molecular mechanisms of effector-triggered immunity elicited by type III secreted effector proteins

USDA-ARS?s Scientific Manuscript database

Bacterial pathogens inject type III secreted effector (T3SE) proteins into their hosts where they display dual roles depending on the host genotype. T3SEs promote bacterial virulence in susceptible hosts, and elicit immunity in resistant hosts. T3SEs are typically recognized when they modify a host ...

Ambient ozone and pulmonary innate immunity

PubMed Central

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

2013-01-01

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

Viral mimicry of cytokines, chemokines and their receptors.

PubMed

Alcami, Antonio

2003-01-01

Viruses have evolved elegant mechanisms to evade detection and destruction by the host immune system. One of the evasion strategies that have been adopted by large DNA viruses is to encode homologues of cytokines, chemokines and their receptors--molecules that have a crucial role in control of the immune response. Viruses have captured host genes or evolved genes to target specific immune pathways, and so viral genomes can be regarded as repositories of important information about immune processes, offering us a viral view of the host immune system. The study of viral immunomodulatory proteins might help us to uncover new human genes that control immunity, and their characterization will increase our understanding of not only viral pathogenesis, but also normal immune mechanisms. Moreover, viral proteins indicate strategies of immune modulation that might have therapeutic potential.

Community acquired Pseudomonas pneumonia in an immune competent host.

PubMed

Gharabaghi, Mehrnaz Asadi; Abdollahi, Seyed Mojtaba Mir; Safavi, Enayat; Abtahi, Seyed Hamid

2012-05-26

Pseudomonas aeruginosa is an uncommon cause of community-acquired pneumonia in immune-competent hosts. It is commonly seen in patients with structural lung abnormality such as cystic fibrosis or in immune compromised hosts. Here, the authors report a case of community-acquired Pseudomonas pneumonia in a 26-year old healthy man who presented with 8-week history of malaise and cough.

Recognition between symbiotic Vibrio fischeri and the hemocytes of Euprymna scolopes

PubMed Central

Nyholm, Spencer V.; Stewart, Jennifer J.; Ruby, Edward G.; McFall-Ngai, Margaret J.

2008-01-01

Summary The light-organ crypts of the squid Euprymna scolopes permit colonization exclusively by the luminous bacterium Vibrio fischeri. Because the crypt interior remains in contact with seawater, the squid must not only foster the specific symbiosis but also continue to exclude other bacteria. Investigation of the role of the innate immune system in these processes revealed that macrophage-like hemocytes isolated from E. scolopes recognized and phagocytosed V. fischeri less than other closely related bacterial species common to the host’s environment. Interestingly, phagocytes isolated from hosts that had been cured of their symbionts bound five-times more V. fischeri cells than those from uncured hosts. No such change in the ability to bind other species of bacteria was observed, suggesting that the host adapts specifically to V. fischeri. Deletion of the gene encoding OmpU, the major outer membrane protein of V. fischeri, increased binding by hemocytes from uncured animals to the level observed for hemocytes from cured animals. Co-incubation with wild-type V. fischeri reduced this binding, suggesting they produce a factor that complements the mutant’s defect. Analyses of the phagocytosis of bound cells by fluorescence-activated cell sorting (FACS) indicated that, once binding to hemocytes had occurred, V. fischeri cells are phagocytosed as effectively as other bacteria. Thus, discrimination by this component of the squid immune system occurs at the level of hemocyte binding, and this response: (i) is modified by previous exposure to the symbiont and, (ii) relies on outer membrane and/or secreted components of the symbionts. These data suggest that regulation of host hemocyte binding by the symbiont may be one of many factors that contribute to specificity in this association. PMID:19196278

The Xanthomonas euvesicatoria type III effector XopAU is an active protein kinase that manipulates plant MAP kinase signaling.

PubMed

Teper, Doron; Girija, Anil Madhusoodana; Bosis, Eran; Popov, Georgy; Savidor, Alon; Sessa, Guido

2018-01-01

The Gram-negative bacterium Xanthomonas euvesicatoria (Xe) is the causal agent of bacterial spot disease of pepper and tomato. Xe delivers effector proteins into host cells through the type III secretion system to promote disease. Here, we show that the Xe effector XopAU, which is conserved in numerous Xanthomonas species, is a catalytically active protein kinase and contributes to the development of disease symptoms in pepper plants. Agrobacterium-mediated expression of XopAU in host and non-host plants activated typical defense responses, including MAP kinase phosphorylation, accumulation of pathogenesis-related (PR) proteins and elicitation of cell death, that were dependent on the kinase activity of the effector. XopAU-mediated cell death was not dependent on early signaling components of effector-triggered immunity and was also observed when the effector was delivered into pepper leaves by Xanthomonas campestris pv. campestris, but not by Xe. Protein-protein interaction studies in yeast and in planta revealed that XopAU physically interacts with components of plant immunity-associated MAP kinase cascades. Remarkably, XopAU directly phosphorylated MKK2 in vitro and enhanced its phosphorylation at multiple sites in planta. Consistent with the notion that MKK2 is a target of XopAU, silencing of the MKK2 homolog or overexpression of the catalytically inactive mutant MKK2K99R in N. benthamiana plants reduced XopAU-mediated cell death and MAPK phosphorylation. Furthermore, yeast co-expressing XopAU and MKK2 displayed reduced growth and this phenotype was dependent on the kinase activity of both proteins. Together, our results support the conclusion that XopAU contributes to Xe disease symptoms in pepper plants and manipulates host MAPK signaling through phosphorylation and activation of MKK2.

MyD88-deficient Hydra reveal an ancient function of TLR signaling in sensing bacterial colonizers

PubMed Central

Franzenburg, Sören; Fraune, Sebastian; Künzel, Sven; Baines, John F.; Domazet-Lošo, Tomislav; Bosch, Thomas C. G.

2012-01-01

Toll-like receptor (TLR) signaling is one of the most important signaling cascades of the innate immune system of vertebrates. Studies in invertebrates have focused on the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, and there is little information regarding the evolutionary origin and ancestral function of TLR signaling. In Drosophila, members of the Toll-like receptor family are involved in both embryonic development and innate immunity. In C. elegans, a clear immune function of the TLR homolog TOL-1 is controversial and central components of vertebrate TLR signaling including the key adapter protein myeloid differentiation primary response gene 88 (MyD88) and the transcription factor NF-κB are not present. In basal metazoans such as the cnidarians Hydra magnipapillata and Nematostella vectensis, all components of the vertebrate TLR signaling cascade are present, but their role in immunity is unknown. Here, we use a MyD88 loss-of-function approach in Hydra to demonstrate that recognition of bacteria is an ancestral function of TLR signaling and that this process contributes to both host-mediated recolonization by commensal bacteria as well as to defense against bacterial pathogens. PMID:23112184

MyD88-deficient Hydra reveal an ancient function of TLR signaling in sensing bacterial colonizers.

PubMed

Franzenburg, Sören; Fraune, Sebastian; Künzel, Sven; Baines, John F; Domazet-Loso, Tomislav; Bosch, Thomas C G

2012-11-20

Toll-like receptor (TLR) signaling is one of the most important signaling cascades of the innate immune system of vertebrates. Studies in invertebrates have focused on the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, and there is little information regarding the evolutionary origin and ancestral function of TLR signaling. In Drosophila, members of the Toll-like receptor family are involved in both embryonic development and innate immunity. In C. elegans, a clear immune function of the TLR homolog TOL-1 is controversial and central components of vertebrate TLR signaling including the key adapter protein myeloid differentiation primary response gene 88 (MyD88) and the transcription factor NF-κB are not present. In basal metazoans such as the cnidarians Hydra magnipapillata and Nematostella vectensis, all components of the vertebrate TLR signaling cascade are present, but their role in immunity is unknown. Here, we use a MyD88 loss-of-function approach in Hydra to demonstrate that recognition of bacteria is an ancestral function of TLR signaling and that this process contributes to both host-mediated recolonization by commensal bacteria as well as to defense against bacterial pathogens.

Effects of Aedes aegypti salivary components on dendritic cell and lymphocyte biology

PubMed Central

2013-01-01

Background Saliva is a key element of interaction between hematophagous mosquitoes and their vertebrate hosts. In addition to allowing a successful blood meal by neutralizing or delaying hemostatic responses, the salivary cocktail is also able to modulate the effector mechanisms of host immune responses facilitating, in turn, the transmission of several types of microorganisms. Understanding how the mosquito uses its salivary components to circumvent host immunity might help to clarify the mechanisms of transmission of such pathogens and disease establishment. Methods Flow cytometry was used to evaluate if increasing concentrations of A. aegypti salivary gland extract (SGE) affects bone marrow-derived DC differentiation and maturation. Lymphocyte proliferation in the presence of SGE was estimated by a colorimetric assay. Western blot and Annexin V staining assays were used to assess apoptosis in these cells. Naïve and memory cells from mosquito-bite exposed mice or OVA-immunized mice and their respective controls were analyzed by flow cytometry. Results Concentration-response curves were employed to evaluate A. aegypti SGE effects on DC and lymphocyte biology. DCs differentiation from bone marrow precursors, their maturation and function were not directly affected by A. aegypti SGE (concentrations ranging from 2.5 to 40 μg/mL). On the other hand, lymphocytes were very sensitive to the salivary components and died in the presence of A. aegypti SGE, even at concentrations as low as 0.1 μg/mL. In addition, A. aegypti SGE was shown to induce apoptosis in all lymphocyte populations evaluated (CD4+ and CD8+ T cells, and B cells) through a mechanism involving caspase-3 and caspase-8, but not Bim. By using different approaches to generate memory cells, we were able to verify that these cells are resistant to SGE effects. Conclusion Our results show that lymphocytes, and not DCs, are the primary target of A. aegypti salivary components. In the presence of A. aegypti SGE, naïve lymphocyte populations die by apoptosis in a caspase-3- and caspase-8-dependent pathway, while memory cells are selectively more resistant to its effects. The present work contributes to elucidate the activities of A. aegypti salivary molecules on the antigen presenting cell-lymphocyte axis and in the biology of these cells. PMID:24238038

Effects of Aedes aegypti salivary components on dendritic cell and lymphocyte biology.

PubMed

Bizzarro, Bruna; Barros, Michele S; Maciel, Ceres; Gueroni, Daniele I; Lino, Ciro N; Campopiano, Júlia; Kotsyfakis, Michalis; Amarante-Mendes, Gustavo P; Calvo, Eric; Capurro, Margareth L; Sá-Nunes, Anderson

2013-11-15

Saliva is a key element of interaction between hematophagous mosquitoes and their vertebrate hosts. In addition to allowing a successful blood meal by neutralizing or delaying hemostatic responses, the salivary cocktail is also able to modulate the effector mechanisms of host immune responses facilitating, in turn, the transmission of several types of microorganisms. Understanding how the mosquito uses its salivary components to circumvent host immunity might help to clarify the mechanisms of transmission of such pathogens and disease establishment. Flow cytometry was used to evaluate if increasing concentrations of A. aegypti salivary gland extract (SGE) affects bone marrow-derived DC differentiation and maturation. Lymphocyte proliferation in the presence of SGE was estimated by a colorimetric assay. Western blot and Annexin V staining assays were used to assess apoptosis in these cells. Naïve and memory cells from mosquito-bite exposed mice or OVA-immunized mice and their respective controls were analyzed by flow cytometry. Concentration-response curves were employed to evaluate A. aegypti SGE effects on DC and lymphocyte biology. DCs differentiation from bone marrow precursors, their maturation and function were not directly affected by A. aegypti SGE (concentrations ranging from 2.5 to 40 μg/mL). On the other hand, lymphocytes were very sensitive to the salivary components and died in the presence of A. aegypti SGE, even at concentrations as low as 0.1 μg/mL. In addition, A. aegypti SGE was shown to induce apoptosis in all lymphocyte populations evaluated (CD4+ and CD8+ T cells, and B cells) through a mechanism involving caspase-3 and caspase-8, but not Bim. By using different approaches to generate memory cells, we were able to verify that these cells are resistant to SGE effects. Our results show that lymphocytes, and not DCs, are the primary target of A. aegypti salivary components. In the presence of A. aegypti SGE, naïve lymphocyte populations die by apoptosis in a caspase-3- and caspase-8-dependent pathway, while memory cells are selectively more resistant to its effects. The present work contributes to elucidate the activities of A. aegypti salivary molecules on the antigen presenting cell-lymphocyte axis and in the biology of these cells.

Modeling the interactions between pathogenic bacteria, bacteriophage and immune response

NASA Astrophysics Data System (ADS)

Leung, Chung Yin (Joey); Weitz, Joshua S.

The prevalence of antibiotic-resistant strains of pathogenic bacteria has led to renewed interest in the use of bacteriophage (phage), or virus that infects bacteria, as a therapeutic agent against bacterial infections. However, little is known about the theoretical mechanism by which phage therapy may work. In particular, interactions between the bacteria, the phage and the host immune response crucially influences the outcome of the therapy. Few models of phage therapy have incorporated all these three components, and existing models suffer from unrealistic assumptions such as unbounded growth of the immune response. We propose a model of phage therapy with an emphasis on nonlinear feedback arising from interactions with bacteria and the immune response. Our model shows a synergistic effect between the phage and the immune response which underlies a possible mechanism for phage to catalyze the elimination of bacteria even when neither the immune response nor phage could do so alone. We study the significance of this effect for different parameters of infection and immune response, and discuss its implications for phage therapy.

Envelope Structures of Gram-Positive Bacteria

PubMed Central

Rajagopal, Mithila; Walker, Suzanne

2016-01-01

Gram-positive organisms, including the pathogens Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis, have dynamic cell envelopes that mediate interactions with the environment and serve as the first line of defense against toxic molecules. Major components of the cell envelope include peptidoglycan, which is a well-established target for antibiotics, teichoic acids, capsular polysaccharides, surface proteins, and phospholipids. These components can undergo modification to promote pathogenesis, decrease susceptibility to antibiotics and host immune defenses, and enhance survival in hostile environments. This chapter will cover the structure, biosynthesis and important functions of major cell envelope components in Gram-positive bacteria. Possible targets for new antimicrobials will be noted. PMID:26919863

Behavioral Immunity in Insects

PubMed Central

de Roode, Jacobus C.; Lefèvre, Thierry

2012-01-01

Parasites can dramatically reduce the fitness of their hosts, and natural selection should favor defense mechanisms that can protect hosts against disease. Much work has focused on understanding genetic and physiological immunity against parasites, but hosts can also use behaviors to avoid infection, reduce parasite growth or alleviate disease symptoms. It is increasingly recognized that such behaviors are common in insects, providing strong protection against parasites and parasitoids. We review the current evidence for behavioral immunity in insects, present a framework for investigating such behavior, and emphasize that behavioral immunity may act through indirect rather than direct fitness benefits. We also discuss the implications for host-parasite co-evolution, local adaptation, and the evolution of non-behavioral physiological immune systems. Finally, we argue that the study of behavioral immunity in insects has much to offer for investigations in vertebrates, in which this topic has traditionally been studied. PMID:26466629

Antimicrobial autophagy: a conserved innate immune response in Drosophila.

PubMed

Moy, Ryan H; Cherry, Sara

2013-01-01

Autophagy is a highly conserved degradative pathway that has rapidly emerged as a critical component of immunity and host defense. Studies have implicated autophagy genes in restricting the replication of a diverse array of pathogens, including bacteria, viruses and protozoans. However, in most cases, the in vivo role of antimicrobial autophagy against pathogens has been undefined. Drosophila provides a genetically tractable model system that can be easily adapted to study autophagy in innate immunity, and recent studies in flies have demonstrated that autophagy is an essential antimicrobial response against bacteria and viruses in vivo. These findings reveal striking conservation of antimicrobial autophagy between flies and mammals, and in particular, the role of pathogen-associated pattern recognition in triggering this response. This review discusses our current understanding of antimicrobial autophagy in Drosophila and its potential relevance to human immunity. Copyright © 2013 S. Karger AG, Basel.

Genetic Diversity of Toll-Like Receptors and Immunity to M. leprae Infection

PubMed Central

Hart, Bryan E.; Tapping, Richard I.

2012-01-01

Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity. PMID:22529866

Recent progress in the understanding of host immunity to avian coccidiosis: IL-17 family cytokines as the sentinels on the intestinal mucosa

USDA-ARS?s Scientific Manuscript database

Host-pathogen interaction leading to protection against coccidiosis is complex, involving many aspects of innate and adaptive immunity to intracellular parasites. Innate immunity is mediated by various subpopulations of innate immune cells through the secretion of soluble factors with diverse functi...

Robustness trade-offs and host–microbial symbiosis in the immune system

PubMed Central

Kitano, Hiroaki; Oda, Kanae

2006-01-01

The immune system provides organisms with robustness against pathogen threats, yet it also often adversely affects the organism as in autoimmune diseases. Recently, the molecular interactions involved in the immune system have been uncovered. At the same time, the role of the bacterial flora and its interactions with the host immune system have been identified. In this article, we try to reconcile these findings to draw a consistent picture of the host defense system. Specifically, we first argue that the network of molecular interactions involved in immune functions has a bow-tie architecture that entails inherent trade-offs among robustness, fragility, resource limitation, and performance. Second, we discuss the possibility that commensal bacteria and the host immune system constitute an integrated defense system. This symbiotic association has evolved to optimize its robustness against pathogen attacks and nutrient perturbations by harboring a broad range of microorganisms. Owing to the inherent propensity of a host immune system toward hyperactivity, maintenance of bacterial flora homeostasis might be particularly important in the development of preventive strategies against immune disorders such as autoimmune diseases. PMID:16738567

The targeting of plant cellular systems by injected type III effector proteins.

PubMed

Lewis, Jennifer D; Guttman, David S; Desveaux, Darrell

2009-12-01

The battle between phytopathogenic bacteria and their plant hosts has revealed a diverse suite of strategies and mechanisms employed by the pathogen or the host to gain the higher ground. Pathogens continually evolve tactics to acquire host resources and dampen host defences. Hosts must evolve surveillance and defence systems that are sensitive enough to rapidly respond to a diverse range of pathogens, while reducing costly and damaging inappropriate misexpression. The primary virulence mechanism employed by many bacteria is the type III secretion system, which secretes and translocates effector proteins directly into the cells of their plant hosts. Effectors have diverse enzymatic functions and can target specific components of plant systems. While these effectors should favour bacterial fitness, the host may be able to thwart infection by recognizing the activity or presence of these foreign molecules and initiating retaliatory immune measures. We review the diverse host cellular systems exploited by bacterial effectors, with particular focus on plant proteins directly targeted by effectors. Effector-host interactions reveal different stages of the battle between pathogen and host, as well as the diverse molecular strategies employed by bacterial pathogens to hijack eukaryotic cellular systems.

A Review of Antimicrobial Peptides and Their Therapeutic Potential as Anti-Infective Drugs

PubMed Central

Gordon, Y. Jerold; Romanowski, Eric G.; McDermott, Alison M.

2006-01-01

Purpose. Antimicrobial peptides (AMPs) are an essential part of innate immunity that evolved in most living organisms over 2.6 billion years to combat microbial challenge. These small cationic peptides are multifunctional as effectors of innate immunity on skin and mucosal surfaces and have demonstrated direct antimicrobial activity against various bacteria, viruses, fungi, and parasites. This review summarizes their progress to date as commercial antimicrobial drugs for topical and systemic indications. Methods. Literature review. Results. Despite numerous clinical trials, no modified AMP has obtained Food & Drug Administration approval yet for any topical or systemic medical indications. Conclusions. While AMPs are recognized as essential components of natural host innate immunity against microbial challenge, their usefulness as a new class of antimicrobial drugs still remains to be proven. PMID:16020284

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus.

PubMed

Ansari, M Azim; Pedergnana, Vincent; L C Ip, Camilla; Magri, Andrea; Von Delft, Annette; Bonsall, David; Chaturvedi, Nimisha; Bartha, Istvan; Smith, David; Nicholson, George; McVean, Gilean; Trebes, Amy; Piazza, Paolo; Fellay, Jacques; Cooke, Graham; Foster, Graham R; Hudson, Emma; McLauchlan, John; Simmonds, Peter; Bowden, Rory; Klenerman, Paul; Barnes, Eleanor; Spencer, Chris C A

2017-05-01

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

Repeat-containing protein effectors of plant-associated organisms

PubMed Central

Mesarich, Carl H.; Bowen, Joanna K.; Hamiaux, Cyril; Templeton, Matthew D.

2015-01-01

Many plant-associated organisms, including microbes, nematodes, and insects, deliver effector proteins into the apoplast, vascular tissue, or cell cytoplasm of their prospective hosts. These effectors function to promote colonization, typically by altering host physiology or by modulating host immune responses. The same effectors however, can also trigger host immunity in the presence of cognate host immune receptor proteins, and thus prevent colonization. To circumvent effector-triggered immunity, or to further enhance host colonization, plant-associated organisms often rely on adaptive effector evolution. In recent years, it has become increasingly apparent that several effectors of plant-associated organisms are repeat-containing proteins (RCPs) that carry tandem or non-tandem arrays of an amino acid sequence or structural motif. In this review, we highlight the diverse roles that these repeat domains play in RCP effector function. We also draw attention to the potential role of these repeat domains in adaptive evolution with regards to RCP effector function and the evasion of effector-triggered immunity. The aim of this review is to increase the profile of RCP effectors from plant-associated organisms. PMID:26557126

The effect of immunodeficiency on the evolution of virulence: an experimental test with the rodent malaria Plasmodium chabaudi.

PubMed

Barclay, Victoria C; Kennedy, David A; Weaver, Veronika C; Sim, Derek; Lloyd-Smith, James O; Read, Andrew F

2014-08-01

Host immunity plays an important role in the evolution of pathogen virulence and disease emergence. There is increasing theoretical and empirical evidence that enhanced immunity through vaccination may have the unfortunate side effect of selecting for more virulent parasites, but the effect of host immune suppression on pathogen evolution is less clear. Here, we use serial passage experiments in mice to test how immune-suppressed hosts may alter pathogen virulence evolution. We passaged Plasmodium chabaudi through CD4(+) T cell-depleted or control mice every 7 days for 20 weeks and then measured virulence differences during infection of immunologically normal mice. We found that those parasites that had been selected through CD4(+) T cell-depleted mice were more virulent than parasites selected through control mice. Virulence increases during serial passage are believed to be caused by pathogen adaptation to the passage host. These data suggest that immune-suppressed hosts could provide a within-host environment that lowers the barrier to parasite adaptation and promotes the evolution of virulence.

Repeat-containing protein effectors of plant-associated organisms.

PubMed

Mesarich, Carl H; Bowen, Joanna K; Hamiaux, Cyril; Templeton, Matthew D

2015-01-01

Many plant-associated organisms, including microbes, nematodes, and insects, deliver effector proteins into the apoplast, vascular tissue, or cell cytoplasm of their prospective hosts. These effectors function to promote colonization, typically by altering host physiology or by modulating host immune responses. The same effectors however, can also trigger host immunity in the presence of cognate host immune receptor proteins, and thus prevent colonization. To circumvent effector-triggered immunity, or to further enhance host colonization, plant-associated organisms often rely on adaptive effector evolution. In recent years, it has become increasingly apparent that several effectors of plant-associated organisms are repeat-containing proteins (RCPs) that carry tandem or non-tandem arrays of an amino acid sequence or structural motif. In this review, we highlight the diverse roles that these repeat domains play in RCP effector function. We also draw attention to the potential role of these repeat domains in adaptive evolution with regards to RCP effector function and the evasion of effector-triggered immunity. The aim of this review is to increase the profile of RCP effectors from plant-associated organisms.

The immune response to human CMV

PubMed Central

La Rosa, Corinna; Diamond, Don J

2012-01-01

This review will summarize and interpret recent literature regarding the human CMV immune response, which is among the strongest measured and is the focus of attention for numerous research groups. CMV is a highly prevalent, globally occurring infection that rarely elicits disease in healthy immunocompetent hosts. The human immune system is unable to clear CMV infection and latency, but mounts a spirited immune-defense targeting multiple immune-evasion genes encoded by this dsDNA β-herpes virus. Additionally, the magnitude of cellular immune response devoted to CMV may cause premature immune senescence, and the high frequencies of cytolytic T cells may aggravate vascular pathologies. However, uncontrolled CMV viremia and life-threatening symptoms, which occur readily after immunosuppression and in the immature host, clearly indicate the essential role of immunity in maintaining asymptomatic co-existence with CMV. Approaches for harnessing the host immune response to CMV are needed to reduce the burden of CMV complications in immunocompromised individuals. PMID:23308079

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components.

PubMed

Bermudez, Adriana; Alba, Martha P; Vanegas, Magnolia; Patarroyo, Manuel A; Patarroyo, Manuel E

2018-01-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ * allele family) and modified i mmune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

Regulation of dendritic cell function through toll-like receptors.

PubMed

Kaisho, Tsuneyasu; Akira, Shizuo

2003-12-01

Higher animals establish host defense by orchestrating innate and adaptive immunity. This is mediated by professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can incorporate pathogens, produce a variety of cytokines, maturate, and present pathogen-derived peptides to T cells, thereby inducing T cell activation and differentiation. These responses are triggered by microbial recognition through type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist of ten members and each TLR is involved in recognizing a variety of microorganism-derived molecular structures. TLR ligands include cell wall components, proteins, nucleic acids, and synthetic chemical compounds, all of which can activate DCs as immune adjuvants.

Identification of the cellular receptor for anthrax toxin

NASA Astrophysics Data System (ADS)

Bradley, Kenneth A.; Mogridge, Jeremy; Mourez, Michael; Collier, R. John; Young, John A. T.

2001-11-01

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

Novel Drosophila Viruses Encode Host-Specific Suppressors of RNAi

PubMed Central

van Mierlo, Joël T.; Overheul, Gijs J.; Obadia, Benjamin; van Cleef, Koen W. R.; Webster, Claire L.; Saleh, Maria-Carla; Obbard, Darren J.; van Rij, Ronald P.

2014-01-01

The ongoing conflict between viruses and their hosts can drive the co-evolution between host immune genes and viral suppressors of immunity. It has been suggested that an evolutionary ‘arms race’ may occur between rapidly evolving components of the antiviral RNAi pathway of Drosophila and viral genes that antagonize it. We have recently shown that viral protein 1 (VP1) of Drosophila melanogaster Nora virus (DmelNV) suppresses Argonaute-2 (AGO2)-mediated target RNA cleavage (slicer activity) to antagonize antiviral RNAi. Here we show that viral AGO2 antagonists of divergent Nora-like viruses can have host specific activities. We have identified novel Nora-like viruses in wild-caught populations of D. immigrans (DimmNV) and D. subobscura (DsubNV) that are 36% and 26% divergent from DmelNV at the amino acid level. We show that DimmNV and DsubNV VP1 are unable to suppress RNAi in D. melanogaster S2 cells, whereas DmelNV VP1 potently suppresses RNAi in this host species. Moreover, we show that the RNAi suppressor activity of DimmNV VP1 is restricted to its natural host species, D. immigrans. Specifically, we find that DimmNV VP1 interacts with D. immigrans AGO2, but not with D. melanogaster AGO2, and that it suppresses slicer activity in embryo lysates from D. immigrans, but not in lysates from D. melanogaster. This species-specific interaction is reflected in the ability of DimmNV VP1 to enhance RNA production by a recombinant Sindbis virus in a host-specific manner. Our results emphasize the importance of analyzing viral RNAi suppressor activity in the relevant host species. We suggest that rapid co-evolution between RNA viruses and their hosts may result in host species-specific activities of RNAi suppressor proteins, and therefore that viral RNAi suppressors could be host-specificity factors. PMID:25032815

Modes of Action for Mucosal Vaccine Adjuvants

PubMed Central

2017-01-01

Abstract Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action. PMID:28436755

Host stress physiology and Trypanosoma haemoparasite infection influence innate immunity in the woylie (Bettongia penicillata).

PubMed

Hing, Stephanie; Currie, Andrew; Broomfield, Steven; Keatley, Sarah; Jones, Krista; Thompson, R C Andrew; Narayan, Edward; Godfrey, Stephanie S

2016-06-01

Understanding immune function is critical to conserving wildlife in view of infectious disease threats, particularly in threatened species vulnerable to stress, immunocompromise and infection. However, few studies examine stress, immune function and infection in wildlife. We used a flow cytometry protocol developed for human infants to assess phagocytosis, a key component of innate immunity, in a critically endangered marsupial, the woylie (Bettongia penicillata). The effects of stress physiology and Trypanosoma infection on phagocytosis were investigated. Blood and faecal samples were collected from woylies in a captive facility over three months. Trypanosoma status was determined using PCR. Faecal cortisol metabolites (FCM) were quantified by enzyme-immunoassay. Mean phagocytosis measured was >90%. An interaction between sex and FCM influenced the percentage of phagocytosing leukocytes, possibly reflecting the influence of sex hormones and glucocorticoids. An interaction between Trypanosoma status and FCM influenced phagocytosis index, suggesting that stress physiology and infection status influence innate immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

No more non-model species: the promise of next generation sequencing for comparative immunology.

PubMed

Dheilly, Nolwenn M; Adema, Coen; Raftos, David A; Gourbal, Benjamin; Grunau, Christoph; Du Pasquier, Louis

2014-07-01

Next generation sequencing (NGS) allows for the rapid, comprehensive and cost effective analysis of entire genomes and transcriptomes. NGS provides approaches for immune response gene discovery, profiling gene expression over the course of parasitosis, studying mechanisms of diversification of immune receptors and investigating the role of epigenetic mechanisms in regulating immune gene expression and/or diversification. NGS will allow meaningful comparisons to be made between organisms from different taxa in an effort to understand the selection of diverse strategies for host defence under different environmental pathogen pressures. At the same time, it will reveal the shared and unique components of the immunological toolkit and basic functional aspects that are essential for immune defence throughout the living world. In this review, we argue that NGS will revolutionize our understanding of immune responses throughout the animal kingdom because the depth of information it provides will circumvent the need to concentrate on a few "model" species. Copyright © 2014 Elsevier Ltd. All rights reserved.

Modes of Action for Mucosal Vaccine Adjuvants.

PubMed

Aoshi, Taiki

Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action.

