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1.
PLoS Pathog ; 14(2): e1006858, 2018 02.
Article in English | MEDLINE | ID: mdl-29390040

ABSTRACT

Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style.


Subject(s)
Bacterial Toxins/genetics , Gene Deletion , Inflammation/genetics , Virulence Factors/genetics , Yersinia pseudotuberculosis Infections/genetics , Yersinia pseudotuberculosis/genetics , Animals , Cecum/microbiology , Disease Progression , Female , Gastroenteritis/genetics , Gastroenteritis/microbiology , Gastrointestinal Diseases/genetics , Gastrointestinal Diseases/microbiology , Gastrointestinal Microbiome/physiology , Inflammation/microbiology , Mice , Mice, Inbred BALB C , Organisms, Genetically Modified , Yersinia pseudotuberculosis/pathogenicity , Yersinia pseudotuberculosis Infections/pathology
2.
J Infect Dis ; 216(6): 752-760, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28329174

ABSTRACT

Background: To successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated. Methods: Survival, bacterial dissemination, and intestinal and systemic pathology of wild-type and CCR7-/- mice were assessed and correlated to the presence of immune cell subsets and cytokine responses throughout the course of infection. Results: The CCR7-/- mice show a significantly higher morbidity and are more prone to pathogen dissemination and intestinal and systemic inflammation during the oral route of infection. Significant impact of CCR7 deficiency over the course of infection on several immunological parameters were observed (ie, elevated neutrophil-dominated innate immune response in Peyer's patches, limited dendritic cell migration to mesenteric lymph nodes [mLNs] causing reduced T cell-mediated adaptive immune responses (in particular Th17-like responses) in mLNs). Conclusions: Our work indicates that CCR7 is required to mount a robust immune response against enteropathogenic Y. pseudotuberculosis by promoting Th17-like responses in mLNs.


Subject(s)
Genetic Predisposition to Disease , Receptors, CCR7/immunology , Th17 Cells/immunology , Yersinia pseudotuberculosis Infections/immunology , Animals , Cell Movement , Dendritic Cells/immunology , Host-Pathogen Interactions/genetics , Intestines/immunology , Intestines/microbiology , Lymph Nodes/immunology , Lymph Nodes/microbiology , Mice , Myeloid Cells/immunology , Peyer's Patches/immunology , Peyer's Patches/microbiology , Receptors, CCR7/genetics , Yersinia pseudotuberculosis , Yersinia pseudotuberculosis Infections/genetics
3.
PLoS One ; 10(8): e0136290, 2015.
Article in English | MEDLINE | ID: mdl-26296209

ABSTRACT

Natural killer cells play a crucial role in the initial defense against bacterial pathogens. The crosstalk between host cells infected with intracellular pathogens and NK cells has been studied intensively, but not much attention has been given to characterize the role of NK cells in the response to extracellular bacterial pathogens such as yersiniae. In this study we used antibody-mediated NK cell depletion to address the importance of this immune cell type in controlling a Y. pseudotuberculosis infection. Analysis of the bacterial counts was used to follow the infection and flow cytometry was performed to characterize the composition and dynamic of immune cells. Depletion of NK cells led to higher bacterial loads within the mesenteric lymph nodes. We further show that in particular CD11b+ CD27+ NK cells which express higher levels of the activation marker CD69 increase within the mesenteric lymph nodes during a Y. pseudotuberculosis infection. Moreover, in response to the activation NK cells secrete higher levels of IFNy, which in turn triggers the production of the proinflammatory cytokine TNFα. These results suggest, that NK cells aid in the clearance of Y. pseudotuberculosis infections mainly by triggering the expression of proinflammatory cytokines manipulating the host immune response.


Subject(s)
Killer Cells, Natural/immunology , Lymph Nodes/immunology , Mesentery/immunology , Yersinia pseudotuberculosis Infections/immunology , Yersinia pseudotuberculosis/immunology , Animals , Antibodies/pharmacology , Antigens, CD/genetics , Antigens, CD/immunology , B-Lymphocytes/immunology , B-Lymphocytes/microbiology , B-Lymphocytes/pathology , Female , Gene Expression , Immunophenotyping , Interferon-gamma/genetics , Interferon-gamma/immunology , Interferon-gamma/metabolism , Killer Cells, Natural/drug effects , Killer Cells, Natural/microbiology , Killer Cells, Natural/pathology , Lymph Nodes/microbiology , Lymph Nodes/pathology , Lymphocyte Count , Lymphocyte Depletion , Macrophages/immunology , Macrophages/microbiology , Macrophages/pathology , Mesentery/microbiology , Mesentery/pathology , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Neutrophils/microbiology , Neutrophils/pathology , Spleen/immunology , Spleen/microbiology , Spleen/pathology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/microbiology , T-Lymphocytes, Cytotoxic/pathology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Yersinia pseudotuberculosis Infections/microbiology , Yersinia pseudotuberculosis Infections/pathology
4.
PLoS One ; 9(7): e103541, 2014.
Article in English | MEDLINE | ID: mdl-25075520

ABSTRACT

The two-component regulatory system PhoP/PhoQ has been shown to (i) control expression of virulence-associated traits, (ii) confer survival and growth within macrophages and (iii) play a role in Yersinia infections. However, the influence of PhoP on virulence varied greatly between different murine models of infection and its role in natural oral infections with frequently used representative isolates of Y. pseudotuberculosis was unknown. To address this issue, we constructed an isogenic set of phoP+ and phoP- variants of strain IP32953 and YPIII and analyzed the impact of PhoP using in vitro functionality experiments and a murine oral infection model, whereby we tested for bacterial dissemination and influence on the host immune response. Our results revealed that PhoP has a low impact on virulence, lymphatic and systemic organ colonization, and on immune response modulation by IP32953 and YPIII, indicating that PhoP is not absolutely essential for oral infections but may be involved in fine-tuning the outcome. Our work further revealed certain strain-specific differences in virulence properties, which do not strongly rely on the function of PhoP, but affect tissue colonization, dissemination and/or persistence of the bacteria. Highlighted intra-species variations may provide a potential means to rapidly adjust to environmental changes inside and outside of the host.


Subject(s)
Bacterial Proteins/metabolism , Mouth Diseases/pathology , Yersinia pseudotuberculosis/physiology , Yersinia pseudotuberculosis/pathogenicity , Adaptive Immunity , Animals , Bacterial Proteins/genetics , Cell Line , Cell Survival , Chemokines/blood , Cytokines/blood , Disease Models, Animal , Female , Immunity, Innate , Macrophages/cytology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mouth Diseases/immunology , Mouth Diseases/microbiology , Mutation , Spleen/cytology , Spleen/immunology , Virulence , Yersinia pseudotuberculosis/genetics , Yersinia pseudotuberculosis Infections/immunology , Yersinia pseudotuberculosis Infections/mortality , Yersinia pseudotuberculosis Infections/pathology
5.
RNA Biol ; 11(5): 580-93, 2014.
Article in English | MEDLINE | ID: mdl-24786463

ABSTRACT

In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrC(IP32953), which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs.


Subject(s)
Bacterial Proteins/metabolism , Gene Expression Regulation, Bacterial , RNA, Bacterial/genetics , RNA, Small Untranslated/genetics , Yersinia pseudotuberculosis/genetics , Yersinia pseudotuberculosis/metabolism , Bacterial Proteins/genetics , Models, Biological , Protein Binding , RNA Stability , RNA, Bacterial/metabolism , RNA, Small Untranslated/metabolism , Regulatory Sequences, Ribonucleic Acid , Transcription Factors/genetics , Transcription Initiation Site , Transcriptional Activation , Virulence/genetics , Yersinia pseudotuberculosis/pathogenicity , Yersinia pseudotuberculosis Infections/microbiology
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