The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Jurgen Heesemann - One of the best experts on this subject based on the ideXlab platform.
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Detection of N-(3-oxohexanoyl)-L-homoserine lactone in mice infected with Yersinia enterocolitica serotype O8.
Infection and immunity, 2003Co-Authors: Christoph A. Jacobi, Alexandra Bach, Leo Eberl, Anette Steidle, Jurgen HeesemannAbstract:Yersinia enterocolitica synthesizes N-acyl-L-homoserine lactone (AHL) signal molecules via the LuxR-LuxI homologues YenR-YenI. In this study we checked two prototypes of mouse-virulent Y. enterocolitica serotype O8 strains WA-314 and 8081 for AHL production in vitro and in vivo (mouse infection model). We used thin-layer chromatography in combination with the Escherichia coli AHL biosensor to identify the AHL species produced. We detected only OHHL [N-(3-oxohexanoyl)-L-homoserine lactone] and not HHL (N-hexanoyl-L-homoserine lactone) produced by Y. enterocolitica O8 in culture supernatant or infected mouse tissue. This is the first report demonstrating AHL production by Yersiniae during infection.
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Characterization of YopT effects on Rho GTPases in Yersinia enterocolitica-infected cells.
Journal of Biological Chemistry, 2003Co-Authors: Martin Aepfelbacher, Agnès Wiedemann, Konrad Trülzsch, Claudia Trasak, Gottfried Wilharm, Kristina Krauss, Peter Gierschik, Jurgen HeesemannAbstract:Pathogenic Yersiniae employ a type III secretion system for translocating up to six effector proteins (Yersinia outer proteins (Yops)) into eukaryotic target cells. YopT is a cysteine protease that was shown to remove the C-terminal isoprenoid group of RhoA, Rac, and CDC42Hs. Here we characterized the cell biological and biochemical activities of YopT in cells infected with pathogenic Yersinia enterocolitica. Bacterially injected YopT located to cell membranes from which it released RhoA but not Rac or CDC42Hs. In the infected cells RhoA was dissociated from guanine nucleotide dissociation inhibitor-1 (GDI-1) and accumulated as a monomeric protein in the cytosol, whereas Rac and CDC42Hs remained GDI-bound. Direct transfer of isoprenylated RhoA to YopT and RhoA modification could be reconstituted in vitro by guanosine 5'-3-O-(thio)triphosphate loading of a recombinant RhoA.GDI-1 complex. Finally, in macrophages infected with a Yersinia strain selectively translocating YopT podosomal adhesion structures required for chemotaxis as well as phagocytic cups mediating uptake of Yersiniae were disrupted. These findings indicate that bacterially translocated YopT acts on membrane-bound and GDI-complexed RhoA but not Rac or CDC42, and this is sufficient for disruption of macrophage immune functions.
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Yersinia V–Antigen Exploits Toll-like Receptor 2 and CD14 for Interleukin 10–mediated Immunosuppression
The Journal of experimental medicine, 2002Co-Authors: Andreas Sing, Andreas Roggenkamp, Dagmar Rost, Natalia Tvardovskaia, Agnès Wiedemann, Carsten J Kirschning, Martin Aepfelbacher, Jurgen HeesemannAbstract:A characteristic of the three human-pathogenic Yersinia spp. (the plague agent Yersinia pestis and the enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica) is the expression of the virulence (V)-antigen (LcrV). LcrV is a released protein which is involved in contact-induced secretion of Yersinia antihost proteins and in evasion of the host's innate immune response. Here we report that recombinant LcrV signals in a CD14- and toll-like receptor 2 (TLR2)-dependent fashion leading to immunosuppression by interleukin 10 induction. The impact of this immunosuppressive effect for Yersinia pathogenesis is underlined by the observation that TLR2-deficient mice are less susceptible to oral Y. enterocolitica infection than isogenic wild-type animals. In summary, these data demonstrate a new ligand specificity of TLR2, as LcrV is the first known secreted and nonlipidated virulence-associated protein of a Gram-negative bacterium using TLR2 for cell activation. We conclude that Yersiniae might exploit host innate pattern recognition molecules and defense mechanisms to evade the host immune response.
