Development of a Murine Model of Severe Scrub Typhus And Its Use to Elucidate the Immune Response to and The Pathology that Occurs during Orientia Tsutsugamushi Infection.
Shelite, Thomas R
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Scrub typhus is an often lethal infection that threatens one billion persons globally and causes illness in one million people annually. There is no vaccine for scrub typhus, and the mechanisms of protective immunity are poorly understood. Scrub typhus is a disseminated infection of endothelial cells by the obligately intracellular bacterium Orientia tsutsugamushi. Mechanistic studies of immunity have been performed primarily in intraperitoneally inoculated mice in which Orientia is largely confined to the peritoneal cavity rather than causing disseminated endothelial infection and multifocal vasculitis that occur in scrub typhus in humans. There is a critical need for a valid endothelial-target mouse model of scrub typhus to enable determination of the mechanisms of protective immunity against Orientia. The first objective was to develop a disease model that demonstrates pathology and cellular tropism similar to those of human disease. Development of this model allows for investigation of the immunological mechanisms that mediate protective immunity in scrub typhus infections. C57BL/6 (B6) mice were determined to be susceptible to intravenous challenge by Orientia with overt signs of illness with a dose-dependent time of onset. Immunohistochemical staining of Orientia antigens demonstrated extensive endothelial infection, most notably in the brain and lungs. The histopathology revealed cerebral perivascular lymphohistiocytic infiltrates, focal hemorrhage, meningoencephalitis, and interstitial pneumonia, resembling that of human scrub typhus. The second objective was to address the role of neutrophils in scrub typhus. All scrub typhus case studies that report blood cell counts, describe neutrophilia during the course of infection and observed in our model, suggesting key a role in scrub typhus. To determine the role of neutrophils in this infection, mice were lethally challenged, and neutrophils were depleted one day prior to and six days post infection. Early depletion resulted in more severe pathology with earlier onset and disease progression similar to non-depleted animals but with increased survival. Animals depleted at 6 dpi recovered weight and had less severe signs of illness. Signs of illness had resolved by 12 dpi. These data suggest a dual role of neutrophils in bacterial clearance and tissue pathology during scrub typhus infection.