The Myriad Properties of Pasteurella multocida Lipopolysaccharide

PubMed Central

Harper, Marina; Boyce, John Dallas

2017-01-01

Pasteurella multocida is a heterogeneous species that is a primary pathogen of many different vertebrates. This Gram-negative bacterium can cause a range of diseases, including fowl cholera in birds, haemorrhagic septicaemia in ungulates, atrophic rhinitis in swine, and lower respiratory tract infections in cattle and pigs. One of the primary virulence factors of P. multocida is lipopolysaccharide (LPS). Recent work has shown that this crucial surface molecule shows significant structural variability across different P. multocida strains, with many producing LPS structures that are highly similar to the carbohydrate component of host glycoproteins. It is likely that this LPS mimicry of host molecules plays a major role in the survival of P. multocida in certain host niches. P. multocida LPS also plays a significant role in resisting the action of chicken cathelicidins, and is a strong stimulator of host immune responses. The inflammatory response to the endotoxic lipid A component is a major contributor to the pathogenesis of certain infections. Recent work has shown that vaccines containing killed bacteria give protection only against other strains with identical, or nearly identical, surface LPS structures. Conversely, live attenuated vaccines give protection that is broadly protective, and their efficacy is independent of LPS structure. PMID:28825691

Analysis of host versus tumor interaction in cancer patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the development of in situ tumor immunity.

PubMed

Tsai, Jy-Ping; Chen, Hsin-Wei; Cheng, Mei-Lien; Liu, Hsiung-Kun; Lee, Yi-Ping; Hsieh, Chia Ling; Luh, Kwen-Tay; Wu, Chew-Wun; Hsu, Li-Han; Chao, Tsu-Yi; Wang, Wen-Hua; Chang, Chung-Ming; Ting, Chou-Chik

2005-01-01

A different degree of immunodeficiency is often found at tumor sites in cancer patients. At the late stage many patients develop malignant effusion that contains large numbers of tumor cells and host immune cells that constantly interact with each other. These sites may provide an ideal model to examine in situ anti-tumor immunity. The T cells in effusion were found to be immunodeficient, which suggested a defective anti-tumor cytotoxic T lymphocytes response. To pursue the mechanism for the T cell deficiency, we determined the production of immunomodulating cytokines in the effusion and detected the presence of transforming growth factor-beta1 (TGFbeta), prostaglandin E2, IL-6, IL-10, and IFNgamma. There was no detectable IL-2, IL-4, IL-12, or TNFalpha. The most prominent feature was the presence of TGFbeta and IL-6 at a very high level. Thus, the possible role of these two cytokines on T cell competence was further determined. TGFbeta was found to induce T cell anergy and reduced the production of perforin in T killer cells and their lytic activity. These events lead to the induction of peripheral T cell tolerance with profound T cell deficiency. IL-6 did not affect perforin production or cytolytic activity of the T killer cells. But the CD4+ CD25+ regulatory T cells (TR) that were often employed by TGFbeta to suppress T cell response were reduced in the malignant effusion, consistent with the fact that IL-6 down-regulates TR and this may represent the host's vigorous response to the tumor's subversion. These results show that TGFbeta and IL-6 might play pivotal but opposing roles in the host tumor interaction that, together with other immunomodulating components, determines the outcome for the development of local tumor immunity.

Post-translational regulation of plant immunity.

PubMed

Withers, John; Dong, Xinnian

2017-08-01

Plants have evolved multi-layered molecular defense strategies to protect against pathogens. Plant immune signaling largely relies on post-translational modifications (PTMs) to induce rapid alterations of signaling pathways to achieve a response that is appropriate to the type of pathogen and infection pressure. In host cells, dynamic PTMs have emerged as powerful regulatory mechanisms that cells use to adjust their immune response. PTM is also a virulence strategy used by pathogens to subvert host immunity through the activities of effector proteins secreted into the host cell. Recent studies focusing on deciphering post-translational mechanisms underlying plant immunity have offered an in-depth view of how PTMs facilitate efficient immune responses and have provided a more dynamic and holistic view of plant immunity. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

No evidence of local adaptation of immune responses to Gyrodactylus in three-spined stickleback (Gasterosteus aculeatus).

PubMed

Robertson, Shaun; Bradley, Janette E; MacColl, Andrew D C

2017-01-01

Parasitism represents one of the most widespread lifestyles in the animal kingdom, with the potential to drive coevolutionary dynamics with their host population. Where hosts and parasites evolve together, we may find local adaptation. As one of the main host defences against infection, there is the potential for the immune response to be adapted to local parasites. In this study, we used the three-spined stickleback and its Gyrodactylus parasites to examine the extent of local adaptation of parasite infection dynamics and the immune response to infection. We took two geographically isolated host populations infected with two distinct Gyrodactylus species and performed a reciprocal cross-infection experiment in controlled laboratory conditions. Parasite burdens were monitored over the course of the infection, and individuals were sampled at multiple time points for immune gene expression analysis. We found large differences in virulence between parasite species, irrespective of host, and maladaptation of parasites to their sympatric host. The immune system responded to infection, with a decrease in expression of innate and Th1-type adaptive response genes in fish infected with the less virulent parasite, representing a marker of a possible resistance mechanism. There was no evidence of local adaptation in immune gene expression levels. Our results add to the growing understanding of the extent of host-parasite local adaptation, and demonstrate a systemic immune response during infection with a common ectoparasite. Further immunological studies using the stickleback-Gyrodactylus system can continue to contribute to our understanding of the function of the immune response in natural populations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions.

PubMed

Kravchenko, Julia; Corsini, Emanuela; Williams, Marc A; Decker, William; Manjili, Masoud H; Otsuki, Takemi; Singh, Neetu; Al-Mulla, Faha; Al-Temaimi, Rabeah; Amedei, Amedeo; Colacci, Anna Maria; Vaccari, Monica; Mondello, Chiara; Scovassi, A Ivana; Raju, Jayadev; Hamid, Roslida A; Memeo, Lorenzo; Forte, Stefano; Roy, Rabindra; Woodrick, Jordan; Salem, Hosni K; Ryan, Elizabeth P; Brown, Dustin G; Bisson, William H; Lowe, Leroy; Lyerly, H Kim

2015-06-01

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria.

PubMed

Shi, Ruizheng; Cao, Zehong; Li, Hong; Graw, Jochen; Zhang, Guogang; Thannickal, Victor J; Cheng, Guangjie

2018-05-01

Innate immune recognition is classically mediated by the interaction of host pattern-recognition receptors and pathogen-associated molecular patterns; this triggers a series of downstream signaling events that facilitate killing and elimination of invading pathogens. In this report, we provide the first evidence that peroxidasin (PXDN; also known as vascular peroxidase-1) directly binds to gram-negative bacteria and mediates bactericidal activity, thus, contributing to lung host defense. PXDN contains five leucine-rich repeats and four immunoglobulin domains, which allows for its interaction with lipopolysaccharide, a membrane component of gram-negative bacteria. Bactericidal activity of PXDN is mediated via its capacity to generate hypohalous acids. Deficiency of PXDN results in a failure to eradicate Pseudomonas aeruginosa and increased mortality in a murine model of Pseudomonas lung infection. These observations indicate that PXDN mediates previously unrecognized host defense functions against gram-negative bacterial pathogens.

Glycan gimmickry by parasitic helminths: a strategy for modulating the host immune response?

PubMed

van Die, Irma; Cummings, Richard D

2010-01-01

Parasitic helminths (worms) co-evolved with vertebrate immune systems to enable long-term survival of worms in infected hosts. Among their survival strategies, worms use their glycans within glycoproteins and glycolipids, which are abundant on helminth surfaces and in their excretory/ secretory products, to regulate and suppress host immune responses. Many helminths express unusual and antigenic (nonhost-like) glycans, including those containing polyfucose, tyvelose, terminal GalNAc, phosphorylcholine, methyl groups, and sugars in unusual linkages. In addition, some glycan antigens are expressed that share structural features with those in their intermediate and vertebrate hosts (host-like glycans), including Le(X) (Galbeta1-4[Fucalpha1-3]GlcNAc-), LDNF (GalNAcbeta1-4[Fucalpha1-3]GlcNAc-), LDN (GalNAcbeta1-4GlcNAc-), and Tn (GalNAcalpha1-O-Thr/Ser) antigens. The expression of host-like glycan determinants is remarkable and suggests that helminths may gain advantages by synthesizing such glycans. The expression of host-like glycans by parasites previously led to the concept of "molecular mimicry," in which molecules are either derived from the pathogen or acquired from the host to evade recognition by the host immune system. However, recent discoveries into the potential of host glycan-binding proteins (GBPs), such as C-type lectin receptors and galectins, to functionally interact with various host-like helminth glycans provide new insights. Host GBPs through their interactions with worm-derived glycans participate in shaping innate and adaptive immune responses upon infection. We thus propose an alternative concept termed "glycan gimmickry," which is defined as an active strategy of parasites to use their glycans to target GBPs within the host to promote their survival.

Molecular Biology of Prune Dwarf Virus—A Lesser Known Member of the Bromoviridae but a Vital Component in the Dynamic Virus–Host Cell Interaction Network

PubMed Central

Bujarski, Józef J.

2017-01-01

Prune dwarf virus (PDV) is one of the members of Bromoviridae family, genus Ilarvirus. Host components that participate in the regulation of viral replication or cell-to-cell movement via plasmodesmata are still unknown. In contrast, viral infections caused by some other Bromoviridae members are well characterized. Bromoviridae can be distinguished based on localization of their replication process in infected cells, cell-to-cell movement mechanisms, and plant-specific response reactions. Depending upon the genus, “genome activation” and viral replication are linked to various membranous structures ranging from endoplasmic reticulum, to tonoplast. In the case of PDV, there is still no evidence of natural resistance sources in the host plants susceptible to virus infection. Apparently, PDV has a great ability to overcome the natural defense responses in a wide spectrum of plant hosts. The first manifestations of PDV infection are specific cell membrane alterations, and the formation of replicase complexes that support PDV RNA replication inside the spherules. During each stage of its life cycle, the virus uses cell components to replicate and to spread in whole plants, within the largely suppressed cellular immunity environment. This work presents the above stages of the PDV life cycle in the context of current knowledge about other Bromoviridae members. PMID:29258199

Up in arms: Immune and nervous system response to sea star wasting disease

USGS Publications Warehouse

Fuess, Lauren E; Eiselord, Morgan E.; Closek, Collin J.; Tracy, Allison M.; Mauntz, Ruth; Gignoux-Wolfsohn, Sarah; Moritsch, Monica M; Yoshioka, Reyn; Burge, Colleen A.; Harvell, Drew; Friedman, Carolyn S.; Hershberger, Paul K.; Roberts, Steven B.

2015-01-01

Echinoderms, positioned taxonomically at the base of deuterostomes, provide an important system for the study of the evolution of the immune system. However, there is little known about the cellular components and genes associated with echinoderm immunity. The 2013–2014 sea star wasting disease outbreak is an emergent, rapidly spreading disease, which has led to large population declines of asteroids in the North American Pacific. While evidence suggests that the signs of this disease, twisting arms and lesions, may be attributed to a viral infection, the host response to infection is still poorly understood. In order to examine transcriptional responses of the sea star Pycnopodia helianthoides to sea star wasting disease, we injected a viral sized fraction (0.2 μm) homogenate prepared from symptomatic P. helianthoides into apparently healthy stars. Nine days following injection, when all stars were displaying signs of the disease, specimens were sacrificed and coelomocytes were extracted for RNA-seq analyses. A number of immune genes, including those involved in Toll signaling pathways, complement cascade, melanization response, and arachidonic acid metabolism, were differentially expressed. Furthermore, genes involved in nervous system processes and tissue remodeling were also differentially expressed, pointing to transcriptional changes underlying the signs of sea star wasting disease. The genomic resources presented here not only increase understanding of host response to sea star wasting disease, but also provide greater insight into the mechanisms underlying immune function in echinoderms.

Regulation of TBK1 activity by Optineurin contributes to cell cycle-dependent expression of the interferon pathway.

PubMed

Weil, Robert; Laplantine, Emmanuel; Génin, Pierre

2016-06-01

The innate immune system has evolved to detect and neutralize viral invasions. Triggering of this defense mechanism relies on the production and secretion of soluble factors that stimulate intracellular antiviral defense mechanisms. The Tank Binding Kinase 1 (TBK1) is a serine/threonine kinase in the innate immune signaling pathways including the antiviral response and the host defense against cytosolic infection by bacteries. Given the critical roles of TBK1, important regulatory mechanisms are required to regulate its activity. Among these, Optineurin (Optn) was shown to negatively regulate the interferon response, in addition to its important role in membrane trafficking, protein secretion, autophagy and cell division. As Optn does not carry any enzymatic activity, its functions depend on its precise subcellular localization and its interaction with other proteins, especially with components of the innate immune pathway. This review highlights advances in our understanding of Optn mechanisms of action with focus on the relationships between Optn and TBK1 and their implication in host defense against pathogens. Specifically, how the antiviral immune system is controlled during the cell cycle by the Optn/TBK1 axis and the physiological consequences of this regulatory mechanism are described. This review may serve to a better understanding of the relationships between the different functions of Optn, including those related to immune responses and its associated pathologies such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget's disease of bone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gut Immune Maturation Depends on Colonization with a Host-Specific Microbiota

PubMed Central

Chung, Hachung; Pamp, Sünje J.; Hill, Jonathan A.; Surana, Neeraj K.; Edelman, Sanna M.; Troy, Erin B.; Reading, Nicola C.; Villablanca, Eduardo J.; Wang, Sen; Mora, Jorge R.; Umesaki, Yoshinori; Mathis, Diane; Benoist, Christophe; Relman, David A.; Kasper, Dennis L.

2012-01-01

SUMMARY Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4+ and CD8+ T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression–all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system. PMID:22726443

β-Glucans Are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia

PubMed Central

Kutty, Geetha; Davis, A. Sally; Ferreyra, Gabriela A.; Qiu, Ju; Huang, Da Wei; Sassi, Monica; Bishop, Lisa; Handley, Grace; Sherman, Brad; Lempicki, Richard; Kovacs, Joseph A.

2016-01-01

β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study, we examined whether β-1,3-glucans are masked by surface proteins in Pneumocystis and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, β-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of β-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon γ, tumor necrosis factor α, interleukin 1β, interleukin 6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses. PMID:27324243

Bacterial Flagella: Twist and Stick, or Dodge across the Kingdoms

PubMed Central

Rossez, Yannick; Wolfson, Eliza B.; Holmes, Ashleigh; Gally, David L.; Holden, Nicola J.

2015-01-01

The flagellum organelle is an intricate multiprotein assembly best known for its rotational propulsion of bacteria. However, recent studies have expanded our knowledge of other functions in pathogenic contexts, particularly adherence and immune modulation, e.g., for Salmonella enterica, Campylobacter jejuni, Pseudomonas aeruginosa, and Escherichia coli. Flagella-mediated adherence is important in host colonisation for several plant and animal pathogens, but the specific interactions that promote flagella binding to such diverse host tissues has remained elusive. Recent work has shown that the organelles act like probes that find favourable surface topologies to initiate binding. An emerging theme is that more general properties, such as ionic charge of repetitive binding epitopes and rotational force, allow interactions with plasma membrane components. At the same time, flagellin monomers are important inducers of plant and animal innate immunity: variation in their recognition impacts the course and outcome of infections in hosts from both kingdoms. Bacteria have evolved different strategies to evade or even promote this specific recognition, with some important differences shown for phytopathogens. These studies have provided a wider appreciation of the functions of bacterial flagella in the context of both plant and animal reservoirs. PMID:25590430

[Immune response of Hansen's disease. Review].

PubMed

Rada, Elsa; Aranzazu, Nacarid; Convit, Jacinto

2009-12-01

Hansen's disease presents a wide spectrum of clinical and histopathological manifestations that reflect the nature of the immunological response of the host towards diverse Mycobacterium leprae components. The immunological system, composed by both innate and adaptive immunology, offers protection towards infections of various etiologies, among them bacterial. Bacteria, of course, have developed multiple strategies for evading host defenses, based on either very complex or simple mechanisms, but with a single purpose: to "resist" host attacks and to be able to survive. We have tried to summarize some recent studies in Hansen's disease, with more emphasis in the inmunology area. We think that in the future, all illnesses should also be very strongly related to other important aspects such as the social, environmental and economic, and whose development is not solved in a laboratory.

The Role of Probiotics and Prebiotics in Inducing Gut Immunity

PubMed Central

Vieira, Angélica T.; Teixeira, Mauro M.; Martins, Flaviano S.

2013-01-01

The gut immune system is influenced by many factors, including dietary components and commensal bacteria. Nutrients that affect gut immunity and strategies that restore a healthy gut microbial community by affecting the microbial composition are being developed as new therapeutic approaches to treat several inflammatory diseases. Although probiotics (live microorganisms) and prebiotics (food components) have shown promise as treatments for several diseases in both clinical and animal studies, an understanding of the molecular mechanisms behind the direct and indirect effects on the gut immune response will facilitate better and possibly more efficient therapy for diseases. In this review, we will first describe the concept of prebiotics, probiotics, and symbiotics and cover the most recently well-established scientific findings regarding the direct and indirect mechanisms by which these dietary approaches can influence gut immunity. Emphasis will be placed on the relationship of diet, the microbiota, and the gut immune system. Second, we will highlight recent results from our group, which suggest a new dietary manipulation that includes the use of nutrient products (organic selenium and Lithothamnium muelleri) and probiotics (Saccharomyces boulardii UFMG 905 and Bifidobacterium sp.) that can stimulate and manipulate the gut immune response, inducing intestinal homeostasis. Furthermore, the purpose of this review is to discuss and translate all of this knowledge into therapeutic strategies and into treatment for extra-intestinal compartment pathologies. We will conclude by discussing perspectives and molecular advances regarding the use of prebiotics or probiotics as new therapeutic strategies that manipulate the microbial composition and the gut immune responses of the host. PMID:24376446

Immunology of Yersinia pestis Infection.

PubMed

Bi, Yujing

2016-01-01

As a pathogen of plague, Yersinia pestis caused three massive pandemics in history that killed hundreds of millions of people. Yersinia pestis is highly invasive, causing severe septicemia which, if untreated, is usually fatal to its host. To survive in the host and maintain a persistent infection, Yersinia pestis uses several stratagems to evade the innate and the adaptive immune responses. For example, infections with this organism are biphasic, involving an initial "noninflammatory" phase where bacterial replication occurs initially with little inflammation and following by extensive phagocyte influx, inflammatory cytokine production, and considerable tissue destruction, which is called "proinflammatory" phase. In contrast, the host also utilizes its immune system to eliminate the invading bacteria. Neutrophil and macrophage are the first defense against Yersinia pestis invading through phagocytosis and killing. Other innate immune cells also play different roles, such as dendritic cells which help to generate more T helper cells. After several days post infection, the adaptive immune response begins to provide organism-specific protection and has a long-lasting immunological memory. Thus, with the cooperation and collaboration of innate and acquired immunity, the bacterium may be eliminated from the host. The research of Yersinia pestis and host immune systems provides an important topic to understand pathogen-host interaction and consequently develop effective countermeasures.

Immune defense and host life history.

PubMed

Zuk, Marlene; Stoehr, Andrew M

2002-10-01

Recent interest has focused on immune response in an evolutionary context, with particular attention to disease resistance as a life-history trait, subject to trade-offs against other traits such as reproductive effort. Immune defense has several characteristics that complicate this approach, however; for example, because of the risk of autoimmunity, optimal immune defense is not necessarily maximum immune defense. Two important types of cost associated with immunity in the context of life history are resource costs, those related to the allocation of essential but limited resources, such as energy or nutrients, and option costs, those paid not in the currency of resources but in functional or structural components of the organism. Resource and option costs are likely to apply to different aspects of resistance. Recent investigations into possible trade-offs between reproductive effort, particularly sexual displays, and immunity have suggested interesting functional links between the two. Although all organisms balance the costs of immune defense against the requirements of reproduction, this balance works out differently for males than it does for females, creating sex differences in immune response that in turn are related to ecological factors such as the mating system. We conclude that immune response is indeed costly and that future work would do well to include invertebrates, which have sometimes been neglected in studies of the ecology of immune defense.

Comparative Proteomics Identifies Host Immune System Proteins Affected by Infection with Mycobacterium bovis

PubMed Central

López, Vladimir; Villar, Margarita; Queirós, João; Vicente, Joaquín; Mateos-Hernández, Lourdes; Díez-Delgado, Iratxe; Contreras, Marinela; Alves, Paulo C.; Alberdi, Pilar; Gortázar, Christian; de la Fuente, José

2016-01-01

Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact human and animal health worldwide. The mycobacterial life cycle is complex, and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils, and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals, when compared to uninfected controls, are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls, but protein levels were higher as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggest that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recovers to limit pathogen multiplication and promote survival, facilitating pathogen transmission. PMID:27027307

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

PubMed

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

2016-01-01

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

Receptor for the F4 fimbriae of enterotoxigenic Escherichia coli (ETEC).

PubMed

Xia, Pengpeng; Zou, Yajie; Wang, Yiting; Song, Yujie; Liu, Wei; Francis, David H; Zhu, Guoqiang

2015-06-01

Infection with F4(+) enterotoxigenic Escherichia coli (ETEC) responsible for diarrhea in neonatal and post-weaned piglets leads to great economic losses in the swine industry. These pathogenic bacteria express either of three fimbrial variants F4ab, F4ac, and F4ad, which have long been known for their importance in host infection and initiating protective immune responses. The initial step in infection for the bacterium is to adhere to host enterocytes through fimbriae-mediated recognition of receptors on the host cell surface. A number of receptors for ETEC F4 have now been described and characterized, but their functions are still poorly understood. The current review summarizes the latest research addressing the characteristics of F4 fimbriae receptors and the interactions of F4 fimbriae and their receptors on host cells. These include observations that as follows: (1) FaeG mediates the binding activities of F4 and is an essential component of the F4 fimbriae, (2) the F4 fimbrial receptor gene is located in a region of chromosome 13, (3) the biochemical properties of F4 fimbrial receptors that form the binding site of the bacterium are now recognized, and (4) specific receptors confer susceptibility/resistance to ETEC F4 infection in pigs. Characterizing the host-pathogen interaction will be crucial to understand the pathogenicity of the bacteria, provide insights into receptor activation of the innate immune system, and develop therapeutic strategies to prevent this illness.

Yersinia vs. host Immunity: how a pathogen evades or triggers a protective response

PubMed Central

Chung, Lawton K.; Bliska, James B.

2015-01-01

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe. PMID:26638030

Differential Lymphocyte and Antibody Responses in Deer Mice Infected with Sin Nombre Hantavirus or Andes Hantavirus

PubMed Central

Quackenbush, Sandra; Rovnak, Joel; Haddock, Elaine; Black, William C.; Feldmann, Heinz; Prescott, Joseph

2014-01-01

ABSTRACT Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV. IMPORTANCE Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggest that a modest immune response may be a component of hantavirus ecology. PMID:24829335

Differential lymphocyte and antibody responses in deer mice infected with Sin Nombre hantavirus or Andes hantavirus.

PubMed

Schountz, Tony; Quackenbush, Sandra; Rovnak, Joel; Haddock, Elaine; Black, William C; Feldmann, Heinz; Prescott, Joseph

2014-08-01

Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV. Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggest that a modest immune response may be a component of hantavirus ecology. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mapping the microbiome of Ictalurid catfish: tissue and species-specific community composition

USDA-ARS?s Scientific Manuscript database

Host mucosal immunity is regulated by the complex interplay between environmental factors, host genetics, and commensal and pathogen dynamics. Microbial imbalances due to physiological stressors, changes in nutrition, and/or antibiotic application can potentiate over-exuberant host immune responses ...

Antigenic Variation and Immune Escape in the MTBC

PubMed Central

2017-01-01

Microbes that infect other organisms encounter host immune responses, and must overcome or evade innate and adaptive immune responses to successfully establish infection. Highly successful microbial pathogens, including M. tuberculosis, are able to evade adaptive immune responses (mediated by antibodies and/or T lymphocytes) and thereby establish long-term chronic infection. One mechanism that diverse pathogens use to evade adaptive immunity is antigenic variation, in which structural variants emerge that alter recognition by established immune responses and allow those pathogens to persist and/or to infect previously-immune hosts. Despite the wide use of antigenic variation by diverse pathogens, this mechanism appears to be infrequent in M. tuberculosis, as indicated by findings that known and predicted human T cell epitopes in this organism are highly conserved, although there are exceptions. These findings have implications for diagnostic tests that are based on measuring host immune responses, and for vaccine design and development. PMID:29116635

Nonencapsulated Trichinella pseudospiralis Infection Impairs Follicular Helper T Cell Differentiation with Subclass-Selective Decreases in Antibody Responses

PubMed Central

Asano, Kazunobu; Wu, Zhiliang; Srinontong, Piyarat; Ikeda, Takahide; Nagano, Isao; Morita, Hirokuyi

2016-01-01

Infectious microorganisms often modify host immunity to escape from immune elimination. Trichinella is a unique nematode of the helminth family, whose members parasitize the muscle cells inside the host without robust eliminative reactions. There are several species of Trichinella; some develop in muscle cells that become encapsulated (e.g., Trichinella spiralis) and others in cells that do not encapsulate (e.g., Trichinella pseudospiralis). It has already been established that Trichinella infection affects host immune responses in several experimental immune diseases in animal models; however, most of those studies were done using T. spiralis infection. As host immune responses to T. spiralis and T. pseudospiralis infections have been reported to be different, it is necessary to clarify how T. pseudospiralis infection influences the host immune responses. In this study, we investigated the influence on host humoral immunity in T. pseudospiralis-infected mice. We demonstrated that T. pseudospiralis infection decreased antigen-specific IgG2a and IgG2b antibody (Ab) production in mice immunized with a model antigen. This selective decrease in gamma interferon (IFN-γ)-dependent Ab production was not due to a decrease in IFN-γ production, and we instead found impaired follicular helper T (Tfh) cell differentiation. The affinity maturation of antigen-specific Ab tended to be delayed but was not significant in T. pseudospiralis-infected mice. We also observed that CD11b+ spleen cells in T. pseudospiralis-infected mice expressed CD206 and PD-L2, the phenotype of which was M2 macrophages with weak production of interleukin-6 (IL-6), possibly resulting in impaired Tfh differentiation. Taken together, our results indicate that nonencapsulated Trichinella infection induces selective dampening in humoral immunity with the suppression of Tfh differentiation. PMID:27736779

Host influence in the genomic composition of flaviviruses: A multivariate approach.

PubMed

Simón, Diego; Fajardo, Alvaro; Sóñora, Martín; Delfraro, Adriana; Musto, Héctor

2017-10-28

Flaviviruses present substantial differences in their host range and transmissibility. We studied the evolution of base composition, dinucleotide biases, codon usage and amino acid frequencies in the genus Flavivirus within a phylogenetic framework by principal components analysis. There is a mutual interplay between the evolutionary history of flaviviruses and their respective vectors and/or hosts. Hosts associated to distinct phylogenetic groups may be driving flaviviruses at different pace and through various sequence landscapes, as can be seen for viruses associated with Aedes or Culex spp., although phylogenetic inertia cannot be ruled out. In some cases, viruses face even opposite forces. For instance, in tick-borne flaviviruses, while vertebrate hosts exert pressure to deplete their CpG, tick vectors drive them to exhibit GC-rich codons. Within a vertebrate environment, natural selection appears to be acting on the viral genome to overcome the immune system. On the other side, within an arthropod environment, mutational biases seem to be the dominant forces. Copyright © 2017 Elsevier Inc. All rights reserved.

The chronicles of Porphyromonas gingivalis: the microbium, the human oral epithelium and their interplay

PubMed Central

Yilmaz, Özlem

2009-01-01

The microbiota of the human oral mucosa consists of a myriad of bacterial species that normally exist in commensal harmony with the host. Porphyromonas gingivalis, an aetiological agent in severe forms of periodontitis (a chronic inflammatory disease), is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium. This Gram-negative anaerobe can also exist within the host epithelium without the existence of overt disease. Gingival epithelial cells, the outer lining of the gingival mucosa, which function as an important part of the innate immune system, are among the first host cells colonized by P. gingivalis. This review describes recent studies implicating the co-existence and intracellular adaptation of the organism in these target host cells. Specifically, recent findings on the putative mechanisms of persistence, intercellular dissemination and opportunism are highlighted. These new findings may also represent an original and valuable model for mechanistic characterization of other successful host-adapted, self-limiting, persistent intracellular bacteria in human epithelial tissues. PMID:18832296

The chronicles of Porphyromonas gingivalis: the microbium, the human oral epithelium and their interplay.

PubMed

Yilmaz, Ozlem

2008-10-01

The microbiota of the human oral mucosa consists of a myriad of bacterial species that normally exist in commensal harmony with the host. Porphyromonas gingivalis, an aetiological agent in severe forms of periodontitis (a chronic inflammatory disease), is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium. This Gram-negative anaerobe can also exist within the host epithelium without the existence of overt disease. Gingival epithelial cells, the outer lining of the gingival mucosa, which function as an important part of the innate immune system, are among the first host cells colonized by P. gingivalis. This review describes recent studies implicating the co-existence and intracellular adaptation of the organism in these target host cells. Specifically, recent findings on the putative mechanisms of persistence, intercellular dissemination and opportunism are highlighted. These new findings may also represent an original and valuable model for mechanistic characterization of other successful host-adapted, self-limiting, persistent intracellular bacteria in human epithelial tissues.

Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke

PubMed Central

Lee, Elaine C.; Armstrong, Elizabeth M.