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Yersinia enterocolitica Evasion of the Host Innate Immune Response by V Antigen-Induced IL-10 Production of Macrophages Is Abrogated in IL-10-Deficient Mice
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Andreas Sing, Andreas Roggenkamp, Anna M. Geiger, Jurgen HeesemannAbstract:The virulence-associated V Ag (LcrV) of pathogenic Yersinia species is part of the translocation apparatus, required to deliver antihost effector proteins ( Yersinia outer proteins) into host cells. An orthologous protein (denoted as PcrV) has also been identified in the ExoS regulon of Pseudomonas aeruginosa . Additionally, it is known that LcrV is released by Yersiniae into the environment and that LcrV causes an immunosuppressive effect when injected into mice. In this study, we demonstrate for the first time that rLcrV, but not PcrV, is capable of suppressing TNF-α production in zymosan A-stimulated mouse macrophages and the human monocytic Mono-Mac-6 cell line. The underlying mechanism of TNF-α suppression could be assigned to LcrV-mediated IL (IL)-10 production, because 1) LcrV induces IL-10 release in macrophages, 2) anti-IL-10 Ab treatment completely abrogated TNF-α suppression, and 3) TNF-α suppression was absent in LcrV-treated macrophages of IL-10-deficient (IL-10 −/− ) mice. The relevance of LcrV-mediated immunosuppression for the pathogenicity of Yersiniae became evident by experimental infection of mice; in contrast to wild-type mice, IL-10 −/− mice were highly resistant against Yersinia infection, as shown by lower bacterial load in spleen and liver, absent abscess formation in these organs, and survival.
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Yersinia V-antigen exploits toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression.
Journal of Experimental Medicine, 2002Co-Authors: Andreas Sing, Andreas Roggenkamp, Dagmar Rost, Natalia Tvardovskaia, Agnès Wiedemann, Carsten J Kirschning, Martin Aepfelbacher, Jurgen HeesemannAbstract:A characteristic of the three human-pathogenic Yersinia spp. (the plague agent Yersinia pestis and the enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica) is the expression of the virulence (V)-antigen (LcrV). LcrV is a released protein which is involved in contact-induced secretion of Yersinia antihost proteins and in evasion of the host's innate immune response. Here we report that recombinant LcrV signals in a CD14- and toll-like receptor 2 (TLR2)-dependent fashion leading to immunosuppression by interleukin 10 induction. The impact of this immunosuppressive effect for Yersinia pathogenesis is underlined by the observation that TLR2-deficient mice are less susceptible to oral Y. enterocolitica infection than isogenic wild-type animals. In summary, these data demonstrate a new ligand specificity of TLR2, as LcrV is the first known secreted and nonlipidated virulence-associated protein of a Gram-negative bacterium using TLR2 for cell activation. We conclude that Yersiniae might exploit host innate pattern recognition molecules and defense mechanisms to evade the host immune response.
Guy R Cornelis - One of the best experts on this subject based on the ideXlab platform.
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Yersinia type iii secretion send in the effectors
Journal of Cell Biology, 2002Co-Authors: Guy R CornelisAbstract:Pathogenic Yersinia spp (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) have evolved an exquisite method for delivering powerful effectors into cells of the host immune system where they inhibit signaling cascades and block the cells' response to infection. Understanding the molecular mechanisms of this system has provided insight into the processes of phagocytosis and inflammation.
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identification of the yope and yoph domains required for secretion and internalization into the cytosol of macrophages using the cyaa gene fusion approach
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Mariepaule Sory, Anne Boland, Isabelle Lambermont, Guy R CornelisAbstract:Pathogenic Yersiniae secrete a set of antihost proteins, called Yops, by a type III secretion mechanism. Upon infection of cultured epithelial cells, extracellular Yersinia pseudotuberculosis and Yersinia enterocolitica translocate cytotoxin YopE across the host cell plasma membrane. Several lines of evidence suggest that tyrosine phosphatase YopH follows the same pathway. We analyzed internalization of YopE and YopH into murine PU5-1.8 macrophages by using recombinant Y. enterocolitica producing truncated YopE and YopH proteins fused to a calmodulin-dependent adenylate cyclase. The YopE-cyclase and YopH-cyclase hybrids were readily secreted by Y. enterocolitica. The N-terminal domain required for secretion was not longer than 15 residues of YopE and 17 residues of YopH. Internalization into eukaryotic cells, revealed by cAMP production, only required the N-terminal 50 amino acid residues of YopE and the N-terminal 71 amino acid residues of YopH. YopE and YopH are thus modular proteins composed of a secretion domain, a translocation domain, and an effector domain. Translocation of YopE and YopH across host cell's membranes was also dependent on the secretion of YopB and YopD by the same bacterium. The cyclase fusion approach could be readily extended to study the fate of other proteins secreted by invasive bacterial pathogens.
