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Infect Immun. 2013 May;81(5):1751-63. doi: 10.1128/IAI.01409-12. Epub 2013 Mar 11.

Neutrophils mediate immunopathology and negatively regulate protective immune responses during fatal bacterial infection-induced toxic shock.

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  • 1Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

Ehrlichia chaffeensis is an obligate intracellular bacterium that infects primarily monocytes and macrophages and causes potentially fatal human monocytic ehrlichiosis (HME) that mimics toxic-shock-like syndrome in immunocompetent hosts. Early recruitment of neutrophils to the sites of infection is critical for the control of bacterial infection and inflammatory responses. We recently observed rapid and sustained neutrophil recruitment at a primary site of infection (peritoneum) following lethal murine ehrlichial infection compared to innocuous ehrlichial infection. We examined here the contribution of neutrophils to protective immunity or immunopathology during infection with monocytic Ehrlichia. Unexpectedly, depletion of neutrophils from lethally infected mice enhanced bacterial elimination, decreased immune-mediated pathology, and prolonged survival. Furthermore, compared to lethally infected sham controls, neutrophil depletion in infected mice resulted in amelioration of pathogenic responses, as evidenced by a decreased number of tumor necrosis factor alpha (TNF-α)-producing CD8(+) T cells, which is known to mediate immunopathology and toxic shock in a murine model of fatal ehrlichiosis. Although neutrophil depletion did not influence the number of CD4(+) Th1 cells and NKT cells producing gamma interferon (IFN-γ), it increased the ratio of IFN-γ- to IL-10-producing NKT cells as well as the ratio of IFN-γ to interleukin 10 (IL-10) transcripts in the liver. This may ameliorate the net suppressive effect of IL-10 on IFN-γ-mediated activation of infected macrophages and thus may account for the enhanced bacterial elimination. Finally, transcriptional analysis of gene expression in the liver indicated that neutrophils contribute to overproduction of cytokines and chemokines during fatal ehrlichiosis. In conclusion, these results revealed an unexpected role of neutrophils in supporting bacterial replication indirectly and promoting immunopathology during severe infection with an intracellular bacterium.

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