2018-01-01

Exertional heatstroke (EHS) is a medical emergency that cannot be predicted, requires immediate whole-body cooling to reduce elevated internal body temperature, and is influenced by numerous host and environmental factors. Widely accepted predisposing factors (PDF) include prolonged or intense exercise, lack of heat acclimatization, sleep deprivation, dehydration, diet, alcohol abuse, drug use, chronic inflammation, febrile illness, older age, and nonsteroidal anti-inflammatory drug use. The present review links these factors to the human intestinal microbiota (IM) and diet, which previously have not been appreciated as PDF. This review also describes plausible mechanisms by which these PDF lead to EHS: endotoxemia resulting from elevated plasma lipopolysaccharide (i.e., a structural component of the outer membrane of Gram-negative bacteria) and tissue injury from oxygen free radicals. We propose that recognizing the lifestyle and host factors which are influenced by intestine-microbial interactions, and modifying habitual dietary patterns to alter the IM ecosystem, will encourage efficient immune function, optimize the intestinal epithelial barrier, and reduce EHS morbidity and mortality. PMID:29850597

Towards Targeting the Aryl Hydrocarbon Receptor in Cystic Fibrosis

PubMed Central

Paolicelli, Giuseppe; De Luca, Antonella; Renga, Giorgia; Borghi, Monica; Pariano, Marilena; Stincardini, Claudia; Scaringi, Lucia; Ricci, Maurizio; Romani, Luigina

2018-01-01

Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis. PMID:29670460

Host immune constraints on malaria transmission: insights from population biology of within-host parasites

PubMed Central

2013-01-01

Background Plasmodium infections trigger complex immune reactions from their hosts against several life stages of the parasite, including gametocytes. These immune responses are highly variable, depending on age, genetics, and exposure history of the host as well as species and strain of parasite. Although the effects of host antibodies that act against gamete stages in the mosquito (due to uptake in the blood meal) are well documented, the effects of host immunity upon within-host gametocytes are not as well understood. This report consists of a theoretical population biology-based analysis to determine constraints that host immunity impose upon gametocyte population growth. The details of the mathematical models used for the analysis were guided by published reports of clinical and animal studies, incorporated plausible modalities of immune reactions to parasites, and were tailored to the life cycl es of the two most widespread human malaria pathogens, Plasmodium falciparum and Plasmodium vivax. Results For the same ability to bind and clear a target, the model simulations suggest that an antibody attacking immature gametocytes would tend to lower the overall density of transmissible mature gametocytes more than an antibody attacking the mature forms directly. Transmission of P. falciparum would be especially vulnerable to complete blocking by antibodies to its immature forms since its gametocytes take much longer to reach maturity than those of P. vivax. On the other hand, antibodies attacking the mature gametocytes directly would reduce the time the mature forms can linger in the host. Simulation results also suggest that varying the standard deviation in the time necessary for individual asexual parasites to develop and produce schizonts can affect the efficiency of production of transmissible gametocytes. Conclusions If mature gametocyte density determines the probability of transmission, both Plasmodium species, but especially P. falciparum, could bolster this probability through evasion or suppression of host immune responses against the immature gametocytes. However, if the long term lingering of mature gametocytes at low density in the host is also important to ensure transmission, then evasion or suppression of antibodies against the mature stages would bolster probability of transmission as well. PMID:23767770

Transcriptomic and proteomic insights into innate immunity and adaptations to a symbiotic lifestyle in the gutless marine worm Olavius algarvensis

DOE PAGES

Wippler, Juliane; Kleiner, Manuel; Lott, Christian; ...

2016-11-21

The gutless marine worm Olavius algarvensis has a completely reduced digestive and excretory system, and lives in an obligate nutritional symbiosis with bacterial symbionts. While considerable knowledge has been gained of the symbionts, the host has remained largely unstudied. We generated transcriptomes and proteomes of O. algarvensis to better understand how this annelid worm gains nutrition from its symbionts, how it adapted physiologically to a symbiotic lifestyle, and how its innate immune system recognizes and responds to its symbiotic microbiota. Key adaptations to the symbiosis include (i) the expression of gut-specific digestive enzymes despite the absence of a gut, mostmore » likely for the digestion of symbionts in the host's epidermal cells; (ii) a modified hemoglobin that may bind hydrogen sulfide produced by two of the worm’s symbionts; and (iii) the expression of a very abundant protein for oxygen storage, hemerythrin, that could provide oxygen to the symbionts and the host under anoxic conditions. In addition, we identified a large repertoire of proteins involved in interactions between the worm's innate immune system and its symbiotic microbiota, such as peptidoglycan recognition proteins, lectins, fibrinogen-related proteins, Toll and scavenger receptors, and antimicrobial proteins.We also show how this worm, over the course of evolutionary time, has modified widely-used proteins and changed their expression patterns in adaptation to its symbiotic lifestyle and describe expressed components of the innate immune system in a marine oligochaete. These results provide further support for the recent realization that animals have evolved within the context of their associations with microbes and that their adaptive responses to symbiotic microbiota have led to biological innovations.« less

Transcriptomic and proteomic insights into innate immunity and adaptations to a symbiotic lifestyle in the gutless marine worm Olavius algarvensis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wippler, Juliane; Kleiner, Manuel; Lott, Christian

The gutless marine worm Olavius algarvensis has a completely reduced digestive and excretory system, and lives in an obligate nutritional symbiosis with bacterial symbionts. While considerable knowledge has been gained of the symbionts, the host has remained largely unstudied. We generated transcriptomes and proteomes of O. algarvensis to better understand how this annelid worm gains nutrition from its symbionts, how it adapted physiologically to a symbiotic lifestyle, and how its innate immune system recognizes and responds to its symbiotic microbiota. Key adaptations to the symbiosis include (i) the expression of gut-specific digestive enzymes despite the absence of a gut, mostmore » likely for the digestion of symbionts in the host's epidermal cells; (ii) a modified hemoglobin that may bind hydrogen sulfide produced by two of the worm’s symbionts; and (iii) the expression of a very abundant protein for oxygen storage, hemerythrin, that could provide oxygen to the symbionts and the host under anoxic conditions. In addition, we identified a large repertoire of proteins involved in interactions between the worm's innate immune system and its symbiotic microbiota, such as peptidoglycan recognition proteins, lectins, fibrinogen-related proteins, Toll and scavenger receptors, and antimicrobial proteins.We also show how this worm, over the course of evolutionary time, has modified widely-used proteins and changed their expression patterns in adaptation to its symbiotic lifestyle and describe expressed components of the innate immune system in a marine oligochaete. These results provide further support for the recent realization that animals have evolved within the context of their associations with microbes and that their adaptive responses to symbiotic microbiota have led to biological innovations.« less

Aspartyl proteases in Candida glabrata are required for suppression of the host innate immune response

PubMed Central

Rasheed, Mubashshir; Battu, Anamika; Kaur, Rupinder

2018-01-01

A family of 11 cell surface-associated aspartyl proteases (CgYps1–11), also referred as yapsins, is a key virulence factor in the pathogenic yeast Candida glabrata. However, the mechanism by which CgYapsins modulate immune response and facilitate survival in the mammalian host remains to be identified. Here, using RNA-Seq analysis, we report that genes involved in cell wall metabolism are differentially regulated in the Cgyps1–11Δ mutant. Consistently, the mutant contained lower β-glucan and mannan levels and exhibited increased chitin content in the cell wall. As cell wall components are known to regulate the innate immune response, we next determined the macrophage transcriptional response to C. glabrata infection and observed differential expression of genes implicated in inflammation, chemotaxis, ion transport, and the tumor necrosis factor signaling cascade. Importantly, the Cgyps1–11Δ mutant evoked a different immune response, resulting in an enhanced release of the pro-inflammatory cytokine IL-1β in THP-1 macrophages. Further, Cgyps1–11Δ–induced IL-1β production adversely affected intracellular proliferation of co-infected WT cells and depended on activation of spleen tyrosine kinase (Syk) signaling in the host cells. Accordingly, the Syk inhibitor R406 augmented intracellular survival of the Cgyps1–11Δ mutant. Finally, we demonstrate that C. glabrata infection triggers elevated IL-1β production in mouse organs and that the CgYPS genes are required for organ colonization and dissemination in the murine model of systemic infection. Altogether, our results uncover the basis for macrophage-mediated killing of Cgyps1–11Δ cells and provide the first evidence that aspartyl proteases in C. glabrata are required for suppression of IL-1β production in macrophages. PMID:29491142

Transcriptomic and proteomic insights into innate immunity and adaptations to a symbiotic lifestyle in the gutless marine worm Olavius algarvensis.

PubMed

Wippler, Juliane; Kleiner, Manuel; Lott, Christian; Gruhl, Alexander; Abraham, Paul E; Giannone, Richard J; Young, Jacque C; Hettich, Robert L; Dubilier, Nicole

2016-11-21

The gutless marine worm Olavius algarvensis has a completely reduced digestive and excretory system, and lives in an obligate nutritional symbiosis with bacterial symbionts. While considerable knowledge has been gained of the symbionts, the host has remained largely unstudied. Here, we generated transcriptomes and proteomes of O. algarvensis to better understand how this annelid worm gains nutrition from its symbionts, how it adapted physiologically to a symbiotic lifestyle, and how its innate immune system recognizes and responds to its symbiotic microbiota. Key adaptations to the symbiosis include (i) the expression of gut-specific digestive enzymes despite the absence of a gut, most likely for the digestion of symbionts in the host's epidermal cells; (ii) a modified hemoglobin that may bind hydrogen sulfide produced by two of the worm's symbionts; and (iii) the expression of a very abundant protein for oxygen storage, hemerythrin, that could provide oxygen to the symbionts and the host under anoxic conditions. Additionally, we identified a large repertoire of proteins involved in interactions between the worm's innate immune system and its symbiotic microbiota, such as peptidoglycan recognition proteins, lectins, fibrinogen-related proteins, Toll and scavenger receptors, and antimicrobial proteins. We show how this worm, over the course of evolutionary time, has modified widely-used proteins and changed their expression patterns in adaptation to its symbiotic lifestyle and describe expressed components of the innate immune system in a marine oligochaete. Our results provide further support for the recent realization that animals have evolved within the context of their associations with microbes and that their adaptive responses to symbiotic microbiota have led to biological innovations.

Endogenous antipyretics.

PubMed

Roth, Joachim

2006-09-01

The febrile increase of body temperature is regarded as a component of the complex host response to infection or inflammation that accompanies the activation of the immune system. Late phases of fever appear mediated by pro-inflammatory cytokines called endogenous pyrogens. The rise of body temperature is beneficial because it accelerates several components of the activated immune system. To prevent an excessive and dangerous rise of body temperature the febrile response is controlled, limited in strength and duration, and sometimes even prevented by the actions of endogenous antipyretic substances liberated systemically or within the brain during fever. In most cases the antipyretic effects are achieved by an inhibitory influence on the formation or action of endogenous pyrogens, or by effects on neuronal thermoregulatory circuits that are activated during fever. Endogenous antipyretic substances include steroid hormones, neuropeptides, cytokines and other molecules. It is the purpose of this review to consider the current state in the research on endogenous antipyretic systems.

The Host Defense Proteome of Human and Bovine Milk

PubMed Central

Hettinga, Kasper; van Valenberg, Hein; de Vries, Sacco; Boeren, Sjef; van Hooijdonk, Toon; van Arendonk, Johan; Vervoort, Jacques

2011-01-01

Milk is the single source of nutrients for the newborn mammal. The composition of milk of different mammals has been adapted during evolution of the species to fulfill the needs of the offspring. Milk not only provides nutrients, but it also serves as a medium for transfer of host defense components to the offspring. The host defense proteins in the milk of different mammalian species are expected to reveal signatures of evolution. The aim of this study is therefore to study the difference in the host defense proteome of human and bovine milk. We analyzed human and bovine milk using a shot-gun proteomics approach focusing on host defense-related proteins. In total, 268 proteins in human milk and 269 proteins in bovine milk were identified. Of these, 44 from human milk and 51 from bovine milk are related to the host defense system. Of these proteins, 33 were found in both species but with significantly different quantities. High concentrations of proteins involved in the mucosal immune system, immunoglobulin A, CD14, lactoferrin, and lysozyme, were present in human milk. The human newborn is known to be deficient for at least two of these proteins (immunoglobulin A and CD14). On the other hand, antimicrobial proteins (5 cathelicidins and lactoperoxidase) were abundant in bovine milk. The high concentration of lactoperoxidase is probably linked to the high amount of thiocyanate in the plant-based diet of cows. This first detailed analysis of host defense proteins in human and bovine milk is an important step in understanding the function of milk in the development of the immune system of these two mammals. PMID:21556375

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

PubMed Central

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

2016-01-01

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

The immunoregulatory effects of Chinese herbal medicine on the maturation and function of dendritic cells.

PubMed

Li, Jinyao; Li, Jinyu; Zhang, Fuchun

2015-08-02

Traditional Chinese herbal medicine (CHM) has a long-history for treatment of various human diseases including tumors, infection, autoimmune diseases in Asian countries, especially in China, Japan, Korea and India. CHM was traditionally used as water extracts and many Chinese herbs were considered to be good for health, which can regulate immune system to protect host from diseases. With the progress of technology, the components of CHM were identified and purified, which included polysaccharides, saponins, phenolic compounds, flavonoids and so on. Recently, accumulating evidence indicates that CHM and its components can regulate immune system through targeting dendritic cells (DCs). We hereby reviewed the immunoregulatory effects of CHM on the maturation, cytokine production and function of DCs. This should help to shed light on the potential mechanism of CHM to improve the usage and clinical efficacy of CHM. Literatures about the effects of CHM on DCs were searched in electronic databases such as Pubmed, Google Scholar and Scopus from 2000 to 2014. 'CHM', 'DC' or 'immune' were used as keywords for the searches. We only reviewed literatures published in English. Over 600 publications were found about 'CHM&immune' and around 120 literatures about 'CHM&DC' were selected and reviewed in this paper. All publications are backed by preclinical or clinical evidences both in vitro and in vivo. Some CHM and its components promote the maturation, pro-inflammatory cytokine production and function of DCs and as the adjuvant enhance immune responses against tumor and infection. In contrast, other CHM and its components suppress the activation status of DCs to induce regulatory T cells, inhibit allergic and inflammatory responses, ameliorate autoimmune diseases, and prolong the allograft survival. A large body of evidence shows that CHM and its components regulate the activation status of DCs through TLRs, NF-κB, MAPK signaling pathways. This review provides useful information for understanding the mechanism of CHM on the treatment of diseases, which facilitates to improve the efficacy of CHM. Based on the immunoregulatory effects of CHM on DCs, it indicated that some CHM and its components could be use to develop adjuvant to enhance antigen-specific immune responses or tolerogenic adjuvant to generate antigen-specific immune tolerance. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A model for the coevolution of immunity and immune evasion in vector-borne diseases with implications for the epidemiology of malaria.

PubMed

Koella, Jacob C; Boëte, C

2003-05-01

We describe a model of host-parasite coevolution, where the interaction depends on the investments by the host in its immune response and by the parasite in its ability to suppress (or evade) its host's immune response. We base our model on the interaction between malaria parasites and their mosquito hosts and thus describe the epidemiological dynamics with the Macdonald-Ross equation of malaria epidemiology. The qualitative predictions of the model are most sensitive to the cost of the immune response and to the intensity of transmission. If transmission is weak or the cost of immunity is low, the system evolves to a coevolutionarily stable equilibrium at intermediate levels of investment (and, generally, at a low frequency of resistance). At a higher cost of immunity and as transmission intensifies, the system is not evolutionarily stable but rather cycles around intermediate levels of investment. At more intense transmission, neither host nor parasite invests any resources in dominating its partner so that no resistance is observed in the population. These results may help to explain the lack of encapsulated malaria parasites generally observed in natural populations of mosquito vectors, despite strong selection pressure for resistance in areas of very intense transmission.

The Immune Interplay between the Host and the Pathogen in Aspergillus fumigatus Lung Infection

PubMed Central

Sales-Campos, Helioswilton; Tonani, Ludmilla; Cardoso, Cristina Ribeiro Barros; Kress, Márcia Regina Von Zeska

2013-01-01

The interplay between Aspergillus fumigatus and the host immune response in lung infection has been subject of studies over the last years due to its importance in immunocompromised patients. The multifactorial virulence factors of A. fumigatus are related to the fungus biological characteristics, for example, structure, ability to grow and adapt to high temperatures and stress conditions, besides capability of evading the immune system and causing damage to the host. In this context, the fungus recognition by the host innate immunity occurs when the pathogen disrupts the natural and chemical barriers followed by the activation of acquired immunity. It seems clear that a Th1 response has a protective role, whereas Th2 reactions are often associated with higher fungal burden, and Th17 response is still controversial. Furthermore, a fine regulation of the effector immunity is required to avoid excessive tissue damage associated with fungal clearance, and this role could be attributed to regulatory T cells. Finally, in this work we reviewed the aspects involved in the complex interplay between the host immune response and the pathogen virulence factors, highlighting the immunological issues and the importance of its better understanding to the development of novel therapeutic approaches for invasive lung aspergillosis. PMID:23984400

Staphylococcus aureus infection dynamics.

PubMed

Pollitt, Eric J G; Szkuta, Piotr T; Burns, Nicola; Foster, Simon J

2018-06-01

Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections. Here we examine the host factors underlying the population bottleneck and subsequent clonal expansion in S. aureus infection models, to identify underpinning principles of infection. The bottleneck is a common feature between models and is independent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used "survival" model results in a reduced population bottleneck, suggesting that host defences have been simply overloaded. This brings into question the applicability of the survival model. Depletion of immune mediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages, including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of the population bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion led to greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack of systemic spread. We also used a novel microscopy approach to examine abscess architecture and distribution within organs. From these observations we developed a conceptual model for S. aureus disease from initial infection to mature abscess. This work highlights the need to understand the complexities of the infectious process to be able to assign functions for host and bacterial components, and why S. aureus disease requires a seemingly high infectious dose and how interventions such as a vaccine may be more rationally developed.

Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Qingzhan; Shi, Kaichuang; Yoo, Dongwan, E-mail: dyoo@illinois.edu

Type I interferons (IFN-α/β) are the major components of the innate immune response of hosts, and in turn many viruses have evolved to modulate the host response during infection. We found that the IFN-β production was significantly suppressed during PEDV infection in cells. To identify viral IFN antagonists and to study their suppressive function, viral coding sequences for the entire structural and nonstructural proteins were cloned and expressed. Of 16 PEDV nonstructural proteins (nsps), nsp1, nsp3, nsp7, nsp14, nsp15 and nsp16 were found to inhibit the IFN-β and IRF3 promoter activities. The sole accessory protein ORF3, structure protein envelope (E),more » membrane (M), and nucleocapsid (N) protein were also shown to inhibit such activities. PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP) by degrading CBP. A further study showed that the CBP degradation by nsp1 was proteasome-dependent. Our data demonstrate that PEDV modulates the host innate immune responses by degrading CBP and suppressing ISGs expression. - Highlights: • PEDV modulates the host innate immune system by suppressing the type I interferon production and ISGs expression. • Ten viral proteins were identified as IFN antagonists, and nsp1 was the most potent viral IFN antagonist. • PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP). • PEDV nsp1 caused the CBP degradation in the nucleus, which may be the key mechanism for PEDV-mediated IFN downregulation.« less

Function of endoplasmic reticulum calcium ATPase in innate immunity-mediated programmed cell death

PubMed Central

Zhu, Xiaohong; Caplan, Jeffrey; Mamillapalli, Padmavathi; Czymmek, Kirk; Dinesh-Kumar, Savithramma P

2010-01-01

Programmed cell death (PCD) initiated at the pathogen-infected sites during the plant innate immune response is thought to prevent the development of disease. Here, we describe the identification and characterization of an ER-localized type IIB Ca2+-ATPase (NbCA1) that function as a regulator of PCD. Silencing of NbCA1 accelerates viral immune receptor N- and fungal-immune receptor Cf9-mediated PCD, as well as non-host pathogen Pseudomonas syringae pv. tomato DC3000 and the general elicitor cryptogein-induced cell death. The accelerated PCD rescues loss-of-resistance phenotype of Rar1, HSP90-silenced plants, but not SGT1-silenced plants. Using a genetically encoded calcium sensor, we show that downregulation of NbCA1 results in the modulation of intracellular calcium signalling in response to cryptogein elicitor. We further show that NbCAM1 and NbrbohB function as downstream calcium decoders in N-immune receptor-mediated PCD. Our results indicate that ER-Ca2+-ATPase is a component of the calcium efflux pathway that controls PCD during an innate immune response. PMID:20075858

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

PubMed

Goverse, Aska; Smant, Geert

2014-01-01

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

Influences of Plant Traits on Immune Responses of Specialist and Generalist Herbivores

PubMed Central

Lampert, Evan

2012-01-01

Specialist and generalist insect herbivore species often differ in how they respond to host plant traits, particularly defensive traits, and these responses can include weakened or strengthened immune responses to pathogens and parasites. Accurate methods to measure immune response in the presence and absence of pathogens and parasites are necessary to determine whether susceptibility to these natural enemies is reduced or increased by host plant traits. Plant chemical traits are particularly important in that host plant metabolites may function as antioxidants beneficial to the immune response, or interfere with the immune response of both specialist and generalist herbivores. Specialist herbivores that are adapted to process and sometimes accumulate specific plant compounds may experience high metabolic demands that may decrease immune response, whereas the metabolic demands of generalist species differ due to more broad-substrate enzyme systems. However, the direct deleterious effects of plant compounds on generalist herbivores may weaken their immune responses. Further research in this area is important given that the ecological relevance of plant traits to herbivore immune responses is equally important in natural systems and agroecosystems, due to potential incompatibility of some host plant species and cultivars with biological control agents of herbivorous pests. PMID:26466545

Cross-talk between virus and host innate immunity in pediatric HIV-1 infection and disease progression.

PubMed

Freguja, Riccardo; Gianesin, Ketty; Zanchetta, Marisa; De Rossi, Anita

2012-07-01

Variability in the susceptibility to HIV-1 infection and disease progression depends on both virus and host determinants. Some exposed individuals remain HIV-1-uninfected and HIV-1-infected subjects develop disease at varying intervals with a small percentage remaining long-term non-progressors. As innate immunity is the earliest response to microbial entry and injury, host factors that impact innate immunity may play a role in viral infectivity and pathogenesis. In the pediatric population the interactions between the virus and the host may be of particular relevance due to the still developing adaptive immune system. Data indicate that genetic variants of defensins and Toll-Like Receptors (TLRs), key elements of innate immunity, play a role in mother-to-child transmission (MTCT) of HIV-1, and in the outcome of pediatric HIV-1 disease. Although the mechanisms by which these genetic variants influence HIV-1 interactions with the host are still largely unknown, defensins and TLRs, along with their link with regulatory T cells (Tregs), may play a critical role in the onset and persistence of immune activation, a hallmark of HIV-1 disease.

Characterization of host immune responses in Ebola virus infections.

PubMed

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

2014-06-01

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

Genetics of immune recognition and response in Drosophila host defense.

PubMed

Ligoxygakis, Petros

2013-01-01

Due to the evolutionary conservation of innate immune mechanisms, Drosophila has been extensively used as a model for the dissection in genetic terms of innate host immunity to infection. Genetic screening in fruit flies has set the stage for the pathways and systems required for responding to immune challenge and the dynamics of the progression of bacterial and fungal infection. In addition, fruit flies have been used as infection models to dissect host-pathogen interactions from both sides of this equation. This chapter describes our current understanding of the genetics of the fruit fly immune response and summarizes the most important findings in this area during the past decade. © 2013 Elsevier Inc. All rights reserved.

A Systems Biology Approach Reveals that Tissue Tropism to West Nile Virus Is Regulated by Antiviral Genes and Innate Immune Cellular Processes

PubMed Central

Suthar, Mehul S.; Brassil, Margaret M.; Blahnik, Gabriele; McMillan, Aimee; Ramos, Hilario J.; Proll, Sean C.; Belisle, Sarah E.; Katze, Michael G.; Gale, Michael

2013-01-01

The actions of the RIG-I like receptor (RLR) and type I interferon (IFN) signaling pathways are essential for a protective innate immune response against the emerging flavivirus West Nile virus (WNV). In mice lacking RLR or IFN signaling pathways, WNV exhibits enhanced tissue tropism, indicating that specific host factors of innate immune defense restrict WNV infection and dissemination in peripheral tissues. However, the immune mechanisms by which the RLR and IFN pathways coordinate and function to impart restriction of WNV infection are not well defined. Using a systems biology approach, we defined the host innate immune response signature and actions that restrict WNV tissue tropism. Transcriptional profiling and pathway modeling to compare WNV-infected permissive (spleen) and nonpermissive (liver) tissues showed high enrichment for inflammatory responses, including pattern recognition receptors and IFN signaling pathways, that define restriction of WNV replication in the liver. Assessment of infected livers from Mavs−/−×Ifnar−/− mice revealed the loss of expression of several key components within the natural killer (NK) cell signaling pathway, including genes associated with NK cell activation, inflammatory cytokine production, and NK cell receptor signaling. In vivo analysis of hepatic immune cell infiltrates from WT mice demonstrated that WNV infection leads to an increase in NK cell numbers with enhanced proliferation, maturation, and effector action. In contrast, livers from Mavs−/−×Ifnar−/− infected mice displayed reduced immune cell infiltration, including a significant reduction in NK cell numbers. Analysis of cocultures of dendritic and NK cells revealed both cell-intrinsic and -extrinsic roles for the RLR and IFN signaling pathways to regulate NK cell effector activity. Taken together, these observations reveal a complex innate immune signaling network, regulated by the RLR and IFN signaling pathways, that drives tissue-specific antiviral effector gene expression and innate immune cellular processes that control tissue tropism to WNV infection. PMID:23544010

Partial venom gland transcriptome of a Drosophila parasitoid wasp, Leptopilina heterotoma, reveals novel and shared bioactive profiles with stinging Hymenoptera

PubMed Central

Heavner, Mary E.; Gueguen, Gwenaelle; Rajwani, Roma; Pagan, Pedro E.; Small, Chiyedza; Govind, Shubha

2013-01-01

Analysis of natural host-parasite relationships reveals the evolutionary forces that shape the delicate and unique specificity characteristic of such interactions. The accessory long gland-reservoir complex of the wasp Leptopilina heterotoma (Figitidae) produces venom with virus-like particles. Upon delivery, venom components delay host larval development and completely block host immune responses. The host range of this Drosophila endoparasitoid notably includes the highly-studied model organism, Drosophila melanogaster. Categorization of 827 unigenes, using similarity as an indicator of putative homology, reveals that approximately 25% are novel or classified as hypothetical proteins. Most of the remaining unigenes are related to processes involved in signaling, cell cycle, and cell physiology including detoxification, protein biogenesis, and hormone production. Analysis of L. heterotoma’s predicted venom gland proteins demonstrates conservation among endo- and ectoparasitoids within the Apocrita (e.g., this wasp and the jewel wasp Nasonia vitripennis) and stinging aculeates (e.g., the honey bee and ants). Enzyme and KEGG pathway profiling predicts that kinases, esterases, and hydrolases may contribute to venom activity in this unique wasp. To our knowledge, this investigation marks the first functional genomic study for a natural parasitic wasp of Drosophila. Our findings will help explain how L. heterotoma shuts down its hosts’ immunity and shed light on the molecular basis of a natural arms race between these insects. PMID:23688557

Bacterial virulence effectors and their activities.

PubMed

Hann, Dagmar R; Gimenez-Ibanez, Selena; Rathjen, John P

2010-08-01

The major virulence strategy for plant pathogenic bacteria is deployment of effector molecules within the host cytoplasm. Each bacterial strain possesses a set of 20-30 effectors which have overlapping activities, are functionally interchangeable, and diverge in composition between strains. Effectors target host molecules to suppress immunity. Two main strategies are apparent. Effectors that target host proteins seem to attack conserved structural domains but otherwise lack specificity. On the other hand, those that influence host gene transcription directly do so with extreme specificity. In both cases, examples are known where the host has exploited effector-target affinities to establish immune recognition of effectors. The molecular activity of each effector links virulence and immune outcomes. Copyright 2010 Elsevier Ltd. All rights reserved.

Antigenic profiling of Yersinia pestis infection in the Wyoming coyote (Canis latrans)

USGS Publications Warehouse

Vernati, G.; Edwards, W.H.; Rocke, T.E.; Little, S.F.; Andrews, G.P.

2011-01-01

Although Yersinia pestis is classified as a "high-virulence" pathogen, some host species are variably susceptible to disease. Coyotes (Canis latrans) exhibit mild, if any, symptoms during infection, but antibody production occurs postinfection. This immune response has been reported to be against the F1 capsule, although little subsequent characterization has been conducted. To further define the nature of coyote humoral immunity to plague, qualitative serology was conducted to assess the antiplague antibody repertoire. Humoral responses to six plasmid-encoded Y. pestis virulence factors were first examined. Of 20 individual immune coyotes, 90% were reactive to at least one other antigen in the panel other than F1. The frequency of reactivity to low calcium response plasmid (pLcr)-encoded Yersinia protein kinase A (YpkA) and Yersinia outer protein D (YopD) was significantly greater than that previously observed in a murine model for plague. Additionally, both V antigen and plasminogen activator were reactive with over half of the serum samples tested. Reactivity to F1 was markedly less frequent in coyotes (35%). Twenty previously tested antibody-negative samples were also examined. While the majority were negative across the panel, 15% were positive for 1-3 non-F1 antigens. In vivo-induced antigen technology employed to identify novel chromosomal genes of Y. pestis that are up-regulated during infection resulted in the identification of five proteins, including a flagellar component (FliP) that was uniquely reactive with the coyote serum compared with immune serum from two other host species. Collectively, these data suggest that humoral immunity to pLcr-encoded antigens and the pesticin plasmid (pPst)-encoded Pla antigen may be relevant to plague resistance in coyotes. The serologic profile of Y. pestis chromosomal antigens up-regulated in vivo specific to C. latrans may provide insight into the differences in the pathogen-host responses during Y. pestis infection.

Immune pathogenesis of pediatric HIV-1 infection

PubMed Central

TIEMESSEN, CAROLINE T.; KUHN, LOUISE

2008-01-01

Vertical exposure to HIV occurs at a time when functional capacity of the infant’s immune system is attenuated through immaturity. Immune response capability is rooted in host genetic makeup, and the broad and fine specificity of innate and adaptive immune responses, respectively, shape the outcomes of HIV encounter in some instances and imprint viral changes through selective immune pressure in others. Findings from recent studies have profound implications for understanding immune pathogenesis of pediatric HIV infection, and in particular highlight the importance of host genetics of both mother and child in determining whether an exposed child acquires HIV infection or not, and if infected, the rate of disease progression. This review focuses on the key host molecules, the CC chemokine CCL3 and HLA, which have taken center stage in these new developments. PMID:16522254

The role of B cells and humoral immunity in Mycobacterium tuberculosis infection.

PubMed

Chan, John; Mehta, Simren; Bharrhan, Sushma; Chen, Yong; Achkar, Jacqueline M; Casadevall, Arturo; Flynn, JoAnne

2014-12-01

Mycobacterium tuberculosis remains a major public health burden. It is generally thought that while B cell- and antibody-mediated immunity plays an important role in host defense against extracellular pathogens, the primary control of intracellular microbes derives from cellular immune mechanisms. Studies on the immune regulatory mechanisms during infection with M. tuberculosis, a facultative intracellular organism, has established the importance of cell-mediated immunity in host defense during tuberculous infection. Emerging evidence suggest a role for B cell and humoral immunity in the control of intracellular pathogens, including obligatory species, through interactions with the cell-mediated immune compartment. Recent studies have shown that B cells and antibodies can significantly impact on the development of immune responses to the tubercle bacillus. In this review, we present experimental evidence supporting the notion that the importance of humoral and cellular immunity in host defense may not be entirely determined by the niche of the pathogen. A comprehensive approach that examines both humoral and cellular immunity could lead to better understanding of the immune response to M. tuberculosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

The role of B cells and humoral immunity in Mycobacterium tuberculosis infection

PubMed Central

Chan, John; Mehta, Simren; Bharrhan, Sushma; Chen, Yong; Achkar, Jacqueline M.; Casadevall, Arturo; Flynn, JoAnne

2014-01-01

Mycobacterium tuberculosis remains a major public health burden. It is generally thought that while B cell- and antibody-mediated immunity plays an important role in host defense against extracellular pathogens, the primary control of intracellular microbes derives from cellular immune mechanisms. Studies on the immune regulatory mechanisms during infection with M. tuberculosis, a facultative intracellular organism, has established the importance of cell-mediated immunity in host defense during tuberculous infection. Emerging evidence suggest a role for B cell and humoral immunity in the control of intracellular pathogens, including obligatory species, through interactions with the cell-mediated immune compartment. Recent studies have shown that B cells and antibodies can significantly impact on the development of immune responses to the tubercle bacillus. In this review, we present experimental evidence supporting the notion that the importance of humoral and cellular immunity in host defense may not be entirely determined by the niche of the pathogen. A comprehensive approach that examines both humoral and cellular immunity could lead to better understanding of the immune response to M. tuberculosis. PMID:25458990

Interaction of microbial agents with the immune system during infectious disease.

