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Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium.

ABSTRACT: Natural killer (NK) cells are traditionally considered in the context of tumor surveillance and viral defense, but their role in bacterial infections, particularly those caused by enteric pathogens, is less clear. C57BL/6 mice were orally gavaged with Citrobacter rodentium, a murine pathogen related to human diarrheagenic Escherichia coli. We used polyclonal anti-asialo GM1 antibody to actively deplete NK cells in vivo. Bioluminescent imaging and direct counts were used to follow infection. Flow cytometry and immunofluorescence microscopy were used to analyze immune responses. During C. rodentium infection, NK cells were recruited to mucosal tissues, where they expressed a diversity of immune-modulatory factors. Depletion of NK cells led to higher bacterial loads but less severe colonic inflammation, associated with reduced immune cell recruitment and lower cytokine levels. NK cell-depleted mice also developed disseminated systemic infection, unlike control infected mice. NK cells were also cytotoxic to C. rodentium in vitro.

SUBMITTER: Hall LJ

PROVIDER: S-EPMC3553819 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium.

Hall Lindsay J LJ Murphy Carola T CT Hurley Grainne G Quinlan Aoife A Shanahan Fergus F Nally Kenneth K Melgar Silvia S

Infection and immunity 20121203 2

Natural killer (NK) cells are traditionally considered in the context of tumor surveillance and viral defense, but their role in bacterial infections, particularly those caused by enteric pathogens, is less clear. C57BL/6 mice were orally gavaged with Citrobacter rodentium, a murine pathogen related to human diarrheagenic Escherichia coli. We used polyclonal anti-asialo GM1 antibody to actively deplete NK cells in vivo. Bioluminescent imaging and direct counts were used to follow infection. Flow ...[more]

PMID: 23208605

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Project description:Mucosal immunity is critical to host protection from enteric pathogens and must be carefully controlled to prevent immunopathology. Regulation of immune responses can occur through a diverse range of mechanisms including bi-directional communication with the neurons. Among which include specialized sensory neurons that detect noxious stimuli due to the expression of transient receptor potential vanilloid receptor 1 (TRPV1) ion channel and have a significant role in the coordination of host-protective responses to enteric bacterial pathogens. Here we have used the mouse-adapted attaching and effacing pathogen Citrobacter rodentium to assess the specific role of the TRPV1 channel in coordinating the host response. TRPV1 knockout (TRPV1 -/- ) mice had a significantly higher C. rodentium burden in the distal colon and fecal pellets compared to wild-type (WT) mice. Increased bacterial burden was correlated with significantly increased colonic crypt hyperplasia and proliferating intestinal epithelial cells in TRPV1 -/- mice compared to WT. Despite the increased C. rodentium burden and histopathology, the recruitment of colonic T cells producing IFNγ, IL-17, or IL-22 was similar between TRPV1 -/- and WT mice. In evaluating the innate immune response, we identified that colonic neutrophil recruitment in C. rodentium infected TRPV1 -/- mice was significantly reduced compared to WT mice; however, this was independent of neutrophil development and maturation within the bone marrow compartment. TRPV1 -/- mice were found to have significantly decreased expression of the neutrophil-specific chemokine Cxcl6 and the adhesion molecules Icam1 in the distal colon compared to WT mice. Corroborating these findings, a significant reduction in ICAM-1 and VCAM-1, but not MAdCAM-1 protein on the surface of colonic blood endothelial cells from C. rodentium infected TRPV1 -/- mice compared to WT was observed. These findings demonstrate the critical role of TRPV1 in regulating the host protective responses to enteric bacterial pathogens, and mucosal immune responses.Author summaryNeuroimmune communications are vital in regulating the immune response to invading pathogens. Here, we show that during a gastrointestinal infection, pain-sensing neuronal fibers can modulate the immune response to recruit phagocytic neutrophils via upregulation of cell adhesion molecules on local blood endothelial cells. This research elucidates a novel impact of the pain-sensing ion channel, TRPV1, on host-pathogen interactions in the gastrointestinal tract as well as a potential methodology for modulating the immune response during enteric infections.

Dataset Information

Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium.

Publications

Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium.

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