Olaf Schneewind - One of the best experts on this subject based on the ideXlab platform.
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Roles of LcrG and LcrV during Type III Targeting of Effector Yops by Yersinia enterocolitica
Journal of bacteriology, 2001Co-Authors: Kristin L. Debord, Vincent T. Lee, Olaf SchneewindAbstract:Yersinia enterocolitica target effector Yop proteins into the cytosol of eukaryotic cells by a mechanism requiring the type III machinery. LcrG and LcrV have been suggested to fulfill essential functions during the type III targeting of effector Yops. It is reported here that knockout mutations of lcrG caused mutant Yersiniae to prematurely secrete Yops into the extracellular medium without abolishing the type III targeting mechanism (Los phenotype [loss of type III targeting specificity]). Knockout mutations in lcrV reduced type III targeting of mutant Yersiniae but did not promote secretion into the extracellular medium (Not [no type III targeting]). However, knockout mutations in both genes caused ΔlcrGV Yersiniae to display a Los phenotype similar to that of strains carrying knockout mutations in lcrG alone. LcrG binding to LcrV resulted in the formation of soluble LcrGV complexes in the bacterial cytoplasm. Membrane-associated, bacterial-surface-displayed or -secreted LcrG could not be detected. Most of LcrV was located in the bacterial cytoplasm; however, small amounts were secreted into the extracellular medium. These data support a model whereby LcrG may act as a negative regulator of type III targeting in the bacterial cytoplasm, an activity that is modulated by LcrG binding to LcrV. No support could be gathered for the hypothesis whereby LcrG and LcrV may act as a bacterial surface receptor for host cells, allowing effector Yop translocation across the eukaryotic plasma membrane.
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LcrV, a Substrate for Yersinia enterocolitica Type III Secretion, Is Required for Toxin Targeting into the Cytosol of HeLa Cells
The Journal of biological chemistry, 2000Co-Authors: Vincent T. Lee, Christina C. Tam, Olaf SchneewindAbstract:Abstract Pathogenic Yersinia species employ type III machines to transport virulence factors across the bacterial envelope. Some substrates for the type III machinery are secreted into the extracellular medium, whereas others are targeted into the cytosol of host cells. We found that during infection of tissue culture cells, Yersiniae secrete small amounts of LcrV into the extracellular medium. Knockout mutations of lcrV abolish Yersiniatargeting and reduce expression of the lcrGVHyopBD operon. In contrast, a block in LcrV secretion does not affect targeting, but results in premature expression and secretion of Yop proteins into the extracellular medium. LcrV-mediated activation of the type III pathway is thought to occur by sequestration of the regulatory factor LcrG, presumably via the formation of LcrV·LcrG complexes. These results suggest that intrabacterial LcrV regulates the expression and targeting of Yop proteins during Yersinia infection, whereas secreted LcrV is required to ensure specificity of Yop injection into eukaryotic cells.
Ingo B Autenrieth - One of the best experts on this subject based on the ideXlab platform.
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Plasmacytoid dendritic cells are crucial in Bifidobacterium adolescentis-mediated inhibition of Yersinia enterocolitica infection.
PloS one, 2013Co-Authors: Alexandra Wittmann, Ingo B Autenrieth, Julia-stefanie FrickAbstract:In industrialized countries bacterial intestinal infections are commonly caused by enteropathogenic Enterobacteriaceae. The interaction of the microbiota with the host immune system determines the adequacy of an appropriate response against pathogens. In this study we addressed whether the probiotic Bifidobacterium adolescentis is protective during intestinal Yersinia enterocolitica infection. Female C57BL/6 mice were fed with B. adolescentis, infected with Yersinia enterocolitica, or B. adolescentis fed and subsequently infected with Yersinia enterocolitica. B. adolescentis fed and Yersinia infected mice were protected from Yersinia infection as indicated by a significantly reduced weight loss and splenic Yersinia load when compared to Yersinia infected mice. Moreover, protection from infection was associated with increased intestinal plasmacytoid dendritic cell and regulatory T-cell frequencies. Plasmacytoid dendritic cell function was investigated using depletion experiments by injecting B. adolescentis fed, Yersinia infected C57BL/6 mice with anti-mouse PDCA-1 antibody, to deplete plasmacytoid dendritic cells, or respective isotype control. The B. adolescentis-mediated protection from Yersinia dissemination to the spleen was abrogated after plasmacytoid dendritic cell depletion indicating a crucial function for pDC in control of intestinal Yersinia infection. We suggest that feeding of B. adolescentis modulates the intestinal immune system in terms of increased plasmacytoid dendritic cell and regulatory T-cell frequencies, which might account for the B. adolescentis-mediated protection from Yersinia enterocolitica infection.
