Determinants of flaviviral neuropathology

Abstract

In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection has brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune response are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of Stimulator of Interferon Genes (STING) and upstream sensor cGAS (cyclic GMP-AMP synthase) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING and cGAS both have roles in programming effective immune responses to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for cGAS and STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.