Innate immune responses to Rift Valley fever virus in the brain

Abstract

Abstract Rift Valley Fever Virus (RVFV) is a category A biodefense pathogen due to the potential for intentional spread by aerosol and the lack of any licensed vaccine or antiviral therapeutics. Despite the brain being a major target of viral replication and tissue damage following aerosol infection, little is known about innate immune responses to RVFV in the brain. Thus, we are investigating the responses of resident innate immune cells of the brain to RVFV infection. Microglia and astrocytes mount a robust response to RVFV infection that is dependent upon MAVS and independent of TLR3 and TLR7. MAVS KO mice have significantly higher viral titers in the brain following intranasal infection, but surprisingly many markers of immune activity were similarly upregulated in the brains of WT and KO mice, including infiltration of CD45+ cells, upregulation of inflammatory genes, and cytokine expression. Indeed, many inflammatory and cytokine genes were upregulated more significantly in infected KO brains than in WT. This is in contrast to the in vitro response of microglia and astrocytes, where MAVS KO cells were virtually unresponsive to RVFV infection. RNA-seq analysis of infected brain tissue revealed that key signal transduction pathways are not activated in MAVS KO animals. These results are an important step towards understanding the precise molecular pathways responsible for controlling RVFV infection in the brain, and will be critical to informing the development of vaccines and antiviral therapeutics that are successful in preventing encephalitis caused by RVFV.