Early expression of IFN-alpha/beta and iNOS in the brains of Venezuelan equine encephalitis virus-infected mice

To investigate the roles of type I interferon (IFN-alpha/beta) and other me diators of innate immune responses (e.g., inducible nitric oxide synthase [ iOS]) in early dissemination of Venezuelan equine encephalitis virus (VEE) infection, we used mice with targeted deletions in either their IFN-alpha/b eta-receptor (IFNAR-1(-/-)) or interferon regulatory factor 2 (IRF-2(-/-)) genes. Following footpad infection, both IFNAR-1(-/-) and IRF-2(-/-) mice w ere more susceptible than control mice to VEE. The IFNAR-1(-/-) mice also e xhibit accelerated VEE dissemination to serum, spleen, and brain, and compa red with control mice, they evidenced faster kinetics in the upregulation o f proinflammatory genes. In contrast, in IRF-2(-/-) mice, iNOS gene inducti on was completely absent following peripheral virulent VEE infection. In ev aluating the role of cells involved in iNOS production, primary microglial cell cultures were found to be highly permissive to VEE infection, Moreover , VEE infection increased levels of nitric oxide (NO) in resting microglial cultures but decreased NO production in IFN-gamma-stimulated microglia, Th us, these findings suggest that reactive nitrogen species play an important contributory role in VEE dissemination and survival of the host, Our resul ts further suggest the necessity for a carefully balanced host response tha t follows a middle course between immunopathology and insufficient inflamma tory response to VEE infection.