PubMed

Frøland, S S

1984-01-01

Research during the last years has revealed a considerable complexity of the immune system. It is clear that immunological reactions depend on extensive and only partly clarified interactions between a number of different cell types (e.g. B lymphocytes, plasma cells, T cell subpopulations, cytotoxic K and NK cells, monocytic cells, neutrophilic and eosinophilic granulocytes) and their molecular products (e.g. immunoglobulins, lymphokines and interleukins). These components further interact with the complement system, as well as with immunologically nonspecific components like acute phase proteins (e.g. C-reactive protein) and with other pathophysiological phenomena occurring during infections, e.g. the fever response. The application of these observations from basic and experimental immunology to the investigation of antimicrobial immune reactions is still only in its beginning, but has already resulted in new concepts of clinical value for the understanding of infectious diseases. The present paper briefly describes certain aspects of the immune response to infections with various microbial agents, with particular emphasis on reactions of clinical importance. In addition to B and T cell reactions, possible antimicrobial functions of K cells and NK cells are discussed, and the possible importance in infectious disease of various T cell subpopulations, particularly T suppressor cells, is discussed. Lastly, various escape mechanisms are mentioned whereby certain microbial agents may evade elimination by the immune response of the host.

Aspergillus fumigatus morphology and dynamic host interactions.

PubMed

van de Veerdonk, Frank L; Gresnigt, Mark S; Romani, Luigina; Netea, Mihai G; Latgé, Jean-Paul

2017-11-01

Aspergillus fumigatus is an environmental filamentous fungus that can cause life-threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus.

Yersinia versus host immunity: how a pathogen evades or triggers a protective response.

PubMed

Chung, Lawton K; Bliska, James B

2016-02-01

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe. Copyright © 2015 Elsevier Ltd. All rights reserved.

HIV therapeutic vaccines: moving towards a functional cure.

PubMed

Mylvaganam, Geetha H; Silvestri, Guido; Amara, Rama Rao

2015-08-01

Anti-viral T-cell and B-cell responses play a crucial role in suppressing HIV and SIV replication during chronic infection. However, these infections are rarely controlled by the host immune response, and most infected individuals need lifelong antiretroviral therapy (ART). Recent advances in our understanding of how anti-HIV immune responses are elicited and regulated prompted a surge of interest in harnessing these responses to reduce the HIV 'residual disease' that is present in ART-treated HIV-infected individuals. Novel approaches that are currently explored include both conventional therapeutic vaccines (i.e., active immunization strategies using HIV-derived immunogens) as well as the use of checkpoint blockers such as anti-PD-1 antibodies. These approaches appear promising as key components of complex therapeutic strategies aimed at curing HIV infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Network representations of immune system complexity

PubMed Central

Subramanian, Naeha; Torabi-Parizi, Parizad; Gottschalk, Rachel A.; Germain, Ronald N.; Dutta, Bhaskar

2015-01-01

The mammalian immune system is a dynamic multi-scale system composed of a hierarchically organized set of molecular, cellular and organismal networks that act in concert to promote effective host defense. These networks range from those involving gene regulatory and protein-protein interactions underlying intracellular signaling pathways and single cell responses to increasingly complex networks of in vivo cellular interaction, positioning and migration that determine the overall immune response of an organism. Immunity is thus not the product of simple signaling events but rather non-linear behaviors arising from dynamic, feedback-regulated interactions among many components. One of the major goals of systems immunology is to quantitatively measure these complex multi-scale spatial and temporal interactions, permitting development of computational models that can be used to predict responses to perturbation. Recent technological advances permit collection of comprehensive datasets at multiple molecular and cellular levels while advances in network biology support representation of the relationships of components at each level as physical or functional interaction networks. The latter facilitate effective visualization of patterns and recognition of emergent properties arising from the many interactions of genes, molecules, and cells of the immune system. We illustrate the power of integrating ‘omics’ and network modeling approaches for unbiased reconstruction of signaling and transcriptional networks with a focus on applications involving the innate immune system. We further discuss future possibilities for reconstruction of increasingly complex cellular and organism-level networks and development of sophisticated computational tools for prediction of emergent immune behavior arising from the concerted action of these networks. PMID:25625853

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

PubMed

Ji, Zhiwei; Su, Jing; Wu, Dan; Peng, Huiming; Zhao, Weiling; Nlong Zhao, Brian; Zhou, Xiaobo

2017-01-31

Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

PubMed Central

Retamal-Díaz, Angello R.; Kalergis, Alexis M.; Bueno, Susan M.; González, Pablo A.

2017-01-01

Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses. PMID:28848543

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PubMed

Telli, M L; Stover, D G; Loi, S; Aparicio, S; Carey, L A; Domchek, S M; Newman, L; Sledge, G W; Winer, E P

2018-05-07

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Hevein-Like Antimicrobial Peptides of Plants.

PubMed

Slavokhotova, A A; Shelenkov, A A; Andreev, Ya A; Odintsova, T I

2017-12-01

Plant antimicrobial peptides represent one of the evolutionarily oldest innate immunity components providing the first line of host defense to pathogen attacks. This review is dedicated to a small, currently actively studied family of hevein-like peptides that can be found in various monocot and dicot plants. The review thoroughly describes all known peptides belonging to this family including data on their structures, functions, and antimicrobial activity. The main features allowing to assign these peptides to a separate family are given, and the specific characteristics of each peptide are described. Further, the mode of action for hevein-like peptides, their role in plant immune system, and the applications of these molecules in biotechnology and medicine are considered.

Immunity and Immunopathology in the Tuberculous Granuloma

PubMed Central

Pagán, Antonio J.; Ramakrishnan, Lalita

2015-01-01

Granulomas, organized aggregates of immune cells, are a defining feature of tuberculosis (TB). Granuloma formation is implicated in the pathogenesis of a variety of inflammatory disorders. However, the tuberculous granuloma has been assigned the role of a host protective structure which “walls-off” mycobacteria. Work conducted over the past decade has provided a more nuanced view of its role in pathogenesis. On the one hand, pathogenic mycobacteria accelerate and exploit granuloma formation for their expansion and dissemination by manipulating host immune responses to turn leukocyte recruitment and cell death pathways in their favor. On the other hand, granuloma macrophages can preserve granuloma integrity by exerting a microbicidal immune response, thus preventing an even more rampant expansion of infection in the extracellular milieu. Even this host-beneficial immune response required to maintain the bacteria intracellular must be tempered, as an overly vigorous immune response can also cause granuloma breakdown, thereby directly supporting bacterial growth extracellularly. This review will discuss how mycobacteria manipulate inflammatory responses to drive granuloma formation and will consider the roles of the granuloma in pathogenesis and protective immunity, drawing from clinical studies of TB in humans and from animal models—rodents, zebrafish, and nonhuman primates. A deeper understanding of TB pathogenesis and immunity in the granuloma could suggest therapeutic approaches to abrogate the host-detrimental aspects of granuloma formation to convert it into the host-beneficial structure that it has been thought to be for nearly a century. PMID:25377142

Life cycle specialization of filamentous pathogens - colonization and reproduction in plant tissues.

PubMed

Haueisen, Janine; Stukenbrock, Eva H

2016-08-01

Filamentous plant pathogens explore host tissues to obtain nutrients for growth and reproduction. Diverse strategies for tissue invasion, defense manipulation, and colonization of inter and intra-cellular spaces have evolved. Most research has focused on effector molecules, which are secreted to manipulate plant immunity and facilitate infection. Effector genes are often found to evolve rapidly in response to the antagonistic host-pathogen co-evolution but other traits are also subject to adaptive evolution during specialization to the anatomy, biochemistry and ecology of different plant hosts. Although not directly related to virulence, these traits are important components of specialization but little is known about them. We present and discuss specific life cycle traits that facilitate exploration of plant tissues and underline the importance of increasing our insight into the biology of plant pathogens. Copyright © 2016. Published by Elsevier Ltd.

Bartonella and Brucella—Weapons and Strategies for Stealth Attack

PubMed Central

Ben-Tekaya, Houchaima; Gorvel, Jean-Pierre; Dehio, Christoph

2013-01-01

Bartonella spp. and Brucella spp. are closely related α-proteobacterial pathogens that by distinct stealth-attack strategies cause chronic infections in mammals including humans. Human infections manifest by a broad spectrum of clinical symptoms, ranging from mild to fatal disease. Both pathogens establish intracellular replication niches and subvert diverse pathways of the host’s immune system. Several virulence factors allow them to adhere to, invade, proliferate, and persist within various host-cell types. In particular, type IV secretion systems (T4SS) represent essential virulence factors that transfer effector proteins tailored to recruit host components and modulate cellular processes to the benefit of the bacterial intruders. This article puts the remarkable features of these two pathogens into perspective, highlighting the mechanisms they use to hijack signaling and trafficking pathways of the host as the basis for their stealthy infection strategies. PMID:23906880

Intestinal commensal microbes as immune modulators

PubMed Central

Ivanov, Ivaylo I.; Honda, Kenya

2012-01-01

Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic strategy for many mucosal and non-mucosal immune-related conditions, such as inflammatory bowel diseases (IBD), celiac disease, metabolic syndrome, diabetes and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis. PMID:23084918

Dynamic two-photon imaging of the immune response to Toxoplasma gondii infection.

PubMed

Luu, L; Coombes, J L

2015-03-01

Toxoplasma gondii is a highly successful parasite that can manipulate host immune responses to optimize its persistence and spread. As a result, a highly complex relationship exists between T. gondii and the immune system of the host. Advances in imaging techniques, and in particular, the application of two-photon microscopy to mouse infection models, have made it possible to directly visualize interactions between parasites and the host immune system as they occur in living tissues. Here, we will discuss how dynamic imaging techniques have provided unexpected new insight into (i) how immune responses are dynamically regulated by cells and structures in the local tissue environment, (ii) how protective responses to T. gondii are generated and (iii) how the parasite exploits the immune system for its own benefit. © 2014 John Wiley & Sons Ltd.

Helicobacter pylori Persistence: an Overview of Interactions between H. pylori and Host Immune Defenses

PubMed Central

Algood, Holly M. Scott; Cover, Timothy L.

2006-01-01

Helicobacter pylori is a gram-negative bacterium that persistently colonizes more than half of the global human population. In order to successfully colonize the human stomach, H. pylori must initially overcome multiple innate host defenses. Remarkably, H. pylori can persistently colonize the stomach for decades or an entire lifetime despite development of an acquired immune response. This review focuses on the immune response to H. pylori and the mechanisms by which H. pylori resists immune clearance. Three main sections of the review are devoted to (i) analysis of the immune response to H. pylori in humans, (ii) analysis of interactions of H. pylori with host immune defenses in animal models, and (iii) interactions of H. pylori with immune cells in vitro. The topics addressed in this review are important for understanding how H. pylori resists immune clearance and also are relevant for understanding the pathogenesis of diseases caused by H. pylori (peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma). PMID:17041136

Can Reproductive Hormones Modulate Host Immunity to Breast Cancer Antigens

DTIC Science & Technology

2005-07-01

AD Award Number: W81XWH-04-1-0668 TITLE: Can Reproductive Hormones Modulate Host Immunity to Breast Cancer Antigens PRINCIPAL INVESTIGATOR: Richard T...AND SUBTITLE 5a. CONTRACT NUMBER Can Reproductive Hormones Modulate Host Immunity to Breast Cancer Antigens 5b. GRANT NUMBER W81XWH-04-!1-0668 5c...neu-N mice can be readily applied to clinical trial development. The goal of the present work is to test the hypothesis that reproductive hormones can

Macroevolutionary Immunology: A Role for Immunity in the Diversification of Animal life

PubMed Central

Loker, Eric S.

2012-01-01

An emerging picture of the nature of immune systems across animal phyla reveals both conservatism of some features and the appearance among and within phyla of novel, lineage-specific defense solutions. The latter collectively represent a major and underappreciated form of animal diversity. Factors influencing this macroevolutionary (above the species level) pattern of novelty are considered and include adoption of different life styles, life histories, and body plans; a general advantage of being distinctive with respect to immune defenses; and the responses required to cope with parasites, many of which afflict hosts in a lineage-specific manner. This large-scale pattern of novelty implies that immunological phenomena can affect microevolutionary processes (at the population level within species) that can eventually lead to macroevolutionary events such as speciation, radiations, or extinctions. Immunologically based phenomena play a role in favoring intraspecific diversification, specialization and host specificity of parasites, and mechanisms are discussed whereby this could lead to parasite speciation. Host switching – the acquisition of new host species by parasites – is a major mechanism that drives parasite diversity and is frequently involved in disease emergence. It is also one that can be favored by reductions in immune competence of new hosts. Mechanisms involving immune phenomena favoring intraspecific diversification and speciation of host species are also discussed. A macroevolutionary perspective on immunology is invaluable in today’s world, including the need to study a broader range of species with distinctive immune systems. Many of these species are faced with extinction, another macroevolutionary process influenced by immune phenomena. PMID:22566909

Regulation of the host immune system by helminth parasites.

PubMed

Maizels, Rick M; McSorley, Henry J

2016-09-01

Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation.

PubMed

Bergsbaken, Tessa; Cookson, Brad T

2009-11-01

Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses.

Cytokines and their STATs in cutaneous and visceral leishmaniasis.

PubMed

Cummings, Hannah E; Tuladhar, Rashmi; Satoskar, Abhay R

2010-01-01

Cytokines play a critical role in shaping the host immune response to Leishmania infection and directing the development of protective and non-protective immunities during infection. Cytokines exert their biological activities through the activation and translocation of transcription factors into the nucleus whether they drive the expression of specific cytokine-responsive genes. Signal transducer and activator of transcription (STATs) are transcription factors which play a critical role in mediating signaling downstream of cytokine receptors and are important for shaping the host immune response during Leishmania infection. Here we discuss the signature cytokines and their associated STATs involved in the host immune response during cutaneous and visceral leishmaniasis.

Mechanisms of Immune Evasion in Leishmaniasis

PubMed Central

Gupta, Gaurav; Oghumu, Steve; Satoskar, Abhay R.

2013-01-01

Diseases caused by Leishmania present a worldwide problem, and current therapeutic approaches are unable to achieve a sterile cure. Leishmania is able to persist in host cells by evading or exploiting host immune mechanisms. A thorough understanding of these mechanisms could lead to better strategies for effective management of Leishmania infections. Current research has focused on parasite modification of host cell signaling pathways, entry into phagocytic cells, and modulation of cytokine and chemokine profiles that alter immune cell activation and trafficking to sites of infection. Immuno-therapeutic approaches that target these mechanisms of immune evasion by Leishmania offer promising areas for preclinical and clinical research. PMID:23415155

Innate immunity in rice

PubMed Central

Chen, Xuewei; Ronald, Pamela C.

2011-01-01

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

Intersections between immune responses and morphological regulation in plants.

PubMed

Uchida, Naoyuki; Tasaka, Masao

2010-06-01

Successful plant pathogens have developed strategies to interfere with the defence mechanisms of their host plants through evolution. Conversely, host plants have evolved systems to counteract pathogen attack. Some pathogens induce pathogenic symptoms on plants that include morphological changes in addition to interference with plant growth. Recent studies, based on molecular biology and genetics using Arabidopsis thaliana, have revealed that factors derived from pathogens can modulate host systems and/or host factors that play important roles in the morphological regulation of host plants. Other reports, meanwhile, have shown that factors known to have roles in plant morphology also function in plant immune responses. Evolutionary conservation of these factors and systems implies that host-pathogen interactions and the evolution they drive have yielded tight links between morphological processes and immune responses. In this review, recent findings about these topics are introduced and discussed.

Bivalve immunity and response to infections: Are we looking at the right place?

PubMed

Allam, Bassem; Pales Espinosa, Emmanuelle

2016-06-01

Significant progress has been made in the understanding of cellular and molecular mediators of immunity in invertebrates in general and bivalve mollusks in particular. Despite this information, there is a lack of understanding of factors affecting animal resistance and specific responses to infections. This in part results from limited consideration of the spatial (and to some extent temporal) heterogeneity of immune responses and very limited information on host-pathogen (and microbes in general) interactions at initial encounter/colonization sites. Of great concern is the fact that most studies on molluscan immunity focus on the circulating hemocytes and the humoral defense factors in the plasma while most relevant host-microbe interactions occur at mucosal interfaces. This paper summarizes information available on the contrasting value of information available on focal and systemic immune responses in infected bivalves, and highlights the role of mucosal immune factors in host-pathogen interactions. Available information underlines the diversity of immune effectors at molluscan mucosal interfaces and highlights the tailored immune response to pathogen stimuli. This context raises fascinating basic research questions around host-microbe crosstalk and feedback controls of these interactions and may lead to novel disease mitigation strategies and improve the assessment of resistant crops or the screening of probiotic candidates. Copyright © 2016 Elsevier Ltd. All rights reserved.

Herpesvirus microRNAs for use in gene therapy immune-evasion strategies.

PubMed

Bots, S T F; Hoeben, R C

2017-07-01

Transplantation of allogeneic cells as well as of genetically corrected autologous cells are potent approaches to restore cellular functions in patients suffering from genetic diseases. The recipient's immune responses against non-self-antigens may compromise the survival of the grafted cells. Recipients of the graft may therefore require lifelong treatment with immunosuppressive drugs. An alternative approach to reduce graft rejection could involve the use of immune-evasion molecules. Expression of such molecules in cells of the graft may subvert recognition by the host's immune system. Viruses in particular are masters of exploitation and modulation of their hosts immune response. The Herpesviridae family provides a proof of concept for this as these viruses are capable to establish latency and a lifelong persistence in the infected hosts. While several viral proteins involved in immune evasion have been characterized, the Herpesviridae also encode a multitude of viral microRNA (miRNAs). Several of these miRNAs have been demonstrated to reduce the sensitivity of the infected cells to the destructive action of the host's immune cells. In this review, the miRNAs of some common herpesviruses that are associated with immune modulation will be discussed with a focus on their potential use in strategies aiming at generating non-immunogenic cells for transplantation.

Microbiota and innate immunity in intestinal inflammation and neoplasia.

PubMed

Cario, Elke

2013-01-01

This review focuses on recent advances and novel insights into the mechanistic events that may link commensal microbiota and host innate immunity in the pathophysiology of intestinal inflammation and neoplasia. Unanswered questions are discussed and future perspectives in the field are highlighted. Commensal microbiota, host innate immunity, and genetics form a multidimensional network that controls homeostasis of the mucosal barrier in the intestine. Large-scale sequencing projects have begun to catalog the healthy human microbiome. Converging evidence suggests that alterations in the regulation of the complex host environment [e.g., dysbiosis and overgrowth of select commensal bacterial species, dietary factors, copresence of facultative pathogens (including viruses), and changes in mucus characteristics] may trigger aberrant innate immune signaling, thereby contributing to the development of intestinal inflammation and associated colon cancer in the susceptible individual. Genetically determined innate immune malfunction may create an inflammatory environment that promotes tumor progression (such as the TLR4-D299G mutation). The next challenging steps to be taken are to decipher changes in the human microbiome (and virome) during well defined diseased states, and relate them to intestinal mucosal immune functions and host genotypes.

Protein-linked glycans in periodontal bacteria: prevalence and role at the immune interface.

PubMed

Settem, Rajendra P; Honma, Kiyonobu; Stafford, Graham P; Sharma, Ashu

2013-10-17

Protein modification with complex glycans is increasingly being recognized in many pathogenic and non-pathogenic bacteria, and is now thought to be central to the successful life-style of those species in their respective hosts. This review aims to convey current knowledge on the extent of protein glycosylation in periodontal pathogenic bacteria and its role in the modulation of the host immune responses. The available data show that surface glycans of periodontal bacteria orchestrate dendritic cell cytokine responses to drive T cell immunity in ways that facilitate bacterial persistence in the host and induce periodontal inflammation. In addition, surface glycans may help certain periodontal bacteria protect against serum complement attack or help them escape immune detection through glycomimicry. In this review we will focus mainly on the generalized surface-layer protein glycosylation system of the periodontal pathogen Tannerella forsythia in shaping innate and adaptive host immunity in the context of periodontal disease. In addition, we will also review the current state of knowledge of surface protein glycosylation and its potential for immune modulation in other periodontal pathogens.

NIK1-mediated translation suppression functions as a plant antiviral immunity mechanism.

PubMed

Zorzatto, Cristiane; Machado, João Paulo B; Lopes, Kênia V G; Nascimento, Kelly J T; Pereira, Welison A; Brustolini, Otávio J B; Reis, Pedro A B; Calil, Iara P; Deguchi, Michihito; Sachetto-Martins, Gilberto; Gouveia, Bianca C; Loriato, Virgílio A P; Silva, Marcos A C; Silva, Fabyano F; Santos, Anésia A; Chory, Joanne; Fontes, Elizabeth P B

2015-04-30

Plants and plant pathogens are subject to continuous co-evolutionary pressure for dominance, and the outcomes of these interactions can substantially impact agriculture and food security. In virus-plant interactions, one of the major mechanisms for plant antiviral immunity relies on RNA silencing, which is often suppressed by co-evolving virus suppressors, thus enhancing viral pathogenicity in susceptible hosts. In addition, plants use the nucleotide-binding and leucine-rich repeat (NB-LRR) domain-containing resistance proteins, which recognize viral effectors to activate effector-triggered immunity in a defence mechanism similar to that employed in non-viral infections. Unlike most eukaryotic organisms, plants are not known to activate mechanisms of host global translation suppression to fight viruses. Here we demonstrate in Arabidopsis that the constitutive activation of NIK1, a leucine-rich repeat receptor-like kinase (LRR-RLK) identified as a virulence target of the begomovirus nuclear shuttle protein (NSP), leads to global translation suppression and translocation of the downstream component RPL10 to the nucleus, where it interacts with a newly identified MYB-like protein, L10-INTERACTING MYB DOMAIN-CONTAINING PROTEIN (LIMYB), to downregulate translational machinery genes fully. LIMYB overexpression represses ribosomal protein genes at the transcriptional level, resulting in protein synthesis inhibition, decreased viral messenger RNA association with polysome fractions and enhanced tolerance to begomovirus. By contrast, the loss of LIMYB function releases the repression of translation-related genes and increases susceptibility to virus infection. Therefore, LIMYB links immune receptor LRR-RLK activation to global translation suppression as an antiviral immunity strategy in plants.

S-Layer Protein Mediates the Stimulatory Effect of Lactobacillus helveticus MIMLh5 on Innate Immunity

PubMed Central

Taverniti, Valentina; Stuknyte, Milda; Minuzzo, Mario; Arioli, Stefania; De Noni, Ivano; Scabiosi, Christian; Cordova, Zuzet Martinez; Junttila, Ilkka; Hämäläinen, Sanna; Turpeinen, Hannu; Mora, Diego; Karp, Matti; Pesu, Marko

2013-01-01

The ability to positively affect host health through the modulation of the immune response is a feature of increasing importance in measuring the probiotic potential of a bacterial strain. However, the identities of the bacterial cell components involved in cross talk with immune cells remain elusive. In this study, we characterized the dairy strain Lactobacillus helveticus MIMLh5 and its surface-layer protein (SlpA) using in vitro and ex vivo analyses. We found that MIMLh5 and SlpA exert anti-inflammatory effects by reducing the activation of NF-κB on the intestinal epithelial Caco-2 cell line. On the contrary, MIMLh5 and SlpA act as stimulators of the innate immune system by triggering the expression of proinflammatory factors tumor necrosis factor alpha and COX-2 in the human macrophage cell line U937 via recognition through Toll-like receptor 2. In the same experiments, SlpA protein did not affect the expression of the anti-inflammatory cytokine interleukin-10. A similar response was observed following stimulation of macrophages isolated from mouse bone marrow or the peritoneal cavity. These results suggest that SlpA plays a major role in mediating bacterial immune-stimulating activity, which could help to induce the host's defenses against and responses toward infections. This study supports the concept that the viability of bacterial cells is not always essential to exert immunomodulatory effects, thus permitting the development of safer therapies for the treatment of specific diseases according to a paraprobiotic intervention. PMID:23220964

Candida Infections and Human Defensins.

PubMed

Polesello, Vania; Segat, Ludovica; Crovella, Sergio; Zupin, Luisa

2017-01-01

Candida species infections are an important worldwide health issue since they do not only affect immunocompromised patients but also healthy individuals. The host developed different mechanisms of protection against Candida infections; specifically the immune system and the innate immune response are the first line of defence. Defensis are a group of antimicrobial peptides, components of the innate immunity, produced at mucosal level and known to be active against bacteria, virus but also fungi. The aim of the current work was to review all previous studies in literature that analysed defensins in the context of Candida spp. infections, in order to investigate and clarify the exact mechanisms of defensins anti-fungal action. Several studies were identified from 1985 to 2017 (9 works form years 1985 to 1999, 44 works ranging from 2000 to 2009 and 35 from 2010 to 2017) searched in two electronic databases (PubMed and Google Scholar). The main key words used for the research were "Candida", "Defensins"," Innate immune system","fungi". The findings of the reviewed studies highlight the pivotal role of defensins antimicrobial peptides in the immune response against Candida infections, since they are able to discriminate host cell from fungi: defensins are able to recognize the pathogens cell wall (different in composition from the human ones), and to disrupt it through membrane permeabilization. However, further research is needed to explain completely defensins' mechanisms of action to fight C. albicans (and other Candida spp.) infections, being the information fragmentary and only in part elucidated. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity.

PubMed

Dodd, K; Nance, S; Quezada, M; Janke, L; Morrison, J B; Williams, R T; Beere, H M

2015-03-05

The anti-apoptotic function and tumor-associated expression of heat-shock protein 70 (HSP70) is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti-tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3(-/-)(Hsp70(-/-)) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70(-/-) murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immunodeficient hosts as efficiently as wild-type (WT) transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70(-/-) bone marrow and progression of B-cell leukemogenesis in vivo revealed no differences in disease onset or survival rates, and Eμ-Myc-driven lymphoma in Hsp70(-/-) mice was phenotypically indistinguishable from that in WT Eμ-Myc mice. However, Hsp70(-/-) E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6 J immune-competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8(+) T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.

Variation of parasite load and immune parameters in two species of New Zealand shore crabs.

PubMed

Dittmer, Jessica; Koehler, Anson V; Richard, Freddie-Jeanne; Poulin, Robert; Sicard, Mathieu

2011-09-01

While parasites are likely to encounter several potential intermediate hosts in natural communities, a parasite's actual range of compatible hosts is limited by numerous biological factors ranging from behaviour to immunology. In crustaceans, two major components of immunity are haemocytes and the prophenoloxidase system involved in the melanisation of foreign particles. Here, we analysed metazoan parasite prevalence and loads in the two sympatric crab species Hemigrapsus crenulatus and Macrophthalmus hirtipes at two sites. In parallel, we analysed the variation in haemocyte concentration and amount of circulating phenoloxidase (PO) in the haemolymph of the same individuals in an attempt to (a) explain differences in parasite prevalence and loads in the two species at two sites and (b) assess the impact of parasites on these immune parameters. M. hirtipes harboured more parasites but also exhibited higher haemocyte concentrations than H. crenulatus independent of the study site. Thus, higher investment in haemocyte production for M. hirtipes does not seem to result in higher resistance to parasites. Analyses of variation in immune parameters for the two crab species between the two sites that differed in parasite prevalence showed common trends. (a) In general, haemocyte concentrations were higher at the site experiencing higher parasitic pressure while circulating PO activity was lower and (b) haemocyte concentrations were influenced by microphallid trematode metacercariae in individuals from the site with higher parasitic pressure. We suggest that the higher haemocyte concentrations observed in both crab species exposed to higher parasitic pressure may represent an adaptive response to the impact of parasites on this immune parameter.

Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism

PubMed Central

Gao, Jing; Xu, Kang; Liu, Hongnan; Liu, Gang; Bai, Miaomiao; Peng, Can; Li, Tiejun; Yin, Yulong

2018-01-01

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system–intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp–microbiome–immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature. PMID:29468141

Fungal Iron Availability during Deep Seated Candidiasis Is Defined by a Complex Interplay Involving Systemic and Local Events

PubMed Central

Potrykus, Joanna; Stead, David; MacCallum, Donna M.; Urgast, Dagmar S.; Raab, Andrea; van Rooijen, Nico; Feldmann, Jörg; Brown, Alistair J. P.

2013-01-01

Nutritional immunity – the withholding of nutrients by the host – has long been recognised as an important factor that shapes bacterial-host interactions. However, the dynamics of nutrient availability within local host niches during fungal infection are poorly defined. We have combined laser ablation-inductively coupled plasma mass spectrometry (LA-ICP MS), MALDI imaging and immunohistochemistry with microtranscriptomics to examine iron homeostasis in the host and pathogen in the murine model of systemic candidiasis. Dramatic changes in the renal iron landscape occur during disease progression. The infection perturbs global iron homeostasis in the host leading to iron accumulation in the renal medulla. Paradoxically, this is accompanied by nutritional immunity in the renal cortex as iron exclusion zones emerge locally around fungal lesions. These exclusion zones correlate with immune infiltrates and haem oxygenase 1-expressing host cells. This local nutritional immunity decreases iron availability, leading to a switch in iron acquisition mechanisms within mature fungal lesions, as revealed by laser capture microdissection and qRT-PCR analyses. Therefore, a complex interplay of systemic and local events influences iron homeostasis and pathogen-host dynamics during disease progression. PMID:24146619

The Dialogue of the Host-Parasite Relationship: Leishmania spp. and Trypanosoma cruzi Infection.

