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PubMed2004

TccP is an enterohaemorrhagic Escherichia coli O157:H7 type III effector protein that couples Tir to the actin-cytoskeleton.

Subversion of host cell actin microfilaments is the hallmark of enterohaemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli infections. Both pathogens translocate the trans-membrane receptor protein-translocated intimin receptor (Tir), which links the extracellular bacterium to the cell cytoskeleton. While both converge on neural Wiskott-Aldrich syndrome protein (N-WASP), Tir-mediated actin accretion by EPEC and EHEC differ in that Tir(EPEC) requires both tyrosine phosphorylation and the host adaptor protein Nck, whereas Tir(EHEC) is not phosphorylated and utilizes an unidentified linker. Here we report the identification of Tir-cytoskeleton coupling protein (TccP), a novel EHEC effector that displays an Nck-like coupling activity following translocation into host cells. A tccP mutant did not affect Tir translocation and focusing but failed to recruit alpha-actinin, Arp3, N-WASP and actin to the site of bacterial adhesion. When expressed in EPEC, bacterial-derived TccP restored actin polymerization activity following infection of an Nck-deficient cell line. TccP has a similar biological activity on infected human intestinal explants ex vivo. Purified TccP activates N-WASP stimulating, in the presence of Arp2/3, actin polymerization in vitro. These results show that EHEC translocates both its own receptor (Tir) and an Nck-like protein (TccP) to facilitate actin polymerization.

Actins↗

PubMed2002

Innate immunity and its role against infections.

LEARNING OBJECTIVES: This article reviews current concepts of the innate immune system that offers protection against infections. It offers an overview for the readers to understand how innate immunity, consisting of different receptors, cells, and mediators recognizes pathogens and exerts protective function against pathogens. DATA SOURCES AND STUDY SELECTION: MEDLINE-search articles including original research papers, review articles, textbooks, and references identified from bibliographies of relevant articles. RESULTS AND CONCLUSIONS: The innate immune system is nonspecific immunity present since birth not requiring repeated exposure to pathogens. It is capable of differentiation between self and nonself. Because of its nonspecificity, it has a broad spectrum of resistance to infection. Further, it is thought to play an important role in the control of adaptive immunity by regulating co-stimulatory molecules and effector cytokines. Innate immunity includes pattern recognition molecules/receptors, antimicrobial peptides, the complement system, inflammatory mediators, and cytokines produced by immune cells. Pattern recognition molecules/receptors recognize pathogen-associated molecular patterns that are essential for microorganisms' survival and pathogenicity. Although innate immunity has recently gained increasing importance, further studies are necessary for a better understanding of its role.

Animals↗

PubMed1995

TCR gamma delta cells: a specialized T-cell subset in the immune system.

Specificity, memory, and self/nonself discrimination are the essential principles that underlie the acquired immune response. From birth through one's life, the immune system is continually responding to new environmental challenges (e.g. bacteria and viruses) and developing a specific, long-lasting immunity to those challenges. The first exposure to a pathogen results in the recruitment of multiple cell types, including macrophages, dendritic cells, and assorted leukocytes, that initiate an antigen nonspecific inflammatory response designed to attract T cells and B cells to the inflammatory sites including the draining lymph nodes. The foreign antigens are concentrated within the professional antigen-presenting cells (APCs) that process and present small antigenic peptides to CD4+ and CD8+ T cells in association with class II and class I major histocompatibility complex (MHC) molecules, respectively. The activated CD4+ T-cell receptor (TCR) alpha beta cells respond vigorously to the pathogen in an antigen-specific manner, liberating a barrage of cytokines that induce B cells to differentiate to antibody-secreting plasma cells and likewise cause CD8+ cells to differentiate into cytolytic effectors. The T cells and B cells expand in an evolving, highly specific manner to control the initial infection while developing long-term acquired immunity such that any further infection by that pathogen is virtually impossible. Thus TCR alpha beta T cells are the central lymphocyte in the immune system, providing specific pathogen recognition and long-term memory all within the context of distinguishing foreign from self antigens. Yet, during a primary immune response, there is a lag time of approximately 3 to 4 days before antigen-specific responses are evident, and TCR alpha beta responses do not peak until approximately day 7. Therefore, it is essential that other strategies are employed by the immune system in order to mount an aggressive early immune response.

Animals↗

PubMed2005

Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection.

