Establishment of a novel endothelial target mouse model of a typhus group rickettsiosis: Evidence for critical roles for gamma interferon and CD8 T lymphocytes

A mouse model of typhus rickettsiosis that reproduces the hematogenous diss emination to the critical target organs, including brain, lungs, heart, and kidneys, primary endothelial and, to a lesser degree, macrophage intracell ular rickettsial infection, and typical vascular-based lesions of louse-bor ne typhus and murine typhus was established. Intravenous inoculation of C3H /HeN mice with Rickettsia typhi caused disease with a duration of the incub ation period and mortality rate that were dependent on the infective dose o f rickettsiae. Lethal infection was associated with high concentrations of R. typhi in the lungs and brain, despite a brisker humoral immune response to the rickettsiae than in the sublethal infection. Gamma interferon and CD 8 T lymphocytes were demonstrated to be crucial to clearance of the rickett siae and recovery from infection in experiments in which specific monoclona l antibodies were administered to deplete these components. Death of animal s depleted of gamma interferon or CD8 T lymphocytes was associated with ove rwhelming rickettsial infection demonstrated by titers of infectious ricket tsiae and by immunohistochemistry. An effective antirickettsial immune resp onse was associated with elevated serum concentrations of IL-12 on Day 5 an d increased secretion of IL-12 by concanavalin-A-stimulated spleen cells on Day 5. Evidence for transient suppression of the immune response consisted of marked reduction in the secretion of IL-2 and IL-12 by concanavalin-A-s timulated spleen cells on Days 10 and 15. This model offers excellent oppor tunities for study of attenuation and pathogenetic mechanisms of typhus ric kettsiae, which are established biologic weapons of potential use in bioter rorism.