PubMed

de Morais, Carlos Gustavo Vieira; Castro Lima, Ana Karina; Terra, Rodrigo; dos Santos, Rosiane Freire; Da-Silva, Silvia Amaral Gonçalves; Dutra, Patrícia Maria Lourenço

2015-01-01

The intracellular protozoa Leishmania spp. and Trypanosoma cruzi and the causative agents of Leishmaniasis and Chagas disease, respectively, belong to the Trypanosomatidae family. Together, these two neglected tropical diseases affect approximately 25 million people worldwide. Whether the host can control the infection or develops disease depends on the complex interaction between parasite and host. Parasite surface and secreted molecules are involved in triggering specific signaling pathways essential for parasite entry and intracellular survival. The recognition of the parasite antigens by host immune cells generates a specific immune response. Leishmania spp. and T. cruzi have a multifaceted repertoire of strategies to evade or subvert the immune system by interfering with a range of signal transduction pathways in host cells, which causes the inhibition of the protective response and contributes to their persistence in the host. The current therapeutic strategies in leishmaniasis and trypanosomiasis are very limited. Efficacy is variable, toxicity is high, and the emergence of resistance is increasingly common. In this review, we discuss the molecular basis of the host-parasite interaction of Leishmania and Trypanosoma cruzi infection and their mechanisms of subverting the immune response and how this knowledge can be used as a tool for the development of new drugs.

MULTISCALE MODEL OF CRISPR-INDUCED COEVOLUTIONARY DYNAMICS: DIVERSIFICATION AT THE INTERFACE OF LAMARCK AND DARWIN

PubMed Central

Childs, Lauren M; Held, Nicole L; Young, Mark J; Whitaker, Rachel J; Weitz, Joshua S

2012-01-01

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system is a recently discovered type of adaptive immune defense in bacteria and archaea that functions via directed incorporation of viral and plasmid DNA into host genomes. Here, we introduce a multiscale model of dynamic coevolution between hosts and viruses in an ecological context that incorporates CRISPR immunity principles. We analyze the model to test whether and how CRISPR immunity induces host and viral diversification and the maintenance of many coexisting strains. We show that hosts and viruses coevolve to form highly diverse communities. We observe the punctuated replacement of existent strains, such that populations have very low similarity compared over the long term. However, in the short term, we observe evolutionary dynamics consistent with both incomplete selective sweeps of novel strains (as single strains and coalitions) and the recurrence of previously rare strains. Coalitions of multiple dominant host strains are predicted to arise because host strains can have nearly identical immune phenotypes mediated by CRISPR defense albeit with different genotypes. We close by discussing how our explicit eco-evolutionary model of CRISPR immunity can help guide efforts to understand the drivers of diversity seen in microbial communities where CRISPR systems are active. PMID:22759281

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

PubMed Central

Sheng, Xinlei; Song, Bokai; Cristea, Ileana M.

2016-01-01

In mammalian cells, early defenses against infection by pathogens are mounted through a complex network of signaling pathways shepherded by immune-modulatory pattern-recognition receptors. As obligate parasites, the survival of viruses is dependent upon the evolutionary acquisition of mechanisms that tactfully dismantle and subvert the cellular intrinsic and innate immune responses. Here, we review the diverse mechanisms by which viruses that accommodate DNA genomes are able to circumvent activation of cellular immunity. We start by discussing viral manipulation of host defense protein levels by either transcriptional regulation or protein degradation. We next review viral strategies used to repurpose or inhibit these cellular immune factors by molecular hijacking or by regulating their post-translational modification status. Additionally, we explore the infection-induced temporal modulation of apoptosis to facilitate viral replication and spread. Lastly, the co-evolution of viruses with their hosts is highlighted by the acquisition of elegant mechanisms for suppressing host defenses via viral mimicry of host factors. In closing, we present a perspective on how characterizing these viral evasion tactics both broadens the understanding of virus-host interactions and reveals essential functions of the immune system at the molecular level. This knowledge is critical in understanding the sources of viral pathogenesis, as well as for the design of antiviral therapeutics and autoimmunity treatments. PMID:27650455

Bacterial effector HopF2 interacts with AvrPto and suppresses Arabidopsis innate immunity at the plasma membrane

USDA-ARS?s Scientific Manuscript database

Plant pathogenic bacteria inject a cocktail of effector proteins into host plant cells to modulate the host immune response, thereby promoting pathogenicity. How or whether these effectors work cooperatively is largely unknown. The Pseudomonas syringae DC3000 effector HopF2 suppresses the host plan...

Inflammatory phenotypes in the intestine of poultry: Not all inflammation is created equally

USDA-ARS?s Scientific Manuscript database

The intestinal tract harbors a diverse community of microbes that have co-evolved with the host immune system. Although many of these microbes execute functions that are critical for host physiology, the host immune system must control the microbial community so that the dynamics of this interdepen...

Small RNAs—The Secret Agents in the Plant-Pathogen Interactions

PubMed Central

Weiberg, Arne; Jin, Hailing

2015-01-01

Eukaryotic regulatory small RNAs (sRNAs) that induce RNA interference (RNAi) are involved in a plethora of biological processes, including host immunity and pathogen virulence. In plants, diverse classes of sRNAs contribute to the regulation of host innate immunity. These immune-regulatory sRNAs operate through distinct RNAi pathways that trigger transcriptional or post-transcriptional gene silencing. Similarly, many pathogen-derived sRNAs also regulate pathogen virulence. Remarkably, the influence of regulatory sRNAs is not limited to the individual organism in which they are generated. It can sometimes extend to interacting species from even different kingdoms. There they trigger gene silencing in the interacting organism, a phenomenon called cross-kingdom RNAi. This is exhibited in advanced pathogens and parasites that produce sRNAs to suppress host immunity. Conversely, in host-induced gene silencing (HIGS), diverse plants are engineered to trigger RNAi against pathogens and pests to confer host resistance. Cross-kingdom RNAi opens up a vastly unexplored area of research on mobile sRNAs in the battlefield between hosts and pathogens. PMID:26123395

Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses

PubMed Central

Lee, Jinhwa; Yu, Hai; Li, Yonghai; Ma, Jingjiao; Lang, Yuekun; Duff, Michael; Henningson, Jamie; Liu, Qinfang; Li, Yuhao; Nagy, Abdou; Bawa, Bhupinder; Li, Zejun; Tong, Guangzhi; Richt, Juergen A.; Ma, Wenjun

2017-01-01

Although several studies have investigated the functions of influenza PA-X, the impact of different expressions of PA-X protein including full-length, truncated or PA-X deficient forms on virus replication, pathogenicity and host response remains unclear. Herein, we generated two mutated viruses expressing a full-length or deficient PA-X protein based on the A/California/04/2009 (H1N1) virus that expresses a truncated PA-X to understand three different expressions of PA-X protein on virus replication, pathogenicity and host immune responses. The results showed that expression of either full-length or truncated PA-X protein enhanced viral replication and pathogenicity as well as reduced host innate immune response in mice by host shutoff activity when compared to the virus expressing the deficient PA-X form. Furthermore, the full-length PA-X expression exhibited a greater effect on virus pathogenicity than the truncated PA-X form. Our results provide novel insights of PA-X on viral replication, pathogenicity and host immune responses. PMID:28142079

Proton irradiation impacts age-driven modulations of cancer progression influenced by immune system transcriptome modifications from splenic tissue.

PubMed

Wage, Justin; Ma, Lili; Peluso, Michael; Lamont, Clare; Evens, Andrew M; Hahnfeldt, Philip; Hlatky, Lynn; Beheshti, Afshin

2015-09-01

Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1-GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74 and RUVBL2 indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Structure and Functional Characterization of the RNA-Binding Element of the NLRX1 Innate Immune Modulator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Minsun; Yoon, Sung-il; Wilson, Ian A.

2012-06-20

Mitochondrial NLRX1 is a member of the family of nucleotide-binding domain and leucine-rich-repeat-containing proteins (NLRs) that mediate host innate immunity as intracellular surveillance sensors against common molecular patterns of invading pathogens. NLRX1 functions in antiviral immunity, but the molecular mechanism of its ligand-induced activation is largely unknown. The crystal structure of the C-terminal fragment (residues 629975) of human NLRX1 (cNLRX1) at 2.65 {angstrom} resolution reveals that cNLRX1 consists of an N-terminal helical (LRRNT) domain, central leucine-rich repeat modules (LRRM), and a C-terminal three-helix bundle (LRRCT). cNLRX1 assembles into a compact hexameric architecture that is stabilized by intersubunit and interdomain interactionsmore » of LRRNT and LRRCT in the trimer and dimer components of the hexamer, respectively. Furthermore, we find that cNLRX1 interacts directly with RNA and supports a role for NLRX1 in recognition of intracellular viral RNA in antiviral immunity.« less

Possible role of laser phototherapy in laser immunotherapy

NASA Astrophysics Data System (ADS)

Hode, Tomas; Hode, Lars

2009-02-01

Laser immunotherapy is a promising cancer treatment method that induces antitumor immunity and appears to be effective both locally and systemically. In this context, an important factor is the overall state of the immune system, both locally and systemically. The success of any immunotherapy treatment depends on the balance between the local immunosuppressive forces induced by the tumor and the immune response of the host organism. Factors that influence this balance include heat-shock proteins (for example HSP70), transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), interleukins, and more. Laser phototherapy, which is based on non-thermal photobiological processes, has been shown to modulate the body's own immune response, both locally and systemically, with a strong influence on for example cytokine production and heat-shock protein synthesis. Laser phototherapy may therefore be an important component in the overall efficacy of laser immunotherapy, and may tip the balance between the immunosuppressive and immunostimulatory forces in favor of immunostimulation.

Immune mechanisms in fish skin against monogeneans--a model.

PubMed

Buchmann, K

1999-01-01

Host responses against skin inhabiting monogeneans are commonly observed but the responsible immune mechanisms in the fish skin are sufficiently described. Based on recent knowledge of fish immunity and skin response mechanisms in mammals a model for the skin immunity in fish to monogenean infections is proposed. Important cellular components of the model are the epithelial cells, the mucous cells and leucocytes. The release of cytokines, e.g., IL-1, following mechanical or chemical injury of the epithelial cells, initiates a series of events leading to decrease of the ectoparasite population. Cytokines (e.g., IL-1, TNF, INF) are suggested to affect secretions from mucous cell and attract neutrophils and macrophages. Leukotrienes are probably involved in the inflammatory reactions. The subsequent production of humoral substances (among others complement factors and peptides) could be responsible for the antiparasitic response in the later stages of infection. Although non-specific factors dominate the response, the involvement of specific antibodies and lymphocytes cannot be excluded.

The plant cell nucleus: a true arena for the fight between plants and pathogens.

PubMed

Deslandes, Laurent; Rivas, Susana

2011-01-01

Communication between the cytoplasm and the nucleus is a fundamental feature shared by both plant and animal cells. Cellular factors involved in the transport of macromolecules through the nuclear envelope, including nucleoporins, importins and Ran-GTP related components, are conserved among a variety of eukaryotic systems. Interestingly, mutations in these nuclear components compromise resistance signalling, illustrating the importance of nucleocytoplasmic trafficking in plant innate immunity. Indeed, spatial restriction of defence regulators by the nuclear envelope and stimulus-induced nuclear translocation constitute an important level of defence-associated gene regulation in plants. A significant number of effectors from different microbial pathogens are targeted to the plant cell nucleus. In addition, key host factors, including resistance proteins, immunity components, transcription factors and transcriptional regulators shuttle between the cytoplasm and the nucleus, and their level of nuclear accumulation determines the output of the defence response, further confirming the crucial role played by the nucleus during the interaction between plants and pathogens. Here, we discuss recent findings that situate the nucleus at the frontline of the mutual recognition between plants and invading microbes.

Nonencapsulated Trichinella pseudospiralis Infection Impairs Follicular Helper T Cell Differentiation with Subclass-Selective Decreases in Antibody Responses.

PubMed

Asano, Kazunobu; Wu, Zhiliang; Srinontong, Piyarat; Ikeda, Takahide; Nagano, Isao; Morita, Hirokuyi; Maekawa, Yoichi

2016-12-01

Infectious microorganisms often modify host immunity to escape from immune elimination. Trichinella is a unique nematode of the helminth family, whose members parasitize the muscle cells inside the host without robust eliminative reactions. There are several species of Trichinella; some develop in muscle cells that become encapsulated (e.g., Trichinella spiralis) and others in cells that do not encapsulate (e.g., Trichinella pseudospiralis). It has already been established that Trichinella infection affects host immune responses in several experimental immune diseases in animal models; however, most of those studies were done using T. spiralis infection. As host immune responses to T. spiralis and T. pseudospiralis infections have been reported to be different, it is necessary to clarify how T. pseudospiralis infection influences the host immune responses. In this study, we investigated the influence on host humoral immunity in T. pseudospiralis-infected mice. We demonstrated that T. pseudospiralis infection decreased antigen-specific IgG2a and IgG2b antibody (Ab) production in mice immunized with a model antigen. This selective decrease in gamma interferon (IFN-γ)-dependent Ab production was not due to a decrease in IFN-γ production, and we instead found impaired follicular helper T (Tfh) cell differentiation. The affinity maturation of antigen-specific Ab tended to be delayed but was not significant in T. pseudospiralis-infected mice. We also observed that CD11b + spleen cells in T. pseudospiralis-infected mice expressed CD206 and PD-L2, the phenotype of which was M2 macrophages with weak production of interleukin-6 (IL-6), possibly resulting in impaired Tfh differentiation. Taken together, our results indicate that nonencapsulated Trichinella infection induces selective dampening in humoral immunity with the suppression of Tfh differentiation. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Defining dysbiosis and its influence on host immunity and disease

PubMed Central

Petersen, Charisse; Round, June L

2014-01-01

Mammalian immune system development depends on instruction from resident commensal microorganisms. Diseases associated with abnormal immune responses towards environmental and self antigens have been rapidly increasing over the last 50 years. These diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS), type I diabetes (T1D), allergies and asthma. The observation that people with immune mediated diseases house a different microbial community when compared to healthy individuals suggests that pathogenesis arises from improper training of the immune system by the microbiota. However, with hundreds of different microorganisms on our bodies it is hard to know which of these contribute to health and more importantly how? Microbiologists studying pathogenic organisms have long adhered to Koch's postulates to directly relate a certain disease to a specific microbe, raising the question of whether this might be true of commensal–host relationships as well. Emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response. Thus, perturbations to the structure of complex commensal communities (referred to as dysbiosis) can lead to deficient education of the host immune system and subsequent development of immune mediated diseases. Here we will overview the literature that describes the causes of dysbiosis and the mechanisms evolved by the host to prevent these changes to community structure. Building off these studies, we will categorize the different types of dysbiosis and define how collections of microorganisms can influence the host response. This research has broad implications for future therapies that go beyond the introduction of a single organism to induce health. We propose that identifying mechanisms to re-establish a healthy complex microbiota after dysbiosis has occurred, a process we will refer to as rebiosis, will be fundamental to treating complex immune diseases. PMID:24798552

Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System

PubMed Central

Cruz-Muñoz, Mario E.; Fuentes-Pananá, Ezequiel M.

2018-01-01

Viruses are the most abundant and diverse biological entities in the planet. Historically, our main interest in viruses has focused on their pathogenic role, recognized by pandemics that have decimated the world population. However, viral infections have also played a major role in the evolution of cellular organisms, both through interchanging of genes with novel functions and shaping the immune system. Examples abound of infections that seriously compromise the host integrity, but evidence of plant and insect viruses mutualistic relationships have recently surfaced in which infected hosts are better suited for survival, arguing that virus-host interactions are initially parasitic but become mutualistic over years of co-evolution. A similar mutual help scenario has emerged with commensal gut bacteria. EBV is a herpesvirus that shares more than a hundred million years of co-evolution with humans, today successfully infecting close to 100% of the adult world population. Infection is usually acquired early in childhood persisting for the host lifetime mostly without apparent clinical symptoms. Disturbance of this homeostasis is rare and results in several diseases, of which the best understood are infectious mononucleosis and several EBV-associated cancers. Less understood are recently found inborn errors of the immune system that result in primary immunodeficiencies with an increased predisposition almost exclusive to EBV-associated diseases. Puzzling to these scenarios of broken homeostasis is the co-existence of immunosuppression, inflammation, autoimmunity and cancer. Homologous to EBV, HCMV, HHV-6 and HHV-7 are herpesviruses that also latently infect most individuals. Several lines of evidence support a mutualistic equilibrium between HCMV/EBV and hosts, that when altered trigger diseases in which the immune system plays a critical role. Interestingly, these beta and gamma herpesviruses persistently infect all immune lineages and early precursor cells. In this review, we will discuss the evidence of the benefits that infection of immune cells with these herpesviruses brings to the host. Also, the circumstances in which this positive relationship is broken, predisposing the host to diseases characterized by an abnormal function of the host immune system. PMID:29354096

Are Evolution and the Intracellular Innate Immune System Key Determinants in HIV Transmission?

PubMed Central

Sumner, Rebecca P.; Thorne, Lucy G.; Fink, Doug L.; Khan, Hataf; Milne, Richard S.; Towers, Greg J.

2017-01-01

HIV-1 is the single most important sexually transmitted disease in humans from a global health perspective. Among human lentiviruses, HIV-1 M group has uniquely achieved pandemic levels of human-to-human transmission. The requirement to transmit between hosts likely provides the strongest selective forces on a virus, as without transmission, there can be no new infections within a host population. Our perspective is that evolution of all of the virus–host interactions, which are inherited and perpetuated from host-to-host, must be consistent with transmission. For example, CXCR4 use, which often evolves late in infection, does not favor transmission and is therefore lost when a virus transmits to a new host. Thus, transmission inevitably influences all aspects of virus biology, including interactions with the innate immune system, and dictates the biological niche in which the virus exists in the host. A viable viral niche typically does not select features that disfavor transmission. The innate immune response represents a significant selective pressure during the transmission process. In fact, all viruses must antagonize and/or evade the mechanisms of the host innate and adaptive immune systems that they encounter. We believe that viewing host–virus interactions from a transmission perspective helps us understand the mechanistic details of antiviral immunity and viral escape. This is particularly true for the innate immune system, which typically acts from the very earliest stages of the host–virus interaction, and must be bypassed to achieve successful infection. With this in mind, here we review the innate sensing of HIV, the consequent downstream signaling cascades and the viral restriction that results. The centrality of these mechanisms to host defense is illustrated by the array of countermeasures that HIV deploys to escape them, despite the coding constraint of a 10 kb genome. We consider evasion strategies in detail, in particular the role of the HIV capsid and the viral accessory proteins highlighting important unanswered questions and discussing future perspectives. PMID:29056936

Monitoring of Immune and Microbial Reconstitution in (HCT) and Novel Immunotherapies

ClinicalTrials.gov

2018-06-25

Immune and Microbial Reconstitution; Systemic Viral Infection; Acute-graft-versus-host Disease; Chronic Graft-versus-host-disease; Recurrent Malignancy; Cytokine Release Syndrome; Allogenic Related Donors; Cell Therapy/Immunotherapy Patients

Hantaviruses induce cell type- and viral species-specific host microRNA expression signatures

PubMed Central

Shin, Ok Sarah; Kumar, Mukesh; Yanagihara, Richard; Song, Jin-Won

2014-01-01

The mechanisms of hantavirus-induced modulation of host cellular immunity remain poorly understood. Recently, microRNAs (miRNAs) have emerged as a class of essential regulators of host immune response genes. To ascertain if differential host miRNA expression toward representative hantavirus species correlated with immune response genes, miRNA expression profiles were analyzed in human endothelial cells, macrophages and epithelial cells infected with pathogenic and nonpathogenic rodent- and shrew-borne hantaviruses. Distinct miRNA expression profiles were observed in a cell type- and viral species-specific pattern. A subset of miRNAs, including miR-151-5p and miR-1973, were differentially expressed between Hantaan virus and Prospect Hill virus. Pathway analyses confirmed that the targets of selected miRNAs were associated with inflammatory responses and innate immune receptor-mediated signaling pathways. Our data suggest that differential immune responses following hantavirus infection may be regulated in part by cellular miRNA through dysregulation of genes critical to the inflammatory process. PMID:24074584

Symbiont-induced odorant binding proteins mediate insect host hematopoiesis

PubMed Central

Benoit, Joshua B; Vigneron, Aurélien; Broderick, Nichole A; Wu, Yineng; Sun, Jennifer S; Carlson, John R; Aksoy, Serap; Weiss, Brian L

2017-01-01

Symbiotic bacteria assist in maintaining homeostasis of the animal immune system. However, the molecular mechanisms that underlie symbiont-mediated host immunity are largely unknown. Tsetse flies (Glossina spp.) house maternally transmitted symbionts that regulate the development and function of their host’s immune system. Herein we demonstrate that the obligate mutualist, Wigglesworthia, up-regulates expression of odorant binding protein six in the gut of intrauterine tsetse larvae. This process is necessary and sufficient to induce systemic expression of the hematopoietic RUNX transcription factor lozenge and the subsequent production of crystal cells, which actuate the melanotic immune response in adult tsetse. Larval Drosophila’s indigenous microbiota, which is acquired from the environment, regulates an orthologous hematopoietic pathway in their host. These findings provide insight into the molecular mechanisms that underlie enteric symbiont-stimulated systemic immune system development, and indicate that these processes are evolutionarily conserved despite the divergent nature of host-symbiont interactions in these model systems. DOI: http://dx.doi.org/10.7554/eLife.19535.001 PMID:28079523

Independently evolved virulence effectors converge onto hubs in a plant immune system network.

PubMed

Mukhtar, M Shahid; Carvunis, Anne-Ruxandra; Dreze, Matija; Epple, Petra; Steinbrenner, Jens; Moore, Jonathan; Tasan, Murat; Galli, Mary; Hao, Tong; Nishimura, Marc T; Pevzner, Samuel J; Donovan, Susan E; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M; Gebreab, Fana; Gutierrez, Bryan J; Tam, Stanley; Monachello, Dario; Boxem, Mike; Harbort, Christopher J; McDonald, Nathan; Gai, Lantian; Chen, Huaming; He, Yijian; Vandenhaute, Jean; Roth, Frederick P; Hill, David E; Ecker, Joseph R; Vidal, Marc; Beynon, Jim; Braun, Pascal; Dangl, Jeffery L

2011-07-29

Plants generate effective responses to infection by recognizing both conserved and variable pathogen-encoded molecules. Pathogens deploy virulence effector proteins into host cells, where they interact physically with host proteins to modulate defense. We generated an interaction network of plant-pathogen effectors from two pathogens spanning the eukaryote-eubacteria divergence, three classes of Arabidopsis immune system proteins, and ~8000 other Arabidopsis proteins. We noted convergence of effectors onto highly interconnected host proteins and indirect, rather than direct, connections between effectors and plant immune receptors. We demonstrated plant immune system functions for 15 of 17 tested host proteins that interact with effectors from both pathogens. Thus, pathogens from different kingdoms deploy independently evolved virulence proteins that interact with a limited set of highly connected cellular hubs to facilitate their diverse life-cycle strategies.

Host Soluble Mediators: Defying the Immunological Inertness of Aspergillus fumigatus Conidia.

PubMed

Wong, Sarah Sze Wah; Aimanianda, Vishukumar

2017-12-24

Aspergillus fumigatus produce airborne spores (conidia), which are inhaled in abundant quantity. In an immunocompromised population, the host immune system fails to clear the inhaled conidia, which then germinate and invade, leading to pulmonary aspergillosis. In an immunocompetent population, the inhaled conidia are efficiently cleared by the host immune system. Soluble mediators of the innate immunity, that involve the complement system, acute-phase proteins, antimicrobial peptides and cytokines, are often considered to play a complementary role in the defense of the fungal pathogen. In fact, the soluble mediators are essential in achieving an efficient clearance of the dormant conidia, which is the morphotype of the fungus upon inhalation by the host. Importantly, harnessing the host soluble mediators challenges the immunological inertness of the dormant conidia due to the presence of the rodlet and melanin layers. In the review, we summarized the major soluble mediators in the lung that are involved in the recognition of the dormant conidia. This knowledge is essential in the complete understanding of the immune defense against A. fumigatus .

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

PubMed Central

Ko, Ya-Ping; Flick, Matthew J.

2017-01-01

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

Xanthomonas euvesicatoria type III effector XopQ interacts with tomato and pepper 14-3-3 isoforms to suppress effector-triggered immunity.

PubMed

Teper, Doron; Salomon, Dor; Sunitha, Sukumaran; Kim, Jung-Gun; Mudgett, Mary Beth; Sessa, Guido

2014-01-01

Effector-triggered immunity (ETI) to host-adapted pathogens is associated with rapid cell death at the infection site. The plant-pathogenic bacterium Xanthomonas euvesicatoria (Xcv) interferes with plant cellular processes by injecting effector proteins into host cells through the type III secretion system. Here, we show that the Xcv effector XopQ suppresses cell death induced by components of the ETI-associated MAP kinase cascade MAPKKKα MEK2/SIPK and by several R/avr gene pairs. Inactivation of xopQ by insertional mutagenesis revealed that this effector inhibits ETI-associated cell death induced by avirulent Xcv in resistant pepper (Capsicum annuum), and enhances bacterial growth in resistant pepper and tomato (Solanum lycopersicum). Using protein-protein interaction studies in yeast (Saccharomyces cerevisiae) and in planta, we identified the tomato 14-3-3 isoform SlTFT4 and homologs from other plant species as XopQ interactors. A mutation in the putative 14-3-3 binding site of XopQ impaired interaction of the effector with CaTFT4 in yeast and its virulence function in planta. Consistent with a role in ETI, TFT4 mRNA abundance increased during the incompatible interaction of tomato and pepper with Xcv. Silencing of NbTFT4 in Nicotiana benthamiana significantly reduced cell death induced by MAPKKKα. In addition, silencing of CaTFT4 in pepper delayed the appearance of ETI-associated cell death and enhanced growth of virulent and avirulent Xcv, demonstrating the requirement of TFT4 for plant immunity to Xcv. Our results suggest that the XopQ virulence function is to suppress ETI and immunity-associated cell death by interacting with TFT4, which is an important component of ETI and a bona fide target of XopQ. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

Successfully resisting a pathogen is rarely costly in Daphnia magna

PubMed Central

2010-01-01

Background A central hypothesis in the evolutionary ecology of parasitism is that trade-offs exist between resistance to parasites and other fitness components such as fecundity, growth, survival, and predator avoidance, or resistance to other parasites. These trade-offs are called costs of resistance. These costs fall into two broad categories: constitutive costs of resistance, which arise from a negative genetic covariance between immunity and other fitness-related traits, and inducible costs of resistance, which are the physiological costs incurred by hosts when mounting an immune response. We sought to study inducible costs in depth using the crustacean Daphnia magna and its bacterial parasite Pasteuria ramosa. Results We designed specific experiments to study the costs induced by exposure to this parasite, and we re-analysed previously published data in an effort to determine the generality of such costs. However, despite the variety of genetic backgrounds of both hosts and parasites, and the different exposure protocols and environmental conditions used in these experiment, this work showed that costs of exposure can only rarely be detected in the D. magna-P. ramosa system. Conclusions We discuss possible reasons for this lack of detectable costs, including scenarios where costs of resistance to parasites might not play a major role in the co-evolution of hosts and parasites. PMID:21083915

Successfully resisting a pathogen is rarely costly in Daphnia magna.

PubMed

Labbé, Pierrick; Vale, Pedro F; Little, Tom J

2010-11-17

A central hypothesis in the evolutionary ecology of parasitism is that trade-offs exist between resistance to parasites and other fitness components such as fecundity, growth, survival, and predator avoidance, or resistance to other parasites. These trade-offs are called costs of resistance. These costs fall into two broad categories: constitutive costs of resistance, which arise from a negative genetic covariance between immunity and other fitness-related traits, and inducible costs of resistance, which are the physiological costs incurred by hosts when mounting an immune response. We sought to study inducible costs in depth using the crustacean Daphnia magna and its bacterial parasite Pasteuria ramosa. We designed specific experiments to study the costs induced by exposure to this parasite, and we re-analysed previously published data in an effort to determine the generality of such costs. However, despite the variety of genetic backgrounds of both hosts and parasites, and the different exposure protocols and environmental conditions used in these experiment, this work showed that costs of exposure can only rarely be detected in the D. magna-P. ramosa system. We discuss possible reasons for this lack of detectable costs, including scenarios where costs of resistance to parasites might not play a major role in the co-evolution of hosts and parasites.

Staphylococcus aureus innate immune evasion is lineage-specific: a bioinfomatics study.

PubMed

McCarthy, Alex J; Lindsay, Jodi A

2013-10-01

Staphylococcus aureus is a major human pathogen, and is targeted by the host innate immune system. In response, S. aureus genomes encode dozens of secreted proteins that inhibit complement, chemotaxis and neutrophil activation resulting in successful evasion of innate immune responses. These proteins include immune evasion cluster proteins (IEC; Chp, Sak, Scn), staphylococcal superantigen-like proteins (SSLs), phenol soluble modulins (PSMs) and several leukocidins. Biochemical studies have indicated that genetic variants of these proteins can have unique functions. To ascertain the scale of genetic variation in secreted immune evasion proteins, whole genome sequences of 88 S. aureus isolates, representing 25 clonal complex (CC) lineages, in the public domain were analysed across 43 genes encoding 38 secreted innate immune evasion protein complexes. Twenty-three genes were variable, with between 2 and 15 variants, and the variants had lineage-specific distributions. They include genes encoding Eap, Ecb, Efb, Flipr/Flipr-like, Hla, Hld, Hlg, Sbi, Scin-B/C and 13 SSLs. Most of these protein complexes inhibit complement, chemotaxis and neutrophil activation suggesting that isolates from each S. aureus lineage respond to the innate immune system differently. In contrast, protein complexes that lyse neutrophils (LukSF-PVL, LukMF, LukED and PSMs) were highly conserved, but can be carried on mobile genetic elements (MGEs). MGEs also encode proteins with narrow host-specificities arguing that their acquisition has important roles in host/environmental adaptation. In conclusion, this data suggests that each lineage of S. aureus evades host immune responses differently, and that isolates can adapt to new host environments by acquiring MGEs and the immune evasion protein complexes that they encode. Cocktail therapeutics that targets multiple variant proteins may be the most appropriate strategy for controlling S. aureus infections. Copyright © 2013 Elsevier B.V. All rights reserved.

Subclinical cytomegalovirus infection associates with altered host immunity, gut microbiota and vaccine responses.

