MAVS mediates a protective immune response in the brain to Rift Valley fever virus

Abstract

Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiated robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo, Mavs-/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified defects in type I interferon and interferon responsive gene expression within microglia in Mavs-/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis.

MAVS signaling is required for clearance of chikungunya heart infection and prevention of chronic inflammation in vascular tissue

“…Intriguingly, we found that in Mavs -/- mice, infected hearts display similar levels of Isg15 compared to WT, suggesting that other pathways may also contribute to IFN-I response in cardiac tissue. This has been observed for Rift Valley fever virus-infected brains, in which no differences in the global induction of the IFN-I signaling between Mavs -/- and WT were observed by bulk RNA-seq (Hum et al, 2022). However, differences in the IFN-I signaling have been observed by single-cell RNA seq (Hum et al, 2022), suggesting heterogeneity in the viral RNA sensing and activation of downstream pathways between different cell types.…”

Lrp1 is essential for lethal Rift Valley fever hepatic disease in mice

“…Given the stark differences in survival between the genotypes after footpad infection, we infected a cohort of mice intranasally with 20 PFUs of RVFV. Infection through the intranasal route is thought to facilitate direct brain infection ( 25 , 26 ). Resulting data revealed that there were no differences in survival between Lrp f/f and Lrp1 f/f Alb-Cre mice ( P = 0.92) following intranasal infection (fig.…”

Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice

“…Moreover, early activation of IFNAR signaling in the glomerular layer of the olfactory bulb seems to be critical for the control of viral replication [ 38 ]. The IFN-I response and cytokine expression of RVFV-infected microglia are largely dependent on RIG-I-like receptors (RLR) signaling via mitochondrial antiviral-signaling protein (MAVS), whereas RNA sensing by toll-like receptors (TLRs) only plays a minor role [ 56 ]. MAVS −/− mice intranasally infected with 5x10 5 PFU of the RVFV MP12 vaccine strain showed high levels of viral RNA inside the brain, which was associated with increased T and NK cell infiltration but an impaired T cell activation [ 56 ].…”

“…The IFN-I response and cytokine expression of RVFV-infected microglia are largely dependent on RIG-I-like receptors (RLR) signaling via mitochondrial antiviral-signaling protein (MAVS), whereas RNA sensing by toll-like receptors (TLRs) only plays a minor role [ 56 ]. MAVS −/− mice intranasally infected with 5x10 5 PFU of the RVFV MP12 vaccine strain showed high levels of viral RNA inside the brain, which was associated with increased T and NK cell infiltration but an impaired T cell activation [ 56 ]. Functional NK cells, macrophages and lymphocytes seem to be essential for RVFV clearance [ 37 ].…”