Peripheral Francisella tularensis infection results in neural invasion and pathologic inflammation.

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Abstract Francisella tularensis infection triggers an overactive inflammatory response by stimulating production of host pro-inflammatory cytokines. Human tularemia, caused by F. tularensis, is a zoonotic disease transmitted by aerosol particles, direct contact, and via arthropod vectors, particularly ticks. Curiously, during peripheral inoculation in a mouse model of tularemia, F. tularensis was unexpectedly found in brain homogenates, though there is no prior evidence suggesting neural tropism. In the periphery, macrophages provide innate immune defense against foreign material, including bacteria. Microglial cells are resident macrophages of the brain and spinal cord and previously have been reported to rapidly respond to pathological changes in the central nervous system, serving a similar function as macrophages. Their rapid activation is an important factor in guarding the neural parenchyma against infectious diseases, inflammation, and neurodegeneration while maintaining and facilitating the return to tissue homeostasis. Therefore, we hypothesized that, having invaded the brain by an unknown mechanism, F. tularensis may be capable of eliciting an immune response following infection of microglial cells. Since macrophage infection leads to elicitation of inflammation, infection of microglia similarly stimulate inflammation leading to neural pathology. Mice were inoculated on the rear flank with fluorescently labeled bacteria. Using fluorescent confocal microscopy, labeled F. tularensis was localized in the brains of infected mice. We analyzed brain homogenates for production of inflammatory cytokines at these sites through Milliplex and qPCR.