PubMed

Santos Rocha, Clarissa; Hirao, Lauren A; Weber, Mariana G; Méndez-Lagares, Gema; Chang, W L William; Jiang, Guochun; Deere, Jesse D; Sparger, Ellen E; Roberts, Jeffrey; Barry, Peter A; Hartigan-O'Connor, Dennis J; Dandekar, Satya

2018-04-18

Subclinical viral infections (SVI) including cytomegalovirus (CMV) are highly prevalent in humans, resulting in life-long persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (SPF) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment as compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producing Firmicutes and higher numbers of lymphocytes, effector T cells and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination as compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level. IMPORTANCE Humans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immune-compromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity. Copyright © 2018 American Society for Microbiology.

Zinc in Infection and Inflammation

PubMed Central

Gammoh, Nour Zahi; Rink, Lothar

2017-01-01

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli. PMID:28629136

Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses

PubMed Central

Barth, Kenneth; Genco, Caroline Attardo

2016-01-01

The NFκB and MAPK signaling pathways are critical components of innate immunity that orchestrate appropriate immune responses to control and eradicate pathogens. Their activation results in the induction of proinflammatory mediators, such as TNFα a potent bioactive molecule commonly secreted by recruited inflammatory cells, allowing for paracrine signaling at the site of an infection. In this study we identified a novel mechanism by which the opportunistic pathogen Porphyromonas gingivalis dampens innate immune responses by disruption of kinase signaling and degradation of inflammatory mediators. The intracellular immune kinases RIPK1, TAK1, and AKT were selectively degraded by the P. gingivalis lysine-specific gingipain (Kgp) in human endothelial cells, which correlated with dysregulated innate immune signaling. Kgp was also observed to attenuate endothelial responsiveness to TNFα, resulting in a reduction in signal flux through AKT, ERK and NFκB pathways, as well as a decrease in downstream proinflammatory mRNA induction of cytokines, chemokines and adhesion molecules. A deficiency in Kgp activity negated decreases to host cell kinase protein levels and responsiveness to TNFα. Given the essential role of kinase signaling in immune responses, these findings highlight a unique mechanism of pathogen-induced immune dysregulation through inhibition of cell activation, paracrine signaling, and dampened cellular proinflammatory responses. PMID:27698456

Zinc in Infection and Inflammation.

PubMed

Gammoh, Nour Zahi; Rink, Lothar

2017-06-17

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli.

Intestinal commensal microbes as immune modulators.

PubMed

Ivanov, Ivaylo I; Honda, Kenya

2012-10-18

Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic strategy for many mucosal and nonmucosal immune-related conditions, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, diabetes, and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved.

Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials.

PubMed

Franz, Sandra; Rammelt, Stefan; Scharnweber, Dieter; Simon, Jan C

2011-10-01

A key for long-term survival and function of biomaterials is that they do not elicit a detrimental immune response. As biomaterials can have profound impacts on the host immune response the concept emerged to design biomaterials that are able to trigger desired immunological outcomes and thus support the healing process. However, engineering such biomaterials requires an in-depth understanding of the host inflammatory and wound healing response to implanted materials. One focus of this review is to outline the up-to-date knowledge on immune responses to biomaterials. Understanding the complex interactions of host response and material implants reveals the need for and also the potential of "immunomodulating" biomaterials. Based on this knowledge, we discuss strategies of triggering appropriate immune responses by functional biomaterials and highlight recent approaches of biomaterials that mimic the physiological extracellular matrix and modify cellular immune responses. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy

PubMed Central

Elsegeiny, Waleed; Marr, Kieren A.; Williamson, Peter R.

2018-01-01

Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30–50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts. PMID:29670625

Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy.

PubMed

Elsegeiny, Waleed; Marr, Kieren A; Williamson, Peter R

2018-01-01

Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30-50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts.

Myxoma virus in the European rabbit: interactions between the virus and its susceptible host.

PubMed

Stanford, Marianne M; Werden, Steven J; McFadden, Grant

2007-01-01

Myxoma virus (MV) is a poxvirus that evolved in Sylvilagus lagomorphs, and is the causative agent of myxomatosis in European rabbits (Oryctolagus cuniculus). This virus is not a natural pathogen of O. cuniculus, yet is able to subvert the host rabbit immune system defenses and cause a highly lethal systemic infection. The interaction of MV proteins and the rabbit immune system has been an ideal model to help elucidate host/poxvirus interactions, and has led to a greater understanding of how other poxvirus pathogens are able to cause disease in their respective hosts. This review will examine how MV causes myxomatosis, by examining a selection of the identified immunomodulatory proteins that this virus expresses to subvert the immune and inflammatory pathways of infected rabbit hosts.

Interaction between HIV-1 Tat and DNA-PKcs modulates HIV transcription and class switch recombination.

PubMed

Zhang, Shi-Meng; Zhang, He; Yang, Tian-Yi; Ying, Tian-Yi; Yang, Pei-Xiang; Liu, Xiao-Dan; Tang, Sheng-Jian; Zhou, Ping-Kun

2014-01-01

HIV-1 tat targets a variety of host cell proteins to facilitate viral transcription and disrupts host cellular immunity by inducing lymphocyte apoptosis, but whether it influences humoral immunity remains unclear. Previously, our group demonstrated that tat depresses expression of DNA-PKcs, a critical component of the non-homologous end joining pathway (NHEJ) of DNA double-strand breaks repair, immunoglobulin class switch recombination (CSR) and V(D)J recombination, and sensitizes cells to ionizing radiation. In this study, we demonstrated that HIV-1 Tat down-regulates DNA-PKcs expression by directly binding to the core promoter sequence. In addition, Tat interacts with and activates the kinase activity of DNA-PKcs in a dose-dependent and DNA independent manner. Furthermore, Tat inhibits class switch recombination (CSR) at low concentrations (≤ 4 µg/ml) and stimulates CSR at high concentrations (≥ 8 µg/ml). On the other hand, low protein level and high kinase activity of DNA-PKcs promotes HIV-1 transcription, while high protein level and low kinase activity inhibit HIV-1 transcription. Co-immunoprecipitation results revealed that DNA-PKcs forms a large complex comprised of Cyclin T1, CDK9 and Tat via direct interacting with CDK9 and Tat but not Cyclin T1. Taken together, our results provide new clues that Tat regulates host humoral immunity via both transcriptional depression and kinase activation of DNA-PKcs. We also raise the possibility that inhibitors and interventions directed towards DNA-PKcs may inhibit HIV-1 transcription in AIDS patients.

The host defense peptide beta-defensin 1 confers protection against Bordetella pertussis in newborn piglets.

PubMed

Elahi, Shokrollah; Buchanan, Rachelle M; Attah-Poku, Sam; Townsend, Hugh G G; Babiuk, Lorne A; Gerdts, Volker

2006-04-01

Innate immunity plays an important role in protection against respiratory infections in humans and animals. Host defense peptides such as beta-defensins represent major components of innate immunity. We recently developed a novel porcine model of pertussis, an important respiratory disease of young children and infants worldwide. Here, we investigated the role of porcine beta-defensin 1 (pBD-1), a porcine defensin homologue of human beta-defensin 2, in conferring protection against respiratory infection with Bordetella pertussis. In this model, newborn piglets were fully susceptible to infection and developed severe bronchopneumonia. In contrast, piglets older than 4 weeks of age were protected against infection with B. pertussis. Protection was associated with the expression of pBD-1 in the upper respiratory tract. In fact, pBD-1 expression was developmentally regulated, and the absence of pBD-1 was thought to contribute to the increased susceptibility of newborn piglets to infection with B. pertussis. Bronchoalveolar lavage specimens collected from older animals as well as chemically synthesized pBD-1 displayed strong antimicrobial activity against B. pertussis in vitro. Furthermore, in vivo treatment of newborn piglets with only 500 mug pBD-1 at the time of challenge conferred protection against infection with B. pertussis. Interestingly, pBD-1 displayed no bactericidal activity in vitro against Bordetella bronchiseptica, a closely related natural pathogen of pigs. Our results demonstrate that host defense peptides play an important role in protection against pertussis and are essential in modulating innate immune responses against respiratory infections.

Host range, immunity and antigenic properties of lambdoid coliphage HK97.

PubMed

Dhillon, E K; Dhillon, T S; Lai, A N; Linn, S

1980-09-01

Temperate coliphage HK97 was isolated from pig dung. Although HK97 is antigenically unrelated to coliphage lambda, it has similar morphology, host range and immunity properties, and can recombine with it.

Characterization and storage of malaria antigens: Fractionation of Plasmodium knowlesi-induced antigens of rhesus monkey erythrocyte membranes*

PubMed Central

Schmidt-Ullrich, R.; Wallach, D. F. H.; Lightholder, J.

1979-01-01

In order to characterize parasite-induced host cell membrane antigens, the plasma membranes of Plasmodium knowlesi-infected rhesus erythrocytes have been compared with those of normal red cells and purified schizonts by immunochemical and biochemical techniques. Host cell membranes and schizonts were separated by differential centrifugation following nitrogen decompression. Isolated schizonts were further fractionated into several subcellular compartments. Crossed-immune electrophoresis, against monkey anti-schizont serum, of Triton X-100-solubilized material identified 7 P. knowlesi-specific antigens, of which 4 could be detected only in the host cell membranes. These membranes also contained 3 proteins, with relative molecular masses of 55 000, 65 000 and 90 000 and isoelectric points at pH 4.5, 4.5 and 5.2, respectively, which are lacking in normal membranes. Pulse-chase experiments with (14C)-glucosamine showed that these parasite-induced host cell membrane components are glycoproteins. ImagesFig. 1Fig. 2 PMID:120762

Extracellular functions of glycolytic enzymes of parasites: unpredicted use of ancient proteins.

PubMed

Gómez-Arreaza, Amaranta; Acosta, Hector; Quiñones, Wilfredo; Concepción, Juan Luis; Michels, Paul A M; Avilán, Luisana

2014-02-01

In addition of their usual intracellular localization where they are involved in catalyzing reactions of carbohydrate and energy metabolism by glycolysis, multiple studies have shown that glycolytic enzymes of many organisms, but notably pathogens, can also be present extracellularly. In the case of parasitic protists and helminths, they can be found either secreted or attached to the surface of the parasites. At these extracellular localizations, these enzymes have been shown to perform additional, very different so-called "moonlighting" functions, such as acting as ligands for a variety of components of the host. Due to this recognition, different extracellular glycolytic enzymes participate in various important parasite-host interactions such as adherence and invasion of parasites, modulation of the host's immune and haemostatic systems, promotion of angiogenesis, and acquisition of specific nutrients by the parasites. Accordingly, extracellular glycolytic enzymes are important for the invasion of the parasites and their establishment in the host, and in determining their virulence. Copyright © 2014 Elsevier B.V. All rights reserved.

Pathobiology of Pneumocystis pneumonia: life cycle, cell wall and cell signal transduction.

PubMed

Skalski, Joseph H; Kottom, Theodore J; Limper, Andrew H

2015-09-01

Pneumocystis is a genus of ascomycetous fungi that are highly morbid pathogens in immunosuppressed humans and other mammals. Pneumocystis cannot easily be propagated in culture, which has greatly hindered understanding of its pathobiology. The Pneumocystis life cycle is intimately associated with its mammalian host lung environment, and life cycle progression is dependent on complex interactions with host alveolar epithelial cells and the extracellular matrix. The Pneumocystis cell wall is a varied and dynamic structure containing a dominant major surface glycoprotein, β-glucans and chitins that are important for evasion of host defenses and stimulation of the host immune system. Understanding of Pneumocystis cell signaling pathways is incomplete, but much has been deduced by comparison of the Pneumocystis genome with homologous genes and proteins in related fungi. In this mini-review, the pathobiology of Pneumocystis is reviewed, with particular focus on the life cycle, cell wall components and cell signal transduction. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Host-pathogen redox dynamics modulate Mycobacterium tuberculosis pathogenesis.

PubMed

Pacl, Hayden T; Reddy, Vineel P; Saini, Vikram; Chinta, Krishna C; Steyn, Adrie J C

2018-07-01

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, encounters variable and hostile environments within the host. A major component of these hostile conditions is reductive and oxidative stresses induced by factors modified by the host immune response, such as oxygen tension, NO or CO gases, reactive oxygen and nitrogen intermediates, the availability of different carbon sources and changes in pH. It is therefore essential for Mtb to continuously monitor and appropriately respond to the microenvironment. To this end, Mtb has developed various redox-sensitive systems capable of monitoring its intracellular redox environment and coordinating a response essential for virulence. Various aspects of Mtb physiology are regulated by these systems, including drug susceptibility, secretion systems, energy metabolism and dormancy. While great progress has been made in understanding the mechanisms and pathways that govern the response of Mtb to the host's redox environment, many questions in this area remain unanswered. The answers to these questions are promising avenues for addressing the tuberculosis crisis.

Feast or famine: the host-pathogen battle over amino acids.

PubMed

Zhang, Yanjia J; Rubin, Eric J

2013-07-01

Intracellular bacterial pathogens often rely on their hosts for essential nutrients. Host cells, in turn, attempt to limit nutrient availability, using starvation as a mechanism of innate immunity. Here we discuss both host mechanisms of amino acid starvation and the diverse adaptations of pathogens to their nutrient-deprived environments. These processes provide both key insights into immune subversion and new targets for drug development. © 2013 John Wiley & Sons Ltd.

Physical mode of bacteria and virus coevolution

NASA Astrophysics Data System (ADS)

Han, Pu; Niestemski, Liang; Deem, Michael

2013-03-01

Single-cell hosts such as bacteria or archaea possess an adaptive, heritable immune system that protects them from viral invasion. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences from viruses or plasmids. The sequences form what are called ``spacers'' in the CRISPR. Spacers in the CRISPR loci provide a record of the host and predator coevolution history. We develop a physical model to study the dynamics of this coevolution due to immune pressure. Hosts and viruses reproduce, die, and evolve due to viral infection pressure, host immune pressure, and mutation. We will discuss the differing effects of point mutation and recombination on CRISPR evolution. We will also discuss the effect of different spacer deletion mechanisms. We will describe population structure of hosts and viruses, how spacer diversity depends on position within CRISPR, and match of the CRISPR spacers to the virus population.

Innate immune activation in neurodegenerative disease.

PubMed

Heneka, Michael T; Kummer, Markus P; Latz, Eicke

2014-07-01

The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways - in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome - by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.

Fitness costs of animal medication: antiparasitic plant chemicals reduce fitness of monarch butterfly hosts.

PubMed

Tao, Leiling; Hoang, Kevin M; Hunter, Mark D; de Roode, Jacobus C

2016-09-01

The emerging field of ecological immunology demonstrates that allocation by hosts to immune defence against parasites is constrained by the costs of those defences. However, the costs of non-immunological defences, which are important alternatives to canonical immune systems, are less well characterized. Estimating such costs is essential for our understanding of the ecology and evolution of alternative host defence strategies. Many animals have evolved medication behaviours, whereby they use antiparasitic compounds from their environment to protect themselves or their kin from parasitism. Documenting the costs of medication behaviours is complicated by natural variation in the medicinal components of diets and their covariance with other dietary components, such as macronutrients. In the current study, we explore the costs of the usage of antiparasitic compounds in monarch butterflies (Danaus plexippus), using natural variation in concentrations of antiparasitic compounds among plants. Upon infection by their specialist protozoan parasite Ophryocystis elektroscirrha, monarch butterflies can selectively oviposit on milkweed with high foliar concentrations of cardenolides, secondary chemicals that reduce parasite growth. Here, we show that these antiparasitic cardenolides can also impose significant costs on both uninfected and infected butterflies. Among eight milkweed species that vary substantially in their foliar cardenolide concentration and composition, we observed the opposing effects of cardenolides on monarch fitness traits. While high foliar cardenolide concentrations increased the tolerance of monarch butterflies to infection, they reduced the survival rate of caterpillars to adulthood. Additionally, although non-polar cardenolide compounds decreased the spore load of infected butterflies, they also reduced the life span of uninfected butterflies, resulting in a hump-shaped curve between cardenolide non-polarity and the life span of infected butterflies. Overall, our results suggest that the use of antiparasitic compounds carries substantial costs, which could constrain host investment in medication behaviours. © 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.

Scabies Mite Peritrophins Are Potential Targets of Human Host Innate Immunity

PubMed Central

Holt, Deborah C.; Kemp, Dave J.; Fischer, Katja

2011-01-01

Background Pruritic scabies lesions caused by Sarcoptes scabiei burrowing in the stratum corneum of human skin facilitate opportunistic bacterial infections. Emerging resistance to current therapeutics emphasizes the need to identify novel targets for protective intervention. We have characterized several protein families located in the mite gut as crucial factors for host-parasite interactions. Among these multiple proteins inhibit human complement, presumably to avoid complement-mediated damage of gut epithelial cells. Peritrophins are major components of the peritrophic matrix often found in the gut of arthropods. We hypothesized that a peritrophin, if abundant in the scabies mite gut, could be an activator of complement. Methodology/Principal Findings A novel full length scabies mite peritrophin (SsPTP1) was identified in a cDNA library from scabies mites. The amino acid sequence revealed four putative chitin binding domains (CBD). Recombinant expression of one CBD of the highly repetitive SsPTP1 sequence as TSP-hexaHis-fusion protein resulted in soluble protein, which demonstrated chitin binding activity in affinity chromatography assays. Antibodies against a recombinant SsPTP1 fragment were used to immunohistochemically localize native SsPTP1 in the mite gut and in fecal pellets within the upper epidermis, co-localizing with serum components such as host IgG and complement. Enzymatic deglycosylation confirmed strong N- and O-glycosylation of the native peritrophin. Serum incubation followed by immunoblotting with a monoclonal antibody against mannan binding lectin (MBL), the recognition molecule of the lectin pathway of human complement activation, indicated that MBL may specifically bind to glycosylated SsPTP1. Conclusions/Significance This study adds a new aspect to the accumulating evidence that complement plays a major role in scabies mite biology. It identifies a novel peritrophin localized in the mite gut as a potential target of the lectin pathway of the complement cascade. These initial findings indicate a novel role of scabies mite peritrophins in triggering a host innate immune response within the mite gut. PMID:21980545

Challenges and Strategies for Proteome Analysis of the Interaction of Human Pathogenic Fungi with Host Immune Cells.

PubMed

Krüger, Thomas; Luo, Ting; Schmidt, Hella; Shopova, Iordana; Kniemeyer, Olaf

2015-12-14

Opportunistic human pathogenic fungi including the saprotrophic mold Aspergillus fumigatus and the human commensal Candida albicans can cause severe fungal infections in immunocompromised or critically ill patients. The first line of defense against opportunistic fungal pathogens is the innate immune system. Phagocytes such as macrophages, neutrophils and dendritic cells are an important pillar of the innate immune response and have evolved versatile defense strategies against microbial pathogens. On the other hand, human-pathogenic fungi have sophisticated virulence strategies to counteract the innate immune defense. In this context, proteomic approaches can provide deeper insights into the molecular mechanisms of the interaction of host immune cells with fungal pathogens. This is crucial for the identification of both diagnostic biomarkers for fungal infections and therapeutic targets. Studying host-fungal interactions at the protein level is a challenging endeavor, yet there are few studies that have been undertaken. This review draws attention to proteomic techniques and their application to fungal pathogens and to challenges, difficulties, and limitations that may arise in the course of simultaneous dual proteome analysis of host immune cells interacting with diverse morphotypes of fungal pathogens. On this basis, we discuss strategies to overcome these multifaceted experimental and analytical challenges including the viability of immune cells during co-cultivation, the increased and heterogeneous protein complexity of the host proteome dynamically interacting with the fungal proteome, and the demands on normalization strategies in terms of relative quantitative proteome analysis.

Control of antiviral immunity by pattern recognition and the microbiome

PubMed Central

Pang, Iris K.; Iwasaki, Akiko

2013-01-01

Summary Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential link between viruses, microbiota and the host immune system. Further, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease, and speculate on the benefit for probiotic therapies against such diseases. PMID:22168422

Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities

PubMed Central

Hohl, Tobias M.

2017-01-01

Purpose of review Invasive aspergillosis is a worldwide disease that primarily affects immune-compromised patients, agricultural workers with corneal abrasions, individuals with structural lung disease, and patients with primary immune deficiency. The critical function of the immune system is to prevent the germination of airborne conidia into tissue-invasive hyphae. This review covers recent advances that shape our understanding of anti-Aspergillus immunity at the molecular and cellular level. Recent findings Host defense against conidia and hyphae occurs via distinct molecular mechanisms that involve intracellular and extracellular killing pathways, as well as cooperation between different myeloid cell subsets. The strength and efficacy of the host response is shaped by the tissue microenvironment. In preclinical models of disease, host immune augmentation strategies have yielded benefits, yet translating these insights into therapeutic strategies in humans remains challenging. Summary Although advances in early diagnostic strategies and in antifungal drugs have ameliorated clinical outcomes of invasive aspergillosis, further improvements depend on gaining deeper insight into and translating advances in anti-Aspergillus immunity. PMID:28509673

Gut barrier in health and disease: focus on childhood.

PubMed

Viggiano, D; Ianiro, G; Vanella, G; Bibbò, S; Bruno, G; Simeone, G; Mele, G

2015-01-01

The gut barrier is a functional unit, organized as a multi-layer system, made up of two main components: a physical barrier surface, which prevents bacterial adhesion and regulates paracellular diffusion to the host tissues, and a deep functional barrier, that is able to discriminate between pathogens and commensal microorganisms, organizing the immune tolerance and the immune response to pathogens. Other mechanisms, such as gastric juice and pancreatic enzymes (which both have antibacterial properties) participate in the luminal integrity of the gut barrier. From the outer layer to the inner layer, the physical barrier is composed of gut microbiota (that competes with pathogens to gain space and energy resources, processes the molecules necessary to mucosal integrity and modulates the immunological activity of deep barrier), mucus (which separates the intraluminal content from more internal layers and contains antimicrobial products and secretory IgA), epithelial cells (which form a physical and immunological barrier) and the innate and adaptive immune cells forming the gut-associated lymphoid tissue (which is responsible for antigen sampling and immune responses). Disruption of the gut barrier has been associated with many gastrointestinal diseases, but also with extra-intestinal pathological condition, such as type 1 diabetes mellitus, allergic diseases or autism spectrum disorders. The maintenance of a healthy intestinal barrier is therefore of paramount importance in children, for both health and economic reasons. Many drugs or compounds used in the treatment of gastrointestinal disorders act through the restoration of a normal intestinal permeability. Several studies have highlighted the role of probiotics in the modulation and reduction of intestinal permeability, considering the strong influence of gut microbiota in the modulation of the function and structure of gut barrier, but also on the immune response of the host. To date, available weapons for the maintenance and repair of gut barrier are however few, even if promising. Considerable efforts, including both a better understanding of the gut barrier features and mechanisms in health and disease, and the development of new pharmacological approaches for the modulation of gut barrier components, are needed for the prevention and treatment of gastrointestinal and extraintestinal diseases associated with gut barrier impairment.

Cell-Penetrating Peptide-Mediated Delivery of Cas9 Protein and Guide RNA for Genome Editing.

PubMed

Suresh, Bharathi; Ramakrishna, Suresh; Kim, Hyongbum

2017-01-01

The clustered, regularly interspaced, short palindromic repeat (CRISPR)-associated (Cas) system represents an efficient tool for genome editing. It consists of two components: the Cas9 protein and a guide RNA. To date, delivery of these two components has been achieved using either plasmid or viral vectors or direct delivery of protein and RNA. Plasmid- and virus-free direct delivery of Cas9 protein and guide RNA has several advantages over the conventional plasmid-mediated approach. Direct delivery results in shorter exposure time at the cellular level, which in turn leads to lower toxicity and fewer off-target mutations with reduced host immune responses, whereas plasmid- or viral vector-mediated delivery can result in uncontrolled integration of the vector sequence into the host genome and unwanted immune responses. Cell-penetrating peptide (CPP), a peptide that has an intrinsic ability to translocate across cell membranes, has been adopted as a means of achieving efficient Cas9 protein and guide RNA delivery. We developed a method for treating human cell lines with CPP-conjugated recombinant Cas9 protein and CPP-complexed guide RNAs that leads to endogenous gene disruption. Here we describe a protocol for preparing an efficient CPP-conjugated recombinant Cas9 protein and CPP-complexed guide RNAs, as well as treatment methods to achieve safe genome editing in human cell lines.

The Eosinophil in Infection.

PubMed

Ravin, Karen A; Loy, Michael

2016-04-01

First described by Paul Ehrlich in 1879, who noted its characteristic staining by acidophilic dyes, for many years, the eosinophil was considered to be an end-effector cell associated with helminth infections and a cause of tissue damage. Over the past 30 years, research has helped to elucidate the complexity of the eosinophil's function and establish its role in host defense and immunity. Eosinophils express an array of ligand receptors which play a role in cell growth, adhesion, chemotaxis, degranulation, and cell-to-cell interactions. They play a role in activation of complement via both classical and alternative pathways. Eosinophils synthesize, store and secrete cytokines, chemokines, and growth factors. They can process antigen, stimulate T cells, and promote humoral responses by interacting with B cells. Eosinophils can function as antigen presenting cells and can regulate processes associated with both T1 and T2 immunity. Although long known to play a role in defense against helminth organisms, the interactions of eosinophils with these parasites are now recognized to be much more complex. In addition, their interaction with other pathogens continues to be investigated. In this paper, we review the eosinophil's unique biology and structure, including its characteristic granules and the effects of its proteins, our developing understanding of its role in innate and adaptive immunity and importance in immunomodulation, and the part it plays in defense against parasitic, viral, fungal and bacterial infections. Rather than our worst enemy, the eosinophil may, in fact, be one of the most essential components in host defense and immunity.

Interaction of the tick immune system with transmitted pathogens

PubMed Central

Hajdušek, Ondřej; Šíma, Radek; Ayllón, Nieves; Jalovecká, Marie; Perner, Jan; de la Fuente, José; Kopáček, Petr

2013-01-01

Ticks are hematophagous arachnids transmitting a wide variety of pathogens including viruses, bacteria, and protozoans to their vertebrate hosts. The tick vector competence has to be intimately linked to the ability of transmitted pathogens to evade tick defense mechanisms encountered on their route through the tick body comprising midgut, hemolymph, salivary glands or ovaries. Tick innate immunity is, like in other invertebrates, based on an orchestrated action of humoral and cellular immune responses. The direct antimicrobial defense in ticks is accomplished by a variety of small molecules such as defensins, lysozymes or by tick-specific antimicrobial compounds such as microplusin/hebraein or 5.3-kDa family proteins. Phagocytosis of the invading microbes by tick hemocytes is likely mediated by the primordial complement-like system composed of thioester-containing proteins, fibrinogen-related lectins and convertase-like factors. Moreover, an important role in survival of the ingested microbes seems to be played by host proteins and redox balance maintenance in the tick midgut. Here, we summarize recent knowledge about the major components of tick immune system and focus on their interaction with the relevant tick-transmitted pathogens, represented by spirochetes (Borrelia), rickettsiae (Anaplasma), and protozoans (Babesia). Availability of the tick genomic database and feasibility of functional genomics based on RNA interference greatly contribute to the understanding of molecular and cellular interplay at the tick-pathogen interface and may provide new targets for blocking the transmission of tick pathogens. PMID:23875177

Oral innate immunity in HIV infection in HAART era

PubMed Central

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

2015-01-01

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

Host Immune Response to Influenza A Virus Infection.

PubMed

Chen, Xiaoyong; Liu, Shasha; Goraya, Mohsan Ullah; Maarouf, Mohamed; Huang, Shile; Chen, Ji-Long

2018-01-01

Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.

Understanding the interplay between host immunity and Epstein-Barr virus in NPC patients

PubMed Central

Shen, Yong; Zhang, Suzhan; Sun, Ren; Wu, Tingting; Qian, Jing

2015-01-01

Epstein-Barr virus (EBV) has been used as a paradigm for studying host–virus interactions, not only because of its importance as a human oncogenic virus associated with several malignancies including nasopharyngeal carcinoma (NPC) but also owing to its sophisticated strategies to subvert the host antiviral responses. An understanding of the interplay between EBV and NPC is critical for the development of EBV-targeted immunotherapy. Here, we summarize the current knowledge regarding the host immune responses and EBV immune evasion mechanisms in the context of NPC. PMID:26038769

Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury

PubMed Central

Kruger, Philipp; Saffarzadeh, Mona; Weber, Alexander N. R.; Rieber, Nikolaus; Radsak, Markus; von Bernuth, Horst; Benarafa, Charaf; Roos, Dirk; Skokowa, Julia; Hartl, Dominik

2015-01-01

Neutrophils, the most abundant human immune cells, are rapidly recruited to sites of infection, where they fulfill their life-saving antimicrobial functions. While traditionally regarded as short-lived phagocytes, recent findings on long-term survival, neutrophil extracellular trap (NET) formation, heterogeneity and plasticity, suppressive functions, and tissue injury have expanded our understanding of their diverse role in infection and inflammation. This review summarises our current understanding of neutrophils in host-pathogen interactions and disease involvement, illustrating the versatility and plasticity of the neutrophil, moving between host defence, immune modulation, and tissue damage. PMID:25764063

Challenges and future perspectives of T cell immunotherapy in cancer

PubMed Central

de Aquino, Maria Teresa P; Malhotra, Anshu; Mishra, Manoj K; Shanker, Anil

2015-01-01

Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signaling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer. PMID:26096822

The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives.

PubMed

Leal, Rodolfo Oliveira; Gil, Solange

2016-10-27

Type I interferons (IFNs) are well-known cytokines that, among their main functions, are key components of the host immune response against viral infections. Due to its immune modulation properties, they are commonly used in the therapeutic approach of various retroviral infections, namely human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV). In HIV infection, it has been shown that IFN therapy limits early viral replication, particularly useful on post-exposure prophylaxis. In veterinary medicine, recombinant feline interferon omega (rFeIFN-ω) was the first interferon licensed for use in cats. Several studies have recently shown that this compound seems to stimulate the innate immunity, decreasing clinical signs and co-infections in naturally FIV-infected cats. More than summarizing the main conclusions about rFeIFN-ω in cats, this review emphasizes the immune-modulation properties of IFN therapy, opening new perspectives for its use in retroviral infections. Either in FIV-infected cats or in HIV individuals, type I IFNs seem to induce an innate immune-modulation and should not be overlooked as a therapeutic option in retroviral infections.

LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways.

