The protective role of macrophages in Francisella tularensis infection (MPF3P.819)

Abstract

Abstract Francisella tularensis causes lethal pneumonia following infection of the lungs. F. tularensis is considered to be an intracellular pathogen that targets macrophages for replication. We therefore hypothesized that depletion of alveolar macrophages would impede bacterial replication and improve host survival. However, it was found that macrophages are essential for survival of F. tularensis infection and depletion of these cells reduced survival rates following infection. Mice with a macrophage-specific defect in interferon gamma (IFN-γ) signaling (MIIG mice) were also highly sensitive to infection, exhibiting reduced survival rates, reduced mean time to death, and increased bacterial burdens in lungs, liver, and spleen relative to wild-type mice. We have previously found that treatment with exogenous interleukin 12 (IL-12) protects against F. tularensis infection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render mice highly sensitive to pneumonic F. tularensis infection. Furthermore, IL-12-mediated protection required NADPH activity. These results indicate that lung macrophages serve a critical protective role in pneumonic F. tularensis infection. Macrophages require IFN-γ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.