Innate immune recognition and response to Rift Valley fever virus

Rift Valley fever virus (RVFV) is widespread throughout the entire African continent and in some endemic areas over 50% of the population is exposed by adulthood. Antiviral responses induced by interferon (IFN) signaling can limit RVFV replication and inhibit RVFV pathogenesis in vivo. RVFV is known to infect mononuclear phagocytic cells (MPCs), hepatocytes, and neurons, consistent with its main clinical manifestations of acute febrile illness, hepatitis, or encephalitis. However, it is largely unknown how each of these cell types recognizes and responds to RVFV infection or how cell type specific innate immune responses modulate viral pathogenesis. The overall objective for this proposal is to determine how the mammalian host innate immune system recognizes and responds to RVFV infection and how this modulates viral pathogenesis. Our central hypothesis is that differential innate immune recognition and response by infected cells modulates viral pathogenesis. To test this hypothesis, we will 1) identify the innate immune sensors and effectors active in biologically relevant human primary cells, 2) define the contribution of key innate immune sensors and effectors in recognition and response to RVFV infection in vivo and 3) define the role of hematopoietic cell infection in RVFV pathogenesis in vivo. The results of this research will define the mechanisms of innate immune recognition and response following RVFV infection. Moreover, it will inform on cell type-specific responses to infection and how virally mediated antagonism of those responses contributes to viral pathogenesis.