PubMed

Zhao, Ke; Du, Juan; Peng, Yanfeng; Li, Peng; Wang, Shaohua; Wang, Yu; Hou, Jingwei; Kang, Jian; Zheng, Wenwen; Hua, Shucheng; Yu, Xiao-Fang

2018-06-01

Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutières syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNβ production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential. LINE1-triggered immune activation could be suppressed by diverse LINE1 inhibitors, including AGS-associated proteins targeting LINE1 RNA or proteins. However, AGS-associated ADAR1 or TREX1 mutants were defective in suppressing LINE1 retrotransposition or LINE1-triggered immune activation. Therefore, we have revealed a new function for LINE1 as an endogenous trigger of innate immune activation, which is important for understanding the molecular basis of IFN-based autoimmune diseases and may offer new intervention strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Inducible MicroRNA-3570 Feedback Inhibits the RIG-I-Dependent Innate Immune Response to Rhabdovirus in Teleost Fish by Targeting MAVS/IPS-1.

PubMed

Xu, Tianjun; Chu, Qing; Cui, Junxia; Bi, Dekun

2018-01-15

Effectively recognizing invading viruses and subsequently inducing innate antiviral immunity are essential for host antiviral defense. Although these processes are closely regulated by the host to maintain immune balance, viruses have evolved the ability to downregulate or upregulate these processes for their survival. MicroRNAs (miRNAs) are a family of small noncoding RNAs that play vital roles in modulating host immune response. Accumulating evidence demonstrates that host miRNAs as mediators are involved in regulating viral replication and host antiviral immunity in mammals. However, the underlying regulatory mechanisms in fish species are still poorly understood. Here, we found that rhabdovirus infection significantly upregulated host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulated RNA virus-triggered type I interferon (IFN) and antiviral gene production, thus facilitating viral replication. Furthermore, miR-3570 was found to target and posttranscriptionally downregulate mitochondrial antiviral signaling protein (MAVS), which functions as a platform for innate antiviral signal transduction. Moreover, we demonstrated that miR-3570 suppressed the expression of MAVS, thereby inhibiting MAVS-mediated NF-κB and IRF3 signaling. The collective results demonstrated a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miRNA. IMPORTANCE RNA viral infection could upregulate host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulates RNA virus-triggered type I IFN and antiviral gene production, thus facilitating viral replication. Remarkably, miR-3570 could target and inhibit MAVS expression, which thus modulates MAVS-mediated NF-κB and IRF3 signaling. The collective results of this study suggest a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miR-3570. Thus, a novel mechanism for virus evasion in fish is proposed. Copyright © 2018 American Society for Microbiology.

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

PubMed

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

2016-09-01

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

Molecular Mimicry between Chikungunya Virus and Host Components: A Possible Mechanism for the Arthritic Manifestations

PubMed Central

Reddy, Vijayalakshmi; Desai, Anita; Krishna, Shankar Susarla; Vasanthapuram, Ravi

2017-01-01

Background Chikungunya virus (CHIKV), a reemerging pathogen causes a self limited illness characterized by fever, headache, myalgia and arthralgia. However, 10–20% affected individuals develop persistent arthralgia which contributes to considerable morbidity. The exact molecular mechanisms underlying these manifestations are not well understood. The present study investigated the possible occurrence of molecular mimicry between CHIKV E1 glycoprotein and host human components. Methodology Bioinformatic tools were used to identify peptides of CHIKV E1 exhibiting similarity to host components. Two peptides (A&B) were identified using several bioinformatic tools, synthesised and used to validate the results obtained in silico. An ELISA was designed to assess the immunoreactivity of serum samples from CHIKV patients to these peptides. Further, experiments were conducted in a C57BL/6J experimental mouse model to investigate if peptide A and peptide B were indeed capable of inducing pathology. Findings The serum samples showed reactivity of varying degrees, indicating that these peptides are indeed being recognized by the host immune system during CHIKV infection. Further, these peptides when injected into C57BL/6J mice were able to induce significant inflammation in the muscles of C57BL/6J mice, similar to that observed in animals that were injected with CHIKV alone. Additionally, animals that were primed initially with CHIKV followed by a subsequent injection of the CHIKV peptides exhibited enhanced inflammatory pathology in the skeletal muscles as compared to animals that were injected with peptides or virus alone. Collectively these observations validate the hypothesis that molecular mimicry between CHIKV E1 protein and host proteins does contribute to pathology in CHIKV infection. PMID:28125580

A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease.

PubMed

Zhou, Jingran; Wu, Ruiqiong; High, Anthony A; Slaughter, Clive A; Finkelstein, David; Rehg, Jerold E; Redecke, Vanessa; Häcker, Hans

2011-11-01

Toll-like receptors (TLRs) are expressed on innate immune cells and trigger inflammation upon detection of pathogens and host tissue injury. TLR-mediated proinflammatory-signaling pathways are counteracted by partially characterized anti-inflammatory mechanisms that prevent exaggerated inflammation and host tissue damage as manifested in inflammatory diseases. We biochemically identified a component of TLR-signaling pathways, A20-binding inhibitor of NF-κB (ABIN1), which recently has been linked by genome-wide association studies to the inflammatory diseases systemic lupus erythematosus and psoriasis. We generated ABIN1-deficient mice to study the function of ABIN1 in vivo and during TLR activation. Here we show that ABIN1-deficient mice develop a progressive, lupus-like inflammatory disease characterized by expansion of myeloid cells, leukocyte infiltrations in different parenchymatous organs, activated T and B lymphocytes, elevated serum Ig levels, and the appearance of autoreactive antibodies. Kidneys develop glomerulonephritis and proteinuria, reflecting tissue injury. Surprisingly, ABIN1-deficient macrophages exhibit normal regulation of major proinflammatory signaling pathways and mediators but show selective deregulation of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) and its target genes, such as colony-stimulating factor 3 (Csf3), nitric oxide synthase, inducible (Nos2), and S100 calcium-binding protein A8 (S100a8). Their gene products, which are intimately linked to innate immune cell expansion (granulocyte colony-stimulating factor), cytotoxicity (inducible nitric oxide synthase), and host factor-derived inflammation (S100A8), may explain, at least in part, the inflammatory phenotype observed. Together, our data reveal ABIN1 as an essential anti-inflammatory component of TLR-signaling pathways that controls C/EBPβ activity.

Balancing Immune Protection and Immune Pathology by CD8+ T-Cell Responses to Influenza Infection

PubMed Central

Duan, Susu; Thomas, Paul G.

2016-01-01

Influenza A virus (IAV) is a significant human pathogen causing annual epidemics and periodic pandemics. CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity contributes to the clearance of virus-infected cells, and CTL immunity targeting the conserved internal proteins of IAVs is a key protection mechanism when neutralizing antibodies are absent during heterosubtypic IAV infection. However, CTL infiltration into the airways, its cytotoxicity, and the effects of produced proinflammatory cytokines can cause severe lung tissue injury, thereby contributing to immunopathology. Studies have discovered complicated and exquisite stimulatory and inhibitory mechanisms that regulate CTL magnitude and effector activities during IAV infection. Here, we review the state of knowledge on the roles of IAV-specific CTLs in immune protection and immunopathology during IAV infection in animal models, highlighting the key findings of various requirements and constraints regulating the balance of immune protection and pathology involved in CTL immunity. We also discuss the evidence of cross-reactive CTL immunity as a positive correlate of cross-subtype protection during secondary IAV infection in both animal and human studies. We argue that the effects of CTL immunity on protection and immunopathology depend on multiple layers of host and viral factors, including complex host mechanisms to regulate CTL magnitude and effector activity, the pathogenic nature of the IAV, the innate response milieu, and the host historical immune context of influenza infection. Future efforts are needed to further understand these key host and viral factors, especially to differentiate those that constrain optimally effective CTL antiviral immunity from those necessary to restrain CTL-mediated non-specific immunopathology in the various contexts of IAV infection, in order to develop better vaccination and therapeutic strategies for modifying protective CTL immunity. PMID:26904022

Costs of immune responses are related to host body size and lifespan

DOE PAGES

Brace, Amber J.; Lajeunesse, Marc J.; Ardia, Daniel R.; ...

2017-06-01

A central assumption in ecological immunology is that immune responses are costly, with costs manifesting directly (e.g., increases in metabolic rate and increased amino acid usage) or as tradeoffs with other life processes (e.g., reduced growth and reproductive success). Across taxa, host longevity, timing of maturity, and reproductive effort affect the organization of immune systems. It is reasonable, therefore, to expect that these and related factors should also affect immune activation costs. Specifically, species that spread their breeding efforts over a long lifetime should experience lower immune costs than those that mature and breed quickly and die comparatively early. Likewise,more » body mass should affect immune costs, as body size affects the extent to which hosts are exposed to parasites as well as how hosts can combat infections (via its effects on metabolic rates and other factors). Here in this paper, we used phylogenetic meta-regression to reveal that, in general, animals incur costs of immune activation, but small species that are relatively long-lived incur the largest costs. These patterns probably arise because of the relative need for defense when infection risk is comparatively high and fitness can only be realized over a comparatively long period. However, given the diversity of species considered here and the overall modest effects of body mass and life history on immune costs, much more research is necessary before generalizations are appropriate.« less

Costs of immune responses are related to host body size and lifespan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brace, Amber J.; Lajeunesse, Marc J.; Ardia, Daniel R.

A central assumption in ecological immunology is that immune responses are costly, with costs manifesting directly (e.g., increases in metabolic rate and increased amino acid usage) or as tradeoffs with other life processes (e.g., reduced growth and reproductive success). Across taxa, host longevity, timing of maturity, and reproductive effort affect the organization of immune systems. It is reasonable, therefore, to expect that these and related factors should also affect immune activation costs. Specifically, species that spread their breeding efforts over a long lifetime should experience lower immune costs than those that mature and breed quickly and die comparatively early. Likewise,more » body mass should affect immune costs, as body size affects the extent to which hosts are exposed to parasites as well as how hosts can combat infections (via its effects on metabolic rates and other factors). Here in this paper, we used phylogenetic meta-regression to reveal that, in general, animals incur costs of immune activation, but small species that are relatively long-lived incur the largest costs. These patterns probably arise because of the relative need for defense when infection risk is comparatively high and fitness can only be realized over a comparatively long period. However, given the diversity of species considered here and the overall modest effects of body mass and life history on immune costs, much more research is necessary before generalizations are appropriate.« less

The role of adaptive immunity as an ecological filter on the gut microbiota in zebrafish.

PubMed

Stagaman, Keaton; Burns, Adam R; Guillemin, Karen; Bohannan, Brendan Jm

2017-07-01

All animals live in intimate association with communities of microbes, collectively referred to as their microbiota. Certain host traits can influence which microbial taxa comprise the microbiota. One potentially important trait in vertebrate animals is the adaptive immune system, which has been hypothesized to act as an ecological filter, promoting the presence of some microbial taxa over others. Here we surveyed the intestinal microbiota of 68 wild-type zebrafish, with functional adaptive immunity, and 61 rag1 - zebrafish, lacking functional B- and T-cell receptors, to test the role of adaptive immunity as an ecological filter on the intestinal microbiota. In addition, we tested the robustness of adaptive immunity's filtering effects to host-host interaction by comparing the microbiota of fish populations segregated by genotype to those containing both genotypes. The presence of adaptive immunity individualized the gut microbiota and decreased the contributions of neutral processes to gut microbiota assembly. Although mixing genotypes led to increased phylogenetic diversity in each, there was no significant effect of adaptive immunity on gut microbiota composition in either housing condition. Interestingly, the most robust effect on microbiota composition was co-housing within a tank. In all, these results suggest that adaptive immunity has a role as an ecological filter of the zebrafish gut microbiota, but it can be overwhelmed by other factors, including transmission of microbes among hosts.

Cell Wall and Secreted Proteins of Candida albicans: Identification, Function, and Expression

PubMed Central

Chaffin, W. Lajean; López-Ribot, José Luis; Casanova, Manuel; Gozalbo, Daniel; Martínez, José P.

1998-01-01

The cell wall is essential to nearly every aspect of the biology and pathogenicity of Candida albicans. Although it was intially considered an almost inert cellular structure that protected the protoplast against osmotic offense, more recent studies have demonstrated that it is a dynamic organelle. The major components of the cell wall are glucan and chitin, which are associated with structural rigidity, and mannoproteins. The protein component, including both mannoprotein and nonmannoproteins, comprises some 40 or more moieties. Wall proteins may differ in their expression, secretion, or topological location within the wall structure. Proteins may be modified by glycosylation (primarily addition of mannose residues), phosphorylation, and ubiquitination. Among the secreted enzymes are those that are postulated to have substrates within the cell wall and those that find substrates in the extracellular environment. Cell wall proteins have been implicated in adhesion to host tissues and ligands. Fibrinogen, complement fragments, and several extracellular matrix components are among the host proteins bound by cell wall proteins. Proteins related to the hsp70 and hsp90 families of conserved stress proteins and some glycolytic enzyme proteins are also found in the cell wall, apparently as bona fide components. In addition, the expression of some proteins is associated with the morphological growth form of the fungus and may play a role in morphogenesis. Finally, surface mannoproteins are strong immunogens that trigger and modulate the host immune response during candidiasis. PMID:9529890

Neuro-immune interactions in inflammation and host defense: Implications for transplantation.

PubMed

Chavan, Sangeeta S; Ma, Pingchuan; Chiu, Isaac M

2018-03-01

Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Positive regulation of humoral and innate immune responses induced by inactivated Avian Influenza Virus vaccine in broiler chickens.

PubMed

Abdallah, Fatma; Hassanin, Ola

2015-12-01

Avian Influenza (AI) vaccines are widely used for mammals and birds in a trial to eliminate the Avian Influenza virus (AIV) infection from the world. However and up till now the virus is still existed via modulation of its antigenic structure to evade the pressure of host immune responses. For a complete understanding of the immune responses following AI vaccination in chickens, the modulations of the chickens humoral immune responses and interferon-alpha signaling pathway, as a fundamental part of the innate immune responses, were investigated. In our study, we measured the humoral immune response using hemagglutination-inhibition (HI) and enzyme-linked immunosorbent assay (ELISA) tests. In addition, chicken interferon-alpha pathway components was measured at RNA levels using Quantitative Real-time PCR (qRT-PCR) following one dose of inactivated H5N1 influenza vaccine at 14 days of age. In this study, the protective levels of humoral antibody responses were observed at 14, 21 and 28 days following immunization with inactivated (Re-1/H5N1) AI vaccine. In the chicken spleen cells, up regulation in the chicken interferon-alpha pathway components (MX1 & IRF7) was existed as early as 48 h post vaccination and remained until 28 days post vaccination at the endogenous state. However, after the recall with ex-vivo stimulation, the up regulation was more pronounced in the transcriptional factor (IRF7) compared to the antiviral gene (MX1) at 28 days post vaccination. So far, from our results it appears that the inactivated H5N1 vaccine can trigger the chicken interferon-alpha signaling pathway as well as it can elicit protective humoral antibody responses.

Commensal microbiome effects on mucosal immune system development in the ruminant gastrointestinal tract.

PubMed

Taschuk, Ryan; Griebel, Philip J

2012-06-01

Commensal microflora play many roles within the mammalian gastrointestinal tract (GIT) that benefit host physiology by way of direct or indirect interactions with mucosal surfaces. Commensal flora comprises members across all microbial phyla, although predominantly bacterial, with population dynamics varying with host species, genotype, and environmental factors. Little is known, however, about the complex mechanisms regulating host-commensal interactions that underlie this mutually beneficial relationship and how alterations in the microbiome may influence host development and susceptibility to infection. Research into the gut microbiome has intensified as it becomes increasingly evident that symbiont-host interactions have a significant impact on mucosal immunity and health. Furthermore, evidence that microbial populations vary significantly throughout the GIT suggest that regional differences in the microbiome may also influence immune function within distinct compartments of the GIT. Postpartum colonization of the GIT has been shown to have a direct effect on mucosal immune system development, but information is limited regarding regional effects of the microbiome on the development, activation, and maturation of the mucosal immune system. This review discusses factors influencing the colonization and establishment of the microbiome throughout the GIT of newborn calves and the evidence that regional differences in the microbiome influence mucosal immune system development and maturation. The implications of this complex interaction are also discussed in terms of possible effects on responses to enteric pathogens and vaccines.

Longevity-modulating effects of symbiosis: insights from Drosophila-Wolbachia interaction.

PubMed

Maistrenko, Oleksandr M; Serga, Svitlana V; Vaiserman, Alexander M; Kozeretska, Iryna A

2016-11-01

Microbial communities are known to significantly affect various fitness components and survival of their insect hosts, including Drosophila. The composition of symbiotic microbiota has been shown to change with the host's aging. It is unclear whether these changes are caused by the aging process or, vice versa, they affect the host's aging and longevity. Recent findings indicate that fitness and lifespan of Drosophila are affected by endosymbiotic bacteria Wolbachia. These effects, however, are inconsistent and have been reported both to extend and shorten longevity. The main molecular pathways underlying the lifespan-modulating effects of Wolbachia remain unclear, however insulin/insulin-like growth factor, immune deficiency, ecdysteroid synthesis and signaling and c-Jun N-terminal kinase pathways as well as heat shock protein synthesis and autophagy have been proposed to play a role. Here we revise the current evidence that elucidates the impact of Wolbachia endosymbionts on the aging processes in Drosophila.

Helicobacter pylori infection and host cell responses.

PubMed

Di Leo, A; Messa, C; Russo, F; Linsalata, M; Amati, L; Caradonna, L; Pece, S; Pellegrino, N M; Caccavo, D; Antonaci, S; Jirillo, E

1999-11-01

It is well known that Helicobacter pylori is able to colonize the gastric mucosa, causing a chronic and persistent infection with complications, such as peptic ulcer and gastric cancer. This review places emphasis on some epidemiological aspects of Helicobacter pylori infection and its mode of transmission. At the same time, invasive and non-invasive methods of diagnosis of Helicobacter pylori infection are illustrated. More space is devoted to the host response following invasion of the stomach. In this respect, the role played by different growth factors and polyamines in the course of Helicobacter pylori disease is discussed also in relation to the result of eradicating treatment. On the other hand, an accurate description of the host immune responses against Helicobacter pylori organism and/or their components (e.g. lipopolysaccharides) is reported. Finally, since Helicobacter pylori has been classified as a class I carcinogen, current researches are focussed on the Helicobacter pylori-induced carcinogenesis.

Resiniferatoxin modulates the Th1 immune response and protects the host during intestinal nematode infection.

PubMed

Muñoz-Carrillo, J L; Contreras-Cordero, J F; Muñoz-López, J L; Maldonado-Tapia, C H; Muñoz-Escobedo, J J; Moreno-García, M A

2017-09-01

In the early stage of the intestinal phase of Trichinella spiralis infection, the host triggers a Th1-type immune response with the aim of eliminating the parasite. However, this response damages the host which favours the survival of the parasite. In the search for novel pharmacological strategies that inhibit the Th1 immune response and assist the host against T. spiralis infection, a recent study showed that resiniferatoxin had anti-inflammatory activity contributed to the host in T. spiralis infection. In this study, we evaluated whether RTX modulates the host immune response through the inhibition of Th1 cytokines in the intestinal phase. In addition, it was determined whether the treatment with RTX affects the infectivity of T. spiralis-L1 and the development of the T. spiralis life cycle. Our results show that RTX decreased serum levels of IL-12, INF-γ, IL-1β, TNF-α and parasite burden on muscle tissue. It was observed that T. spiralis-L1 treated with RTX decreased their infectivity affecting the development of the T. spiralis life cycle in mouse. These results demonstrate that RTX is able to inhibit the production of Th1 cytokines, contributing to the defence against T. spiralis, which places it as a potential drug modulator of the immune response. © 2017 John Wiley & Sons Ltd.

Delineation of the function of a major gamma delta T cell subset during infection.

PubMed

Andrew, Elizabeth M; Newton, Darren J; Dalton, Jane E; Egan, Charlotte E; Goodwin, Stewart J; Tramonti, Daniela; Scott, Philip; Carding, Simon R

2005-08-01

Gammadelta T cells play important but poorly defined roles in pathogen-induced immune responses and in preventing chronic inflammation and pathology. A major obstacle to defining their function is establishing the degree of functional redundancy and heterogeneity among gammadelta T cells. Using mice deficient in Vgamma1+ T cells which are a major component of the gammadelta T cell response to microbial infection, a specific immunoregulatory role for Vgamma1+ T cells in macrophage and gammadelta T cell homeostasis during infection has been established. By contrast, Vgamma1+ T cells play no significant role in pathogen containment or eradication and cannot protect mice from immune-mediated pathology. Pathogen-elicited Vgamma1+ T cells also display different functional characteristics at different stages of the host response to infection that involves unique and different populations of Vgamma1+ T cells. These findings, therefore, identify distinct and nonoverlapping roles for gammadelta T cell subsets in infection and establish the complexity and adaptability of a single population of gammadelta T cells in the host response to infection that is not predetermined, but is, instead, shaped by environmental factors.

Poly-N-Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

PubMed Central

Ferreirinha, Pedro; Pérez-Cabezas, Begoña; Correia, Alexandra; Miyazawa, Bruna; França, Angela; Carvalhais, Virgínia; Faustino, Augusto; Cordeiro-da-Silva, Anabela; Teixeira, Luzia; Pier, Gerald B.

2016-01-01

Poly-N-acetylglucosamine (PNAG) is a major component of the Staphylococcus epidermidis biofilm extracellular matrix. However, it is not yet clear how this polysaccharide impacts the host immune response and infection-associated pathology. Faster neutrophil recruitment and bacterial clearance were observed in mice challenged intraperitoneally with S. epidermidis biofilm cells of the PNAG-producing 9142 strain than in mice similarly challenged with the isogenic PNAG-defective M10 mutant. Moreover, intraperitoneal priming with 9142 cells exacerbated liver inflammatory pathology induced by a subsequent intravenous S. epidermidis challenge, compared to priming with M10 cells. The 9142-primed mice had elevated splenic CD4+ T cells producing gamma interferon and interleukin-17A, indicating that PNAG promoted cell-mediated immunity. Curiously, despite having more marked liver tissue pathology, 9142-primed mice also had splenic T regulatory cells with greater suppressive activity than those of their M10-primed counterparts. By showing that PNAG production by S. epidermidis biofilm cells exacerbates host inflammatory pathology, these results together suggest that this polysaccharide contributes to the clinical features associated with biofilm-derived infections. PMID:27481237

Nlrp6- and ASC-Dependent Inflammasomes Do Not Shape the Commensal Gut Microbiota Composition.

PubMed

Mamantopoulos, Michail; Ronchi, Francesca; Van Hauwermeiren, Filip; Vieira-Silva, Sara; Yilmaz, Bahtiyar; Martens, Liesbet; Saeys, Yvan; Drexler, Stefan K; Yazdi, Amir S; Raes, Jeroen; Lamkanfi, Mohamed; McCoy, Kathy D; Wullaert, Andy

2017-08-15

The gut microbiota regulate susceptibility to multiple human diseases. The Nlrp6-ASC inflammasome is widely regarded as a hallmark host innate immune axis that shapes the gut microbiota composition. This notion stems from studies reporting dysbiosis in mice lacking these inflammasome components when compared with non-littermate wild-type animals. Here, we describe microbial analyses in inflammasome-deficient mice while minimizing non-genetic confounders using littermate-controlled Nlrp6-deficient mice and ex-germ-free littermate-controlled ASC-deficient mice that were all allowed to shape their gut microbiota naturally after birth. Careful microbial phylogenetic analyses of these cohorts failed to reveal regulation of the gut microbiota composition by the Nlrp6- and ASC-dependent inflammasomes. Our results obtained in two geographically separated animal facilities dismiss a generalizable impact of Nlrp6- and ASC-dependent inflammasomes on the composition of the commensal gut microbiota and highlight the necessity for littermate-controlled experimental design in assessing the influence of host immunity on gut microbial ecology. Copyright © 2017 Elsevier Inc. All rights reserved.

Exploiting fungal cell wall components in vaccines.

PubMed

Levitz, Stuart M; Huang, Haibin; Ostroff, Gary R; Specht, Charles A

2015-03-01

Innate recognition of fungi leads to strong adaptive immunity. Investigators are trying to exploit this observation in vaccine development by combining antigens with evolutionarily conserved fungal cell wall carbohydrates to induce protective responses. Best studied is β-1,3-glucan, a glycan that activates complement and is recognized by dectin-1. Administration of antigens in association with β-1,3-glucan, either by direct conjugation or complexed in glucan particles, results in robust humoral and cellular immune responses. While the host has a host of mannose receptors, responses to fungal mannoproteins generally are amplified if cells are cooperatively stimulated with an additional danger signal such as a toll-like receptor agonist. Chitosan, a polycationic homopolymer of glucosamine manufactured by the deacetylation of chitin, is being studied as an adjuvant in DNA and protein-based vaccines. It appears particularly promising in mucosal vaccines. Finally, universal and organism-specific fungal vaccines have been formulated by conjugating fungal cell wall glycans to carrier proteins. A major challenge will be to advance these experimental findings so that at risk patients can be protected.

Exploiting fungal cell wall components in vaccines

PubMed Central

Levitz, Stuart M.; Huang, Haibin; Ostroff, Gary R.; Specht, Charles A.

2014-01-01

Innate recognition of fungi leads to strong adaptive immunity. Investigators are trying to exploit this observation in vaccine development by combining antigens with evolutionarily conserved fungal cell wall carbohydrates to induce protective responses. Best studied is β-1,3-glucan, a glycan that activates complement and is recognized by Dectin-1. Administration of antigens in association with β-1,3-glucan, either by direct conjugation or complexed in glucan particles, results in robust humoral and cellular immune responses. While the host has a host of mannose receptors, responses to fungal mannoproteins generally are amplified if cells are cooperatively stimulated with an additional danger signal such as a toll-like receptor agonist. Chitosan, a polycationic homopolymer of glucosamine manufactured by the deacetylation of chitin, is being studied as an adjuvant in DNA and protein-based vaccines. It appears particularly promising in mucosal vaccines. Finally, universal and organism-specific fungal vaccines have been formulated by conjugating fungal cell wall glycans to carrier proteins. A major challenge will be to advance these experimental findings so that at risk patients can be protected. PMID:25404118

Parasite Carbohydrate Vaccines.

PubMed

Jaurigue, Jonnel A; Seeberger, Peter H

2017-01-01

Vaccination is an efficient means of combating infectious disease burden globally. However, routine vaccines for the world's major human parasitic diseases do not yet exist. Vaccines based on carbohydrate antigens are a viable option for parasite vaccine development, given the proven success of carbohydrate vaccines to combat bacterial infections. We will review the key components of carbohydrate vaccines that have remained largely consistent since their inception, and the success of bacterial carbohydrate vaccines. We will then explore the latest developments for both traditional and non-traditional carbohydrate vaccine approaches for three of the world's major protozoan parasitic diseases-malaria, toxoplasmosis, and leishmaniasis. The traditional prophylactic carbohydrate vaccine strategy is being explored for malaria. However, given that parasite disease biology is complex and often arises from host immune responses to parasite antigens, carbohydrate vaccines against deleterious immune responses in host-parasite interactions are also being explored. In particular, the highly abundant glycosylphosphatidylinositol molecules specific for Plasmodium, Toxoplasma , and Leishmania spp. are considered exploitable antigens for this non-traditional vaccine approach. Discussion will revolve around the application of these protozoan carbohydrate antigens for vaccines currently in preclinical development.

Parasite Carbohydrate Vaccines

PubMed Central

Jaurigue, Jonnel A.; Seeberger, Peter H.

2017-01-01

Vaccination is an efficient means of combating infectious disease burden globally. However, routine vaccines for the world's major human parasitic diseases do not yet exist. Vaccines based on carbohydrate antigens are a viable option for parasite vaccine development, given the proven success of carbohydrate vaccines to combat bacterial infections. We will review the key components of carbohydrate vaccines that have remained largely consistent since their inception, and the success of bacterial carbohydrate vaccines. We will then explore the latest developments for both traditional and non-traditional carbohydrate vaccine approaches for three of the world's major protozoan parasitic diseases—malaria, toxoplasmosis, and leishmaniasis. The traditional prophylactic carbohydrate vaccine strategy is being explored for malaria. However, given that parasite disease biology is complex and often arises from host immune responses to parasite antigens, carbohydrate vaccines against deleterious immune responses in host-parasite interactions are also being explored. In particular, the highly abundant glycosylphosphatidylinositol molecules specific for Plasmodium, Toxoplasma, and Leishmania spp. are considered exploitable antigens for this non-traditional vaccine approach. Discussion will revolve around the application of these protozoan carbohydrate antigens for vaccines currently in preclinical development. PMID:28660174

Relationship between the entomologic inoculation rate and the force of infection for Plasmodium falciparum malaria.

PubMed

Smith, Thomas; Maire, Nicolas; Dietz, Klaus; Killeen, Gerry F; Vounatsou, Penelope; Molineaux, Louis; Tanner, Marcel

2006-08-01

We propose a stochastic model for the relationship between the entomologic inoculation rate (EIR) for Plasmodium falciparum malaria and the force of infection in endemic areas. The model incorporates effects of increased exposure to mosquito bites as a result of the growth in body surface area with the age of the host, naturally acquired pre-erythrocytic immunity, and the reduction in the proportion of entomologically assessed inoculations leading to infection, as the EIR increases. It is fitted to multiple datasets from field studies of the relationship between malaria infection and the EIR. We propose that this model can account for non-monotonic relationships between the age of the host and the parasite prevalence and incidence of disease. It provides a parsimonious explanation for the faster acquisition of natural immunity in adults than in children exposed to high EIRs. This forms one component of a new stochastic model for the entire transmission cycle of P. falciparum that we have derived to estimate the potential epidemiologic impact of malaria vaccines and other malaria control interventions.

Plasma membrane signaling in HIV-1 infection.

PubMed

Abbas, Wasim; Herbein, Georges

2014-04-01

Plasma membrane is a multifunctional structure that acts as the initial barrier against infection by intracellular pathogens. The productive HIV-1 infection depends upon the initial interaction of virus and host plasma membrane. Immune cells such as CD4+ T cells and macrophages contain essential cell surface receptors and molecules such as CD4, CXCR4, CCR5 and lipid raft components that facilitate HIV-1 entry. From plasma membrane HIV-1 activates signaling pathways that prepare the grounds for viral replication. Through viral proteins HIV-1 hijacks host plasma membrane receptors such as Fas, TNFRs and DR4/DR5, which results in immune evasion and apoptosis both in infected and uninfected bystander cells. These events are hallmark in HIV-1 pathogenesis that leads towards AIDS. The interplay between HIV-1 and plasma membrane signaling has much to offer in terms of viral fitness and pathogenicity, and a better understanding of this interplay may lead to development of new therapeutic approaches. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking. Copyright © 2013 Elsevier B.V. All rights reserved.

Interactome of E. piscicida and grouper liver proteins reveals strategies of bacterial infection and host immune response.