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translocation of Yersinia enterocolitica across reconstituted intestinal epithelial monolayers is triggered by Yersinia invasin binding to β1 integrins apically expressed on m like cells
Cellular Microbiology, 2000Co-Authors: Ralf Schulte, Sophie Kerneis, Sigrid Klinke, Helmut Bartels, Sonja Preger, Jeanpierre Kraehenbuhl, Eric Pringault, Ingo B AutenriethAbstract:Yersinia enterocolitica cross the intestinal epithelium via translocation through M cells, which are located in the follicle-associated epithelium (FAE) of Peyer's patches (PP). To investigate the molecular basis of this process, studies were performed using a recently developed in vitro model, in which the enterocyte-like cell line Caco-2 and PP lymphocytes are co-cultured in order to establish FAE-like structures including M cells. Here, we demonstrate that Y. enterocolitica does not adhere significantly to the apical membrane of differentiated enterocyte-like Caco-2 cells that express binding sites for Ulex europaeus agglutinin (UEA)-1. In contrast, Y. enterocolitica adhered to, and was internalized by, cells that lacked UEA-1 binding sites and displayed a disorganized brush border. These cells were considered to be converted to M-like cells. Further analysis revealed that part of these cells expressed β1 integrins at their apical surface and, as revealed by comparison of wild-type and mutant strains, interacted with invasin of Y. enterocolitica. Consistently, anti-β1 integrin antibodies significantly inhibited internalization of inv-expressing Yersiniae. Experiments with Yersinia mutant strains deficient in YadA or Yop secretion revealed that these virulence factors play a minor role in this process. After internalization, Yersiniae were transported within LAMP-1-negative vacuoles to, and released at, the basal surface. Internalization and transport of Yersiniae was inhibited by cytochalasin D, suggesting that F-actin assembly is required for this process. These results provide direct evidence that expression of β1 integrins at the apical surface of M cells enables interaction with the invasin of Y. enterocolitica, and thereby initiates internalization and translocation of bacteria.
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Desferrioxamine-Promoted Virulence of Yersinia enterocolitica in Mice Depends on Both Desferrioxamine Type and Mouse Strain
The Journal of Infectious Diseases, 1994Co-Authors: Ingo B Autenrieth, Elisabeth Saken, Reinhard Berner, Ulrich Vogel, Rolf Reissbrodt, Wolfgang Rabsch, Jurgen HeesemannAbstract:The effects of desferrioxamine B (DFOB) and G (DFOG) on growth promotion and virulence of Yersinia enterocolitica as well as on T cell activation and proliferation were investigated. Both desferrioxamines promoted growth of Y. enterocolitica O:8 (WA-314) and O:3 (Y-108). DFOB had a greater immunosuppressive effect on T cells than did DFOG. These results suggest a dual role of DFOB in yersiniosis: growth promotion of the pathogen and immunosuppression of the host. The LD 50 of both Yersinia strains for mice was reduced by DFOB but not by DFOG. However, the LD 50 of Yersiniae was reduced by DFOB to a greater extent in Yersinia-resistant C57BL/6 than in Yersinia-susceptible BALB/c mice
James B Bliska - One of the best experts on this subject based on the ideXlab platform.
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yopj promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin 18 gamma interferon and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection
Infection and Immunity, 2010Co-Authors: Yue Zhang, James B BliskaAbstract:Several Yersinia species have been utilized as live attenuated vaccines to prime protective immunity against Yersiniae and other pathogens. A type III secretion system effector known as YopJ in Y. pseudotuberculosis and Y. pestis and YopP in Y. enterocolitica has been shown to regulate host immune responses to live Yersinia vaccines. YopJ/P kills macrophages and dendritic cells, reduces their production of tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12), and promotes systemic colonization in mouse models of intestinal Yersinia infection. Furthermore, YopP activity decreases antigen presentation by dendritic cells, and a yopP mutant of a live Y. enterocolitica carrier vaccine elicited effective priming of CD8 T cells to a heterologous antigen in mice. These results suggest that YopJ/P activity suppresses both innate and adaptive immune responses to live Yersinia vaccines. Here, a sublethal intragastric mouse infection model using wild-type and catalytically inactive yopJ mutant strains of Y. pseudotuberculosis was developed to further investigate how YopJ action impacts innate and adaptive immune responses to a live vaccine. Surprisingly, YopJ-promoted cytotoxicity and systemic colonization were associated with significant increases in neutrophils in spleens and the proinflammatory cytokines IL-18 and gamma interferon (IFN-γ) in serum samples of mice vaccinated with Y. pseudotuberculosis. Secretion of IL-18 accompanied YopJ-mediated killing of macrophages infected ex vivo with Y. pseudotuberculosis, suggesting a mechanism by which this effector directly increases proinflammatory cytokine levels in vivo. Mice vaccinated with the wild-type strain or the yopJ mutant produced similar levels of antibodies to Y. pseudotuberculosis antigens and were equally resistant to lethal intravenous challenge with Y. pestis. The findings indicate that a proinflammatory, rather than anti-inflammatory, process accompanies YopJ-promoted cytotoxicity, leading to increased systemic colonization by Y. pseudotuberculosis and potentially enhancing adaptive immunity to a live vaccine.
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turning Yersinia pathogenesis outside in subversion of macrophage function by intracellular Yersiniae
Clinical Immunology, 2005Co-Authors: Celine Pujol, James B BliskaAbstract:Three bacterial species within the genus Yersinia are causative agents of human disease. Yersinia pestis is transmitted by fleas or in aerosols, infects regional lymph nodes or lungs, and causes the highly lethal disease known as plague. Yersinia enterocolitica and Yersinia pseudotuberculosis are enteric pathogens most commonly associated with self-limiting infections of the mesenteric lymph nodes. Although Y. pestis and the enteropathogenic Yersinia species utilize different modes of transmission and cause different diseases, they rely on a common set of "core" virulence determinants to successfully infect a mammalian host. These virulence factors are encoded on the bacterial chromosome and on an approximately 70-kb plasmid. Once established in lymphoid tissue, all three Yersinia species replicate as aggregates of extracellular bacteria within necrotic lesions or abscesses. At this stage of the infectious process, the bacteria resist phagocytosis by neutrophils, which are able to destroy the bacteria if they are internalized. A type III secretion system encoded on the 70-kb plasmid functions to export multiple proteins (the Yops and LcrV) that are delivered to the extracellular milieu, the plasma membrane, or the cytosol of a host target cell. The Yops and LcrV act in concert to inhibit phagocytosis and downregulate inflammation. Although it is clear that the bulk of bacterial multiplication occurs in an extracellular phase, there is also evidence that all three pathogenic Yersinia survive and multiply in macrophages. Survival and replication of Yersinia in macrophages may occur throughout the infection, but is likely to be of greatest importance at early stages of colonization. That macrophages can serve as permissive sites for bacterial replication in vivo is supported by in vitro experiments, which demonstrate that Y. pestis, Y. peudotuberculosis, and Y. enterocolitica share the ability to survive and multiply in macrophage phagosomes. There is also evidence that the bacteria can subvert the functions of macrophages from within, by inhibiting phagosome acidification (Y. pseudotuberculosis) and the production of nitric oxide (Y. pestis and Y. pseudotuberculosis). Although considerable attention has been focused on how Yersinia subverts the functions of phagocytes from the outside, the study of how these bacteria subvert macrophage functions from the inside will lead to a better overall understanding of Yersinia pathogenesis.
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Role of macrophage apoptosis in the pathogenesis of Yersinia.
Current topics in microbiology and immunology, 2005Co-Authors: Yue Zhang, James B BliskaAbstract:Yersinia species that are pathogenic for humans (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) induce apoptosis in macrophages. Yersinia-induced apoptosis utilizes the mitochondrial pathway and is executed by activation of caspase cascades. The mechanism of Yersinia-induced apoptosis in macrophages has two essential components. One component is the innate immune response of macrophages to the pathogen, which leads to the activation of a survival response and a death response. Recognition of the bacterial cell envelope component lipopolysaccharide by Toll-like receptor 4 (TLR4) constitutes an important part of the innate immune response to the pathogen. The second essential component is YopJ, a protein secreted into Yersinia-infected macrophages via a bacterial type III secretion system, which selectively shuts down the survival pathway. In the absence of the survival pathway, the death pathway is executed, and Yersinia-infected macrophages undergo apoptosis. In this review, we introduce the basic features of Yersinia pathogenesis, summarize our current understanding of Yersinia-induced apoptosis, and discuss the role of apoptosis during Yersinia infection.