Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease 2038

Description West Nile virus (WNV) can cause meningitis and encephalitis in humans and vertebrates, with about 1% of cases progressing to severe neuroinvasive disease. Though most infections are asymptomatic, risk factors for severe cases such as older age are known, but the role of immunological and genetic factors remains unclear. WNV-infected individuals often report gastrointestinal (GI) symptoms, yet the virus’s impact on the GI tract is understudied. Using human and mouse intestinal organoids and an in vivo mouse model, we investigated WNV infection in the GI tract and its effects on disease severity. WNV’s tropism was analyzed via immunofluorescence, while