PubMed

Li, Hui; Zhu, Qing-Feng; Peng, Xuan-Xian; Peng, Bo

2017-01-03

The occurrence of infectious diseases is related to heterogeneous protein interactions between a host and a microbe. Therefore, elucidating the host-pathogen interplay is essential. We previously revealed the protein interactome between Edwardsiella piscicida and fish gill cells, and the present study identified the protein interactome between E. piscicida and E. drummondhayi liver cells. E. drummondhayi liver cells and bacterial pull-down approaches were used to identify E. piscicida outer membrane proteins that bind to liver cells and fish liver cell proteins that interact with bacterial cells, respectively. Eight bacterial proteins and 11 fish proteins were characterized. Heterogeneous protein-protein interactions between these bacterial cells and fish liver cells were investigated through far-Western blotting and co-immunoprecipitation. A network was constructed based on 42 heterogeneous protein-protein interactions between seven bacterial proteins and 10 fish proteins. A comparison of the new interactome with the previously reported interactome showed that four bacterial proteins overlapped, whereas all of the identified fish proteins were new, suggesting a difference between bacterial tricks for evading host immunity and the host strategy for combating bacterial infection. Furthermore, these bacterial proteins were found to regulate the expression of host innate immune-related proteins. These findings indicate that the interactome contributes to bacterial infection and host immunity.

The Dialogue of the Host-Parasite Relationship: Leishmania spp. and Trypanosoma cruzi Infection

PubMed Central

de Morais, Carlos Gustavo Vieira; Castro Lima, Ana Karina; dos Santos, Rosiane Freire; Da-Silva, Silvia Amaral Gonçalves; Dutra, Patrícia Maria Lourenço

2015-01-01

The intracellular protozoa Leishmania spp. and Trypanosoma cruzi and the causative agents of Leishmaniasis and Chagas disease, respectively, belong to the Trypanosomatidae family. Together, these two neglected tropical diseases affect approximately 25 million people worldwide. Whether the host can control the infection or develops disease depends on the complex interaction between parasite and host. Parasite surface and secreted molecules are involved in triggering specific signaling pathways essential for parasite entry and intracellular survival. The recognition of the parasite antigens by host immune cells generates a specific immune response. Leishmania spp. and T. cruzi have a multifaceted repertoire of strategies to evade or subvert the immune system by interfering with a range of signal transduction pathways in host cells, which causes the inhibition of the protective response and contributes to their persistence in the host. The current therapeutic strategies in leishmaniasis and trypanosomiasis are very limited. Efficacy is variable, toxicity is high, and the emergence of resistance is increasingly common. In this review, we discuss the molecular basis of the host-parasite interaction of Leishmania and Trypanosoma cruzi infection and their mechanisms of subverting the immune response and how this knowledge can be used as a tool for the development of new drugs. PMID:26090399

Disparate host immunity to Mycobacterium avium subsp. paratuberculosis antigens in calves inoculated with M. avium subsp. paratuberculosis, M. avium subsp. avium, M. kansasii and M. bovis

USDA-ARS?s Scientific Manuscript database

Cross-reactivity of mycobacterial antigens in immune-based diagnostic assays has been a major concern and criticism of current tests for the detection of paratuberculosis. In the present study, host immune responses to antigen preparations of Mycobacterium avium subsp. paratuberculosis (MAP), consis...

Heightened exposure to parasites favors the evolution of immunity in brood parasitic cowbirds

USGS Publications Warehouse

Hahn, Caldwell; Reisen, William K.

2011-01-01

Immunologists and evolutionary biologists are interested in how the immune system evolves to fit an ecological niche. We studied the relationship between exposure to parasites and strength of immunity by investigating the response of two species of New World cowbirds (genus Molothrus, Icteridae), obligate brood parasites with contrasting life history strategies, to experimental arboviral infection. The South American shiny cowbird (M. bonariensis) is an extreme host-generalist that lays its eggs in the nests of >225 different avian species. The Central American bronzed cowbird (M. aeneus) is a relative host-specialist that lays its eggs preferentially in the nests of approximately 12 orioles in a single sister genus. West Nile virus provided a strong challenge and delineated immune differences between these species. The extreme host-generalist shiny cowbird, like the North American host-generalist, the brown-headed cowbird, showed significantly lower viremia to three arboviruses than related icterid species that were not brood parasites. The bronzed cowbird showed intermediate viremia. These findings support the interpretation that repeated exposure to a high diversity of parasites favors the evolution of enhanced immunity in brood parasitic cowbirds and makes them useful models for future studies of innate immunity.

The Role of Plant Innate Immunity in the Legume-Rhizobium Symbiosis.

PubMed

Cao, Yangrong; Halane, Morgan K; Gassmann, Walter; Stacey, Gary

2017-04-28

A classic view of the evolution of mutualism is that it derives from a pathogenic relationship that attenuated over time to a situation in which both partners can benefit. If this is the case for rhizobia, then one might uncover features of the symbiosis that reflect this earlier pathogenic state. For example, as with plant pathogens, it is now generally assumed that rhizobia actively suppress the host immune response to allow infection and symbiosis establishment. Likewise, the host has retained mechanisms to control the nutrient supply to the symbionts and the number of nodules so that they do not become too burdensome. The open question is whether such events are strictly ancillary to the central symbiotic nodulation factor signaling pathway or are essential for rhizobial host infection. Subsequent to these early infection events, plant immune responses can also be induced inside nodules and likely play a role in, for example, nodule senescence. Thus, a balanced regulation of innate immunity is likely required throughout rhizobial infection, symbiotic establishment, and maintenance. In this review, we discuss the significance of plant immune responses in the regulation of symbiotic associations with rhizobia, as well as rhizobial evasion of the host immune system.

Dynamic intervention: pathogen disarmament of mitochondrial-based immune surveillance.

PubMed

Holland, Robin L; Blanke, Steven R

2014-11-12

In this issue of Cell Host & Microbe, Suzuki et al. (2014) describe a Vibrio cholerae Type-III-secreted effector that targets mitochondrial dynamics to dampen host innate immune signaling. This suggests that mammalian hosts possess surveillance mechanisms to monitor pathogen-mediated alterations in the integrity of normal cellular processes and organelles. Copyright © 2014 Elsevier Inc. All rights reserved.

Impact of Nosema ceranae and Nosema apis on individual worker bees of the two host species (Apis cerana and Apis mellifera) and regulation of host immune response.

PubMed

Sinpoo, Chainarong; Paxton, Robert J; Disayathanoowat, Terd; Krongdang, Sasiprapa; Chantawannakul, Panuwan

Nosema apis and Nosema ceranae are obligate intracellular microsporidian parasites infecting midgut epithelial cells of host adult honey bees, originally Apis mellifera and Apis cerana respectively. Each microsporidia cross-infects the other host and both microsporidia nowadays have a worldwide distribution. In this study, cross-infection experiments using both N. apis and N. ceranae in both A. mellifera and A. cerana were carried out to compare pathogen proliferation and impact on hosts, including host immune response. Infection by N. ceranae led to higher spore loads than by N. apis in both host species, and there was greater proliferation of microsporidia in A. mellifera compared to A. cerana. Both N. apis and N. ceranae were pathogenic in both host Apis species. N. ceranae induced subtly, though not significantly, higher mortality than N. apis in both host species, yet survival of A. cerana was no different to that of A. mellifera in response to N. apis or N. ceranae. Infections of both host species with N. apis and N. ceranae caused significant up-regulation of AMP genes and cellular mediated immune genes but did not greatly alter apoptosis-related gene expression. In this study, A. cerana enlisted a higher immune response and displayed lower loads of N. apis and N. ceranae spores than A. mellifera, suggesting it may be better able to defend itself against microsporidia infection. We caution against over-interpretation of our results, though, because differences between host and parasite species in survival were insignificant and because size differences between microsporidia species and between host Apis species may alternatively explain the differential proliferation of N. ceranae in A. mellifera. Copyright © 2017 Elsevier Ltd. All rights reserved.

Simplified CRISPR tools for efficient genome editing and streamlined protocols for their delivery into mammalian cells and mouse zygotes.

PubMed

Jacobi, Ashley M; Rettig, Garrett R; Turk, Rolf; Collingwood, Michael A; Zeiner, Sarah A; Quadros, Rolen M; Harms, Donald W; Bonthuis, Paul J; Gregg, Christopher; Ohtsuka, Masato; Gurumurthy, Channabasavaiah B; Behlke, Mark A

2017-05-15

Genome editing using the CRISPR/Cas9 system requires the presence of guide RNAs bound to the Cas9 endonuclease as a ribonucleoprotein (RNP) complex in cells, which cleaves the host cell genome at sites specified by the guide RNAs. New genetic material may be introduced during repair of the double-stranded break via homology dependent repair (HDR) if suitable DNA templates are delivered with the CRISPR components. Early methods used plasmid or viral vectors to make these components in the host cell, however newer approaches using recombinant Cas9 protein with synthetic guide RNAs introduced directly as an RNP complex into cells shows faster onset of action with fewer off-target effects. This approach also enables use of chemically modified synthetic guide RNAs that have improved nuclease stability and reduces the risk of triggering an innate immune response in the host cell. This article provides detailed methods for genome editing using the RNP approach with synthetic guide RNAs using lipofection or electroporation in mammalian cells or using microinjection in murine zygotes, with or without addition of a single-stranded HDR template DNA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts.

PubMed

Wu, Jia-Feng; Chang, Mei-Hwei

2015-10-20

Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.

Conservation of NLR-triggered immunity across plant lineages.

PubMed

Maekawa, Takaki; Kracher, Barbara; Vernaldi, Saskia; Ver Loren van Themaat, Emiel; Schulze-Lefert, Paul

2012-12-04

The nucleotide-binding domain and leucine-rich repeat (NLR) family of plant receptors detects pathogen-derived molecules, designated effectors, inside host cells and mediates innate immune responses to pathogenic invaders. Genetic evidence revealed species-specific coevolution of many NLRs with effectors from host-adapted pathogens, suggesting that the specificity of these NLRs is restricted to the host or closely related plant species. However, we report that an NLR immune receptor (MLA1) from monocotyledonous barley is fully functional in partially immunocompromised dicotyledonous Arabidopsis thaliana against the barley powdery mildew fungus, Blumeria graminis f. sp. hordei. This implies ~200 million years of evolutionary conservation of the underlying immune mechanism. A time-course RNA-seq analysis in transgenic Arabidopsis lines detected sustained expression of a large MLA1-dependent gene cluster. This cluster is greatly enriched in genes known to respond to the fungal cell wall-derived microbe-associated molecular pattern chitin. The MLA1-dependent sustained transcript accumulation could define a conserved function of the nuclear pool of MLA1 detected in barley and Arabidopsis. We also found that MLA1-triggered immunity was fully retained in mutant plants that are simultaneously depleted of ethylene, jasmonic acid, and salicylic acid signaling. This points to the existence of an evolutionarily conserved and phytohormone-independent MLA1-mediated resistance mechanism. This also suggests a conserved mechanism for internalization of B. graminis f. sp. hordei effectors into host cells of flowering plants. Furthermore, the deduced connectivity of the NLR to multiple branches of immune signaling pathways likely confers increased robustness against pathogen effector-mediated interception of host immune signaling and could have contributed to the evolutionary preservation of the immune mechanism.

Ultrastructure of the replication sites of positive-strand RNA viruses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harak, Christian; Lohmann, Volker, E-mail: volker_lohmann@med.uni-heidelberg.de

2015-05-15

Positive strand RNA viruses replicate in the cytoplasm of infected cells and induce intracellular membranous compartments harboring the sites of viral RNA synthesis. These replication factories are supposed to concentrate the components of the replicase and to shield replication intermediates from the host cell innate immune defense. Virus induced membrane alterations are often generated in coordination with host factors and can be grouped into different morphotypes. Recent advances in conventional and electron microscopy have contributed greatly to our understanding of their biogenesis, but still many questions remain how viral proteins capture membranes and subvert host factors for their need. Inmore » this review, we will discuss different representatives of positive strand RNA viruses and their ways of hijacking cellular membranes to establish replication complexes. We will further focus on host cell factors that are critically involved in formation of these membranes and how they contribute to viral replication. - Highlights: • Positive strand RNA viruses induce massive membrane alterations. • Despite the great diversity, replication complexes share many similarities. • Host factors play a pivotal role in replication complex biogenesis. • Use of the same host factors by several viruses hints to similar functions.« less

A Host Susceptibility Gene, DR1, Facilitates Influenza A Virus Replication by Suppressing Host Innate Immunity and Enhancing Viral RNA Replication

PubMed Central

Hsu, Shih-Feng; Su, Wen-Chi; Jeng, King-Song

2015-01-01

ABSTRACT Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV may facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNA interference (RNAi) screen. Knockdown (KD) of DR1 resulted in reductions of viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was a strong induction of interferon-stimulated gene (ISG) expression after prolonged DR1 KD. We found that beta interferon (IFN-β) was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISG expression, which led to a strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction, probably to prevent undesired cytokine production, but that this suppression may create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of viral RNA replication showed that DR1 KD suppressed viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may interact with individual components of the viral RdRp complex to enhance viral RNA replication. Thus, DR1 may be considered a novel host susceptibility gene for IAV replication via a dual mechanism, not only suppressing the host defense to indirectly favor IAV replication but also directly facilitating viral RNA replication. IMPORTANCE Investigations of virus-host interactions involved in influenza A virus (IAV) replication are important for understanding viral pathogenesis and host defenses, which may manipulate influenza virus infection or prevent the emergence of drug resistance caused by a high error rate during viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppressed the gene expression of a large set of host innate immunity genes, which indirectly facilitated IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity, likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, not only suppressing the host defense but also enhancing viral RNA replication. DR1 may be a potential target for drug development against influenza virus infection. PMID:25589657

Sequence diversity and evolution of antimicrobial peptides in invertebrates.

PubMed

Tassanakajon, Anchalee; Somboonwiwat, Kunlaya; Amparyup, Piti

2015-02-01

Antimicrobial peptides (AMPs) are evolutionarily ancient molecules that act as the key components in the invertebrate innate immunity against invading pathogens. Several AMPs have been identified and characterized in invertebrates, and found to display considerable diversity in their amino acid sequence, structure and biological activity. AMP genes appear to have rapidly evolved, which might have arisen from the co-evolutionary arms race between host and pathogens, and enabled organisms to survive in different microbial environments. Here, the sequence diversity of invertebrate AMPs (defensins, cecropins, crustins and anti-lipopolysaccharide factors) are presented to provide a better understanding of the evolution pattern of these peptides that play a major role in host defense mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Beyond mice and men: Environmental change, immunity and infections in wild ungulates

PubMed Central

Jolles, Anna E.; Beechler, Brianna R.; Dolan, Brian P.

2014-01-01

In the face of rapid environmental change, anticipating shifts in microparasite and macroparasite dynamics, including emergence events, is an enormous challenge. We argue that immunological studies in natural populations are pivotal to meeting this challenge: Many components of environmental change – shifts in biotic assemblages, altered climate patterns, and reduced environmental predictability – may affect host immunity. We suggest that wild ungulates can serve as model systems aiding the discovery of immunological mechanisms that link environmental change with parasite transmission dynamics. Our review of eco-immunological studies in wild ungulates reveals progress in understanding how co-infections affect immunity and parasite transmission; and how environmental and genetic factors interact to shape immunity. Changes in bioavailability of micronutrients have been linked to immunity and health in wild ungulates. Although physiological stress in response to environmental change has been assessed, downstream effects on immunity have not been studied. Moreover, the taxonomic range of ungulates studied is limited to bovids (bighorn sheep, Soay sheep, chamois, musk oxen, bison, African buffalo) and a few cervids (red deer, black-tailed deer). We discuss areas where future studies in ungulates could lead to significant contributions in understanding patterns of immunity and infection in natural populations and across species. PMID:25354672

The Skin Microbiome: Is It Affected by UV-induced Immune Suppression?

PubMed Central

Patra, VijayKumar; Byrne, Scott N.; Wolf, Peter

2016-01-01

Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation (UV-R) from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin’s microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs) that interfere with UV-induced immune suppression. PMID:27559331

Are fish immune systems really affected by parasites? an immunoecological study of common carp (Cyprinus carpio)

PubMed Central

2011-01-01

Background The basic function of the immune system is to protect an organism against infection in order to minimize the fitness costs of being infected. According to life-history theory, energy resources are in a trade-off between the costly demands of immunity and other physiological demands. Concerning fish, both physiology and immunity are influenced by seasonal changes (i.e. temporal variation) associated to the changes of abiotic factors (such as primarily water temperature) and interactions with pathogens and parasites. In this study, we investigated the potential associations between the physiology and immunocompetence of common carp (Cyprinus carpio) collected during five different periods of a given year. Our sampling included the periods with temporal variability and thus, it presented a different level in exposure to parasites. We analyzed which of two factors, seasonality or parasitism, had the strongest impact on changes in fish physiology and immunity. Results We found that seasonal changes play a key role in affecting the analyzed measurements of physiology, immunity and parasitism. The correlation analysis revealed the relationships between the measures of overall host physiology, immunity and parasite load when temporal variability effect was removed. When analyzing separately parasite groups with different life-strategies, we found that fish with a worse condition status were infected more by monogeneans, representing the most abundant parasite group. The high infection by cestodes seems to activate the phagocytes. A weak relationship was found between spleen size and abundance of trematodes when taking into account seasonal changes. Conclusions Even if no direct trade-off between the measures of host immunity and physiology was confirmed when taking into account the seasonality, it seems that seasonal variability affects host immunity and physiology through energy allocation in a trade-off between life important functions, especially reproduction and fish condition. Host immunity measures were not found to be in a trade-off with the investigated physiological traits or functions, but we confirmed the immunosuppressive role of 11-ketotestosterone on fish immunity measured by complement activity. We suggest that the different parasite life-strategies influence different aspects of host physiology and activate the different immunity pathways. PMID:21708010

Quantitative analysis of cellular proteome alterations in human influenza A virus-infected mammalian cell lines.

PubMed

Vester, Diana; Rapp, Erdmann; Gade, Dörte; Genzel, Yvonne; Reichl, Udo

2009-06-01

Over the last years virus-host cell interactions were investigated in numerous studies. Viral strategies for evasion of innate immune response, inhibition of cellular protein synthesis and permission of viral RNA and protein production were disclosed. With quantitative proteome technology, comprehensive studies concerning the impact of viruses on the cellular machinery of their host cells at protein level are possible. Therefore, 2-D DIGE and nanoHPLC-nanoESI-MS/MS analysis were used to qualitatively and quantitatively determine the dynamic cellular proteome responses of two mammalian cell lines to human influenza A virus infection. A cell line used for vaccine production (MDCK) was compared with a human lung carcinoma cell line (A549) as a reference model. Analyzing 2-D gels of the proteomes of uninfected and influenza-infected host cells, 16 quantitatively altered protein spots (at least +/-1.7-fold change in relative abundance, p<0.001) were identified for both cell lines. Most significant changes were found for keratins, major components of the cytoskeleton system, and for Mx proteins, interferon-induced key components of the host cell defense. Time series analysis of infection processes allowed the identification of further proteins that are described to be involved in protein synthesis, signal transduction and apoptosis events. Most likely, these proteins are required for supporting functions during influenza viral life cycle or host cell stress response. Quantitative proteome-wide profiling of virus infection can provide insights into complexity and dynamics of virus-host cell interactions and may accelerate antiviral research and support optimization of vaccine manufacturing processes.

Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection.

PubMed

Licona-Limón, Paula; Henao-Mejia, Jorge; Temann, Angela U; Gagliani, Nicola; Licona-Limón, Ileana; Ishigame, Harumichi; Hao, Liming; Herbert, De'broski R; Flavell, Richard A

2013-10-17

Type 2 inflammatory cytokines, including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, drive the characteristic features of immunity against parasitic worms and allergens. Whether IL-9 serves an essential role in the initiation of host-protective responses is controversial, and the importance of IL-9- versus IL-4-producing CD4⁺ effector T cells in type 2 immunity is incompletely defined. Herein, we generated IL-9-deficient and IL-9-fluorescent reporter mice that demonstrated an essential role for this cytokine in the early type 2 immunity against Nippostrongylus brasiliensis. Whereas T helper 9 (Th9) cells and type 2 innate lymphoid cells (ILC2s) were major sources of infection-induced IL-9 production, the adoptive transfer of Th9 cells, but not Th2 cells, caused rapid worm expulsion, marked basophilia, and increased mast cell numbers in Rag2-deficient hosts. Taken together, our data show a critical and nonredundant role for Th9 cells and IL-9 in host-protective type 2 immunity against parasitic worm infection. Copyright © 2013 Elsevier Inc. All rights reserved.

Human immunity against EBV—lessons from the clinic

PubMed Central

2017-01-01

The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell–mediated therapy to treat disorders associated with or induced by EBV infection. PMID:28108590

Natural history of chronic hepatitis B: phases in a complex relationship.

PubMed

Croagh, Catherine M N; Lubel, John S

2014-08-14

Chronic hepatitis B (CHB) is a condition of global prevalence and its sequelae include cirrhosis and hepatocellular carcinoma. The natural history of CHB is a complex interplay of virological, environmental and host factors. The dynamic relationship between the virus and host evolves over the duration of the infection and different phases of the disease have been observed and described. These have been conceptualized in terms of the state of balance between the host immune system and the hepatitis B virus and have been given the labels immune tolerant, immune clearance, immune control and immune escape although other nomenclature is also used. Host factors, such as age at infection, determine progression to chronicity. Virological factors including hepatitis B viral load, mutations and genotype also have an impact on the adverse outcomes of the infection, as do hepatotoxic cofactors such as alcohol. Our understanding of the natural history of CHB has evolved significantly over the past few decades and characterizing the phase of disease of CHB remains an integral part of managing this virus in the clinic.

KAPOSI’S SARCOMA–ASSOCIATED HERPESVIRUS IMMUNOEVASION AND TUMORIGENESIS: TWO SIDES OF THE SAME COIN?

PubMed Central

Moore, Patrick S.; Chang, Yuan

2013-01-01

Kaposi’s sarcoma–associated herpesvirus (KSHV) [or human herpesvirus 8 (HHV-8)] is the most frequent cause of malignancy among AIDS patients. KSHV and related herpesviruses have extensively pirated cellular cDNAs from the host genome, providing a unique opportunity to examine the range of viral mechanisms for controlling cell proliferation. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins target retinoblastoma protein and p53 control of tumor suppressor pathways, which also play key effector roles in intracellular immune responses. The immune evasion strategies employed by KSHV, by targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts. PMID:14527293

B cells in chronic obstructive pulmonary disease: moving to center stage

PubMed Central

Polverino, Francesca; Seys, Leen J. M.; Bracke, Ken R.

2016-01-01

Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD. PMID:27542809

The commensal microbiota and the development of human disease - an introduction.

PubMed

Marsh, Philip D

2015-01-01

Humans have co-evolved with microorganisms, and both exist in a symbiotic or mutualistic relationship. We are colonised by a diverse, resident microbiota, which develop into structurally and functionally organised biofilms. The resident microorganisms gain a secure, warm, nutritious habitat from the host and, in return, contribute to the development of many important host functions. The resident microbiota of each habitat is natural and provides important benefits for the host including immunological priming, down-regulation of excessive pro-inflammatory responses, regulation of gastrointestinal and cardiovascular systems, and prevention of colonisation by exogenous microbes. The biological properties of each habitat determine which microorganisms can colonise and grow, and dictate which will be major or minor components of the resident microbiota of a site. This results in different surfaces having distinct but characteristic microbiotas. This relationship between the resident microbiota and the host is dynamic and, on occasions, this symbiotic relationship breaks down due to, for example, changes in lifestyle, immune status or following broad spectrum antibiotic therapy. This 'dysbiosis' can result in previously minor components of the microbiota out-competing the normally dominant and beneficial bacteria, thereby increasing the risk of disease. Such perturbations have been associated with a number of clinical disorders such as obesity, allergy, and a variety of inflammatory diseases, including periodontal diseases. A better understanding of the delicate balance between the host and its resident microbiota could lead to novel approaches to the promotion of health and the prevention of dysbiosis.

The Influence of MHC and Immunoglobulins A and E on Host Resistance to Gastrointestinal Nematodes in Sheep

PubMed Central

Lee, C. Y.; Munyard, K. A.; Gregg, K.; Wetherall, J. D.; Stear, M. J.; Groth, D. M.

2011-01-01

Gastrointestinal nematode parasites in farmed animals are of particular importance due to their effects on production. In Australia, it is estimated that the direct and indirect effects of parasite infestation cost the animal production industries hundreds of millions of dollars each year. The main factors considered by immunologists when studying gastrointestinal nematode infections are the effects the host's response has on the parasite, which immunological components are responsible for these effects, genetic factors involved in controlling immunological responses, and the interactions between these forming an interconnecting multilevel relationship. In this paper, we describe the roles of immunoglobulins, in particular IgA and IgE, and the major histocompatibility complex in resistance to gastrointestinal parasites in sheep. We also draw evidence from other animal models to support the involvement of these immune components. Finally, we examine how IgA and IgE exert their influence and how methods may be developed to manage susceptible animals. PMID:21584228

Establishment of Chronic Infection: Brucella's Stealth Strategy

PubMed Central

Ahmed, Waqas; Zheng, Ke; Liu, Zheng-Fei

2016-01-01

Brucella is a facultative intracellular pathogen that causes zoonotic infection known as brucellosis which results in abortion and infertility in natural host. Humans, especially in low income countries, can acquire infection by direct contact with infected animal or by consumption of animal products and show high morbidity, severe economic losses and public health problems. However for survival, host cells develop complex immune mechanisms to defeat and battle against attacking pathogens and maintain a balance between host resistance and Brucella virulence. On the other hand as a successful intracellular pathogen, Brucella has evolved multiple strategies to evade immune response mechanisms to establish persistent infection and replication within host. In this review, we mainly summarize the “Stealth” strategies employed by Brucella to modulate innate and the adaptive immune systems, autophagy, apoptosis and possible role of small noncoding RNA in the establishment of chronic infection. The purpose of this review is to give an overview for recent understanding how this pathogen evades immune response mechanisms of host, which will facilitate to understanding the pathogenesis of brucellosis and the development of novel, more effective therapeutic approaches to treat brucellosis. PMID:27014640

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

PubMed Central

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

2014-01-01

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

Modulation of Specific and Allergy-Related Immune Responses by Helminths

PubMed Central

Daniłowicz-Luebert, Emilia; O'Regan, Noëlle L.; Steinfelder, Svenja; Hartmann, Susanne

2011-01-01

Helminths are master regulators of host immune responses utilising complex mechanisms to dampen host protective Th2-type responses and favour long-term persistence. Such evasion mechanisms ensure mutual survival of both the parasite and the host. In this paper, we present recent findings on the cells that are targeted by helminths and the molecules and mechanisms that are induced during infection. We discuss the impact of these factors on the host response as well as their effect in preventing the development of aberrant allergic inflammation. We also examine recent findings on helminth-derived molecules that can be used as tools to pinpoint the underlying mechanisms of immune regulation or to determine new anti-inflammatory therapeutics. PMID:22219659

Mechanism study of tumor-specific immune responses induced by laser immunotherapy

NASA Astrophysics Data System (ADS)

Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2011-03-01

Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans.

PubMed

Soltész, Beáta; Tóth, Beáta; Sarkadi, Adrien Katalin; Erdős, Melinda; Maródi, László

2015-01-01

The discovery of interleukin (IL)-17-mediated immunity has provided a robust framework upon which our current understanding of the mechanism involved in host defense against mucocutaneous candidiasis (CMC) has been built. Studies have shed light on how pattern recognition receptors expressed by innate immune cells recognize various components of Candida cell wall. Inborn errors of immunity affecting IL-17+ T cell differentiation have recently been defined, such as deficiencies of signal transducer and activator of transcription (STAT)3, STAT1, IL-12Rβ1 and IL-12p40, and caspase recruitment domain 9. Impaired receptor-ligand coupling was identified in patients with IL-17F and IL-17 receptor A (IL17RA) deficiency and autoimmune polyendocrine syndrome (APS) type 1. Mutation in the nuclear factor kappa B activator (ACT) 1 was described as a cause of impaired IL-17R-mediated signaling. CMC may be part of a complex clinical phenotype like in patients with deficiencies of STAT3, IL-12Rβ1/IL-12p40 and APS-1 or may be the only or dominant phenotypic manifestation of disease which is referred to as CMC disease. CMCD may result from deficiencies of STAT1, IL-17F, IL-17RA and ACT1. In this review we discuss how recent research on IL-17-mediated immunity shed light on host defense against mucocutaneous infection by Candida and how the discovery of various germ-line mutations and the characterization of associated clinical phenotypes have provided insights into the role of CD4+IL-17+ lymphocytes in the regulation of anticandidal defense of body surfaces.

Autoacetylation of the Ralstonia solanacearum effector PopP2 targets a lysine residue essential for RRS1-R-mediated immunity in Arabidopsis.

PubMed

Tasset, Céline; Bernoux, Maud; Jauneau, Alain; Pouzet, Cécile; Brière, Christian; Kieffer-Jacquinod, Sylvie; Rivas, Susana; Marco, Yves; Deslandes, Laurent

2010-11-18

Type III effector proteins from bacterial pathogens manipulate components of host immunity to suppress defence responses and promote pathogen development. In plants, host proteins targeted by some effectors called avirulence proteins are surveyed by plant disease resistance proteins referred to as "guards". The Ralstonia solanacearum effector protein PopP2 triggers immunity in Arabidopsis following its perception by the RRS1-R resistance protein. Here, we show that PopP2 interacts with RRS1-R in the nucleus of living plant cells. PopP2 belongs to the YopJ-like family of cysteine proteases, which share a conserved catalytic triad that includes a highly conserved cysteine residue. The catalytic cysteine mutant PopP2-C321A is impaired in its avirulence activity although it is still able to interact with RRS1-R. In addition, PopP2 prevents proteasomal degradation of RRS1-R, independent of the presence of an integral PopP2 catalytic core. A liquid chromatography/tandem mass spectrometry analysis showed that PopP2 displays acetyl-transferase activity leading to its autoacetylation on a particular lysine residue, which is well conserved among all members of the YopJ family. These data suggest that this lysine residue may correspond to a key binding site for acetyl-coenzyme A required for protein activity. Indeed, mutation of this lysine in PopP2 abolishes RRS1-R-mediated immunity. In agreement with the guard hypothesis, our results favour the idea that activation of the plant immune response by RRS1-R depends not only on the physical interaction between the two proteins but also on its perception of PopP2 enzymatic activity.

Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts.

PubMed

Daugherty, Matthew D; Young, Janet M; Kerns, Julie A; Malik, Harmit S

2014-01-01

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.