Shiftless inhibits flavivirus replication in vitro and is neuroprotective in a mouse model of Zika virus pathogenesis
Natasha W. Hanners, Katrina B. Mar, Ian N. Boys, Jennifer L. Eitson, Pamela C. De La Cruz-Rivera, R. Blake Richardson, Wenchun Fan, Mary Wight‐Carter, John W. Schoggins
Abstract
Significance Flaviviruses are significant human pathogens and emerging infectious disease threats. A screen of interferon-inducible genes revealed Shiftless (SHFL) as a potent antiviral effector, inhibiting all Flaviviridae tested, including West Nile, Zika, dengue, yellow fever, and hepatitis C viruses. Mechanistic studies showed that SHFL inhibits viral replication at a point after translation of the incoming genome. In whole-body Shfl knockout (KO) mice, compared to wild-type mice, the Shfl KO mice were more susceptible to Zika virus. Notably, Shfl was uniquely required for controlling replication in the brain and spinal cord, demonstrating an unappreciated neuroprotective role for this effector in vivo. SHFL is a key antiviral effector that specifically inhibits flavivirus genome replication, and Shfl protects mice from Zika virus–induced neuropathogenesis.