Immunity to the opportunistic fungus Cryptococcus neoformans is dependent on cell-mediated immunity. Individuals with defects in cellular immunity, CD4(+) T cells in particular, are susceptible to infection with this pathogen. In host defense against a number of pathogens, CD8(+) T cell responses are dependent upon CD4(+) T cell help. The goal of these studies was to determine whether CD4(+) T cells are required for the generation of antifungal CD8(+) T cell effectors during pulmonary C. neoformans infection. Using a murine intratracheal infection model, our results demonstrated that CD4(+) T cells were not required for the expansion and trafficking of CD8(+) T cells to the site of infection. CD4(+) T cells were also not required for the generation of IFN-gamma-producing CD8(+) T cell effectors in the lungs. In CD4(-) mice, depletion of CD8(+) T cells resulted in increased intracellular infection of pulmonary macrophages by C. neoformans, increasing the pulmonary burden of the infection. Neutralization of IFN-gamma in CD4(-)CD8(+) mice similarly increased macrophage infection by C. neoformans, thereby blocking the protection provided by CD8(+) T cells. Altogether, these data support the hypothesis that effector CD8(+) T cell function is independent of CD4(+) T cells and that IFN-gamma production from CD8(+) T cells plays a role in controlling C. neoformans by limiting survival of C. neoformans within macrophages.

Animals↗

PubMed2006

Pseudomonas aeruginosa infection of airway epithelial cells modulates expression of Kruppel-like factors 2 and 6 via RsmA-mediated regulation of type III exoenzymes S and Y.

Pseudomonas aeruginosa is an important opportunistic pathogen which is capable of causing both acute and chronic infections in immunocompromised patients. Successful adaptation of the bacterium to its host environment relies on the ability of the organism to tightly regulate gene expression. RsmA, a small RNA-binding protein, controls the expression of a large number of virulence-related genes in P. aeruginosa, including those encoding the type III secretion system and associated effector proteins, with important consequences for epithelial cell morphology and cytotoxicity. In order to examine the influence of RsmA-regulated functions in the pathogen on gene expression in the host, we compared global expression profiles of airway epithelial cells in response to infection with P. aeruginosa PAO1 and an rsmA mutant. The RsmA-dependent response of host cells was characterized by significant changes in the global transcriptional pattern, including the increased expression of two Kruppel-like factors, KLF2 and KLF6. This increased expression was mediated by specific type III effector proteins. ExoS was required for the enhanced expression of KLF2, whereas both ExoS and ExoY were required for the enhanced expression of KLF6. Neither ExoT nor ExoU influenced the expression of the transcription factors. Additionally, the increased gene expression of KLF2 and KLF6 was associated with ExoS-mediated cytotoxicity. Therefore, this study identifies for the first time the human transcription factors KLF2 and KLF6 as targets of the P. aeruginosa type III exoenzymes S and Y, with potential importance in host cell death.

ADP Ribose Transferases↗

PubMed2005

Distribution of tccP in clinical enterohemorrhagic and enteropathogenic Escherichia coli isolates.

Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are diarrheagenic pathogens that colonize the gut through the formation of attaching and effacing lesions, which depend on the translocation of effector proteins via a locus of enterocyte effacement-encoded type III secretion system. Recently, two effector proteins, EspJ and TccP, which are encoded by adjacent genes on prophage CP-933U in EHEC O157:H7, have been identified. TccP consists of a unique N-terminus region and several proline-rich domains. In this project we determined the distribution of tccP in O157:H7, in non-O157 EHEC, and in typical and atypical EPEC isolates. All the EHEC O157:H7 strains tested were tccP(+). Unexpectedly, tccP was also found in non-O157 EHEC, and in typical and atypical EPEC isolates, particularly in strains belonging to serogroups O26 (EHEC), O119 (typical EPEC), and O55 (atypical EPEC). We recorded some variation in the length of tccP, which reflects diversity in the number of the proline-rich repeats. These results show the existence of a class of "attaching and effacing" pathogens which express a combination of EPEC and EHEC virulence determinants.

Animals↗

PubMed2005

Enteropathogenic Escherichia coli (EPEC) effector-mediated suppression of antimicrobial nitric oxide production in a small intestinal epithelial model system.

