Peripheral macrophages are responsible for neuroinvasive Francisella tularensis eliciting neuroinflammatory disease 4295

Description Francisella tularensis, the causative agent of human tularemia, is transmitted by a variety of modalities, including aerosol and arthropod transmission, resulting in severe disease in the lungs and peripheral organs. However, a limited number of clinical cases of tularemia meningitis have been diagnosed since 1931, with no defined infection modality. Following intradermal infection on the rear flank, viable bacteria were identified in the brain parenchyma within 40 hours post inoculation. Analysis of the mechanism by which F. tularensis invades the brain identified the Trojan Horse usurpation of peripheral macrophages. In response to infection, macrophages phagocytose bacteria for destruction; F. tularensis, however, escapes the phagosome into the cytosol prior to fusion with the lysosome. Our data reveal that infected macrophages are trafficked into the brain parenchyma where it is the disseminated and infects other brain cells, including microglia, astrocytes and oligodendrocytes. Depletion of macrophages prevented transit of the blood brain barrier by F. tularensis ruling out paracellular and transcellular processes. Within the brain, immune cells respond to F. tularensis by production of pro-inflammatory cytokines leading to tularemia meningitis. This is the first documentation of F. tularensis invading immune cells and identification of its invasive modality. Funding Sources NIH SC1AI148753 Topic Categories Neuroimmunology (NEUR)