In vivo studies with the mouse-specific member of the attaching and effacing (A/E) family of pathogens raised the possibility that these non-invasive enteric pathogens can specifically inhibit inducible nitric oxide synthase (iNOS) expression to prevent the production of antimicrobial nitric oxide (NO). In this study we use polarized Caco-2 cells, a model of human small intestinal epithelia, to (i) demonstrate conclusively that an A/E member, human specific enteropathogenic Escherichia coli (EPEC), can inhibit cytokine-induced iNOS expression, (ii) show that this activity is dependent on the delivery of effector molecules into host cells and (iii) investigate the mechanism of inhibition. Analysis of the level of iNOS-related mRNA, protein and NO production demonstrated that EPEC can inhibit iNOS expression at the transcriptional, by direct and indirect mechanisms, and post-transcriptional levels. This transcriptional block was linked to the failure of the iNOS-related transcriptional factor NF-kappaB, but not STAT1, to undergo phosphorylation-associated activation. A selective pressure to prevent iNOS production was evidenced by the finding that iNOS activity had a potent antimicrobial effect on adherent but not non-adherent bacteria. Moreover, given the central role NF-kappaB plays in transcribing genes associated with early host immune responses, this inhibitory mechanism presumably represents an important role in pathogenesis. Our study also provides insights into the nature of NO production in response to bacterial infection as well as the role of the locus of enterocyte effacement (LEE)-encoded effector molecules in inhibiting iNOS expression.

Bacterial Adhesion↗

PubMed2004

Molecular profile of the T cell receptors of regulatory and effector CD4+ T cells recognizing overlapping determinants on glutamic acid decarboxylase (524-543).

Glutamic acid decarboxylase (GAD65) is one of the autoantigens that initiates pathogenic T cell responses against insulin-secreting pancreatic beta cells in Type 1 diabetes (T1D). Previously it was shown that spontaneously arising pathogenic T cell responses in the NOD mouse model are confined to GAD530-543 (p530). However, regulatory T cell subpopulations, which can prevent diabetes, can also be generated, for example, by immunization with GAD524-538 (p524) or GAD524-543. Interestingly, two functionally distinct subpopulations of T cells which recognize overlapping determinants of GAD524-543, p524 and p530, utilize distinct TCR Vbeta families, Vbeta4 for pathogenic, and Vbeta12 for regulatory T cells. We characterized T cell receptors (TCRs) from each subpopulation of T cells and visualized p524-specific TCR/p524/I-A(g7) and p530-specific TCR/p530/I-A(g7) complexes via molecular modeling to help us understand, at a molecular level, the in vivo expansion of p524- or p530-specific T cells in the NOD model of T1D. The absolute restriction in Vbeta usage but not Valpha usage and conserved CDR3beta lengths for both T cell subpopulations demonstrates that the beta chains are main contributors in shaping both p524/I-A(g7) and p530/I-A(g7) restricted TCRs. However, only Vbeta4+ T cells but not Vbeta12+ T cells contain a common motif (DWG) in CDR3beta and may involve all of CDR1beta, CDR2beta, and CDR3beta in the recognition of the C-terminus of p530. These observations imply that the spontaneously arising p530-restricted TCRs may be selected under stringent structural frameworks to bind p530/I-A(g7) with high affinity. Thus, the pathogenic p530-specific T cells may arise from a small pool of autoreactive T cells upon breaking tolerance.

Amino Acid Motifs↗

PubMed2006

Attaching and effacing pathogen-induced tight junction disruption in vivo.

Diarrhoea is a hallmark of infections by the human attaching and effacing (A/E) pathogens, enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). Although the mechanisms underlying diarrhoea induced by these pathogens remain unknown, cell culture results have suggested that these pathogens may target tight junctions. Tight junctions in the colon function as physical intercellular barriers that separate and prevent mixing of the luminal contents with adlumenal regions of the epithelium. Consequently, it is thought that the disruption of intestinal epithelial tight junctions by A/E pathogens could result in a loss of barrier function in the alimentary tract; however, this remains unexamined. Here we demonstrate for the first time that A/E pathogen infection results in the morphological alteration of tight junctions during natural disease. Tight junction alteration, characterized by relocalization of the transmembrane tight junction proteins claudin 1, 3 and 5, is a functional disruption; molecular tracers, which do not normally penetrate uninfected epithelia, pass across pathogen-infected epithelia. Functional junction disruption occurs with a concomitant increase in colon luminal water content. The effects on tissue are dependent upon the bacterial type III effector EspF (E. coli secreted protein F), because bacteria lacking EspF, while able to colonize, are defective for junction disruption and result in decreased proportions of water in the colon compared with wild-type infection. These results suggest that the diarrhoea induced by A/E pathogens occurs as part of functional tight junction disruption.

Animals↗

PubMed1991

Lymphocytes in the intestine: role and distribution.

Once a pathogen penetrates the surface epithelium, the process of immune activation begins. The pathogen is transported across the intestinal epithelium by M cells and presented to the underlying lymphocytes in Peyer's patches by MHCII positive enterocytes. At the same time, intraepithelial lymphocytes are activated and secrete interferon tau which increases the ability of enterocytes to present antigen. Simultaneously, intraepithelial lymphocytes may also cytolyse pathogens. In Peyer's patches, T-lymphocytes in parafollicular areas interact with antigen presenting cells and antigenic peptides to become activated. B-lymphocytes in follicular areas are also initially activated by the interaction of antigen and their surface Ig. B-lymphocyte activation is enhanced by helper T-lymphocytes so that B-lymphocytes begin to proliferate in germinal centres. Most B-lymphocytes at this stage are surface IgA positive whether induced by T-switch cells or by isotype specific T-lymphocytes. At the same time activated T-suppressor cells and contrasuppressors regulate the immune response to maintain it at an optim level. All these lymphocytes then leave Peyer's patches via blood vessels to mesenteric lymph nodes and the spleen where further cellular activation occurs. Thereafter, activated lymphocytes return to the intestine either directly or via the peripheral circulation. Those that reach the intestine directly, differentiate into effector cells and enter the lamina propria. In the lamina propria, plasma cells and cytotoxic T-lymphocytes destroy pathogens by secreting specific Ig and by cytotoxicity respectively. Activated helper T-lymphocytes in the lamina propria probably help in local responses by acting on the few resting B-lymphocytes present there. T-suppressor lymphocytes enter the epithelium to become intraepithelial lymphocytes and regulate responses by suppressor and contrasuppressor activities. Intraepithelial lymphocytes are also cytotoxic for luminal pathogens. Activated lymphocytes which do not return to the intestine directly enter the thoracic duct and thereby the general circulation. In this way a local gut response is converted into a systemic one and memory lymphocytes are disseminated throughout the body. In addition, suppressor and contrasuppressor T-lymphocytes also become available for peripheral effects. Large number of these lymphocytes remain in circulation, while others return to the intestine to provide local protection. A schematic representation of thetraffic of lymphocytes is shown in Fig. 3.

Cell Movement↗

PubMed2002

SHIV-KB9 infection of rhesus monkeys does not always cause disease-contribution of host immune factors and thymic output.

Simian-human immunodeficiency virus (SHIV) infection in the macaque is a model of HIV pathogenesis. KB9, a molecular clone of SHIV 89.6P, induced rapid and profound CD4(+) T cell loss in rhesus monkeys, followed by partial recovery in some. We describe another clinical outcome after intravenous SHIV-KB9 inoculation in two of six infected rhesus macaques: lack of signs of immunodeficiency with sustained CD4(+) T cell counts, despite virus load levels similar to those of the animals with CD4(+) lymphocyte decline. To dissect the role of host factors in determining pathogenicity of this viral clone, humoral and cellular immune responses were studied. Differences in CD8(+) T cell effector responses and activation profiles and in thymic output, but not in specific antibody production, were observed in animals with different disease outcomes during acute infection. Thymic involvement may thus be a critical factor in determining disease progression.

Animals↗

PubMed2006

Generation and maintenance of human memory cells during viral infection.

Long-term maintenance of memory T cell response is the hallmark of immune protection and hence the holy grail of most vaccine development studies. Persistent memory cells, developed after either viral infection or vaccination, ensure the generation of an antiviral response upon reexposure to the pathogen. During acute viral infections, as in the case of measles and influenza viruses, strong T cell effector functions, which eradicate the virus and protect patients against reexposure, are achieved by the generation of persistent protective memory cells. However, in chronic infections, T cells drastically lose effector functions before acquiring a memory phenotype. Chronic infections can be categorized into infections where viremia is controlled and protective memory cells are maintained as in the case of EBV and CMV infections, or where the virus persists and memory cells are exhausted and disrupted as in the case of human immunodeficiency virus infection. In this review, we will discuss the different phenotypical and functional characteristics of memory cells subsets, the importance of the role they play during acute and chronic infections, and the mechanisms behind their effectiveness and persistence.

Acute Disease↗

PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH-cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗

PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Here, Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗

PubMed2006

Structural correlates of antimicrobial efficacy in IL-8 and related human kinocidins.

Chemokines are small (8-12 kDa) effector proteins that potentiate leukocyte chemonavigation. Beyond this role, certain chemokines have direct antimicrobial activity against human pathogenic organisms; such molecules are termed kinocidins. The current investigation was designed to explore the structure-activity basis for direct microbicidal activity of kinocidins. Amino acid sequence and 3-dimensional analyses demonstrated these molecules to contain iterations of the conserved gamma-core motif found in broad classes of classical antimicrobial peptides. Representative CXC, CC and C cysteine-motif-group kinocidins were tested for antimicrobial activity versus human pathogenic bacteria and fungi. Results demonstrate that these molecules exert direct antimicrobial activity in vitro, including antibacterial activity of native IL-8 and MCP-1, and microbicidal activity of native IL-8. To define molecular determinants governing its antimicrobial activities, the IL-8 gamma-core (IL-8gamma) and alpha-helical (IL-8alpha) motifs were compared to native IL-8 for antimicrobial efficacy in vitro. Microbicidal activity recapitulating that of native IL-8 localized to the autonomous IL-8alpha motif in vitro, and demonstrated durable microbicidal activity in human blood and blood matrices ex vivo. These results offer new insights into the modular architecture, context-related deployment and function, and evolution of host defense molecules containing gamma-core motifs and microbicidal helices associated with antimicrobial activity.

Amino Acid Motifs↗

PubMed2006

Impaired allogeneic activation and T-helper 1 differentiation of human cord blood naive CD4 T cells.

CD4 T cells, particularly those of the T-helper 1 (Th1) subset, are important effectors in alloimmune diseases, such as graft-versus-host disease, and in controlling infections with intracellular pathogens. Thus, it is plausible that impaired neonatal CD4 T-cell immunity might contribute to the low incidence of acute graft-versus-host disease after allogeneic transplantation of hematopoietic stem cells using cord blood (CB) compared with adult sources of hematopoietic stem cells. In support of this hypothesis, we found that CB naive CD4 T cells had reduced activation and impaired early Th1 differentiation compared with adult peripheral blood naive CD4 T cells after stimulation by allogeneic dendritic cells derived from adult monocytes. Early Th1 polarization was dependent on interleukin-12 and CD154, and CB CD4 T cell/dendritic cell co-cultures had impaired expression of both proteins. CB naive CD4 T cells had low basal levels of signal transduction and activation of transcription 4 messenger RNA and protein, and, after alloantigen stimulation, reduced interleukin-12-induced signal transduction and activation of transcription 4 tyrosine phosphorylation, compared with adult peripheral blood naive T cells. Lastly, FoxP3 protein expression, a marker for regulatory CD25(high) CD4 T cells, was lower for naive CD4 T cells of CB compared with those of adult peripheral blood, which argued against increased T-regulatory activity as a mechanism for the decreased Th1 differentiation of CB CD4 T cells. Together, these intrinsic limitations in T-cell activation and Th1 differentiation may impair the ability of T cells in CB and the neonate to respond to allogeneic or infectious challenges.

Adult↗

PubMed2005

Invertebrates as animal models for Staphylococcus aureus pathogenesis: a window into host-pathogen interaction.

Recently, the use of invertebrate models of infection has given exciting insights into host-pathogen interaction for a number of bacteria. In particular, this has revealed important factors of the host response with remarkable parallels in higher organisms. Here, we review the advances attained in the elucidation of virulence determinants of a major human pathogen, Staphylococcus aureus, in relation to the invertebrate models thus far applied, the silkworm (Bombyx mori), the fruit fly (Drosophila melanogaster) and the roundworm (Caenorhabditis elegans). Also, the major pathways of host defence are covered in light of the response to S. aureus and the similarities and divergences in innate immunity of vertebrates and invertebrates. Consequently, we comparatively consider pathogen recognition receptors, signal transduction pathways (including Toll, Imd and others), and the humoral and cellular antimicrobial effectors. The technically convenient and ethically acceptable invertebrates appear as a valuable first tool to discriminate molecules participating from both sides of the host-S. aureus interaction as well as a high throughput method for antimicrobial screening.

Animals↗

PubMed2004

The antibody-catalyzed water oxidation pathway--a new chemical arm to immune defense?

Antibodies are the classical adaptor molecules of the immune system, linking recognition and killing of foreign pathogens. However, the recent discovery of a new property of the antibody molecule suggests a previously unexplored effector function of the immune system. All immunoglobulins, regardless of source or antigenic specificity, can catalyze the reaction between singlet (1Deltag) oxygen and water to give hydrogen peroxide (H(2)O(2)). Both the chemical and biological aspects of this pathway are being explored and intriguing new insights into how this pathway might have a role in immune defense are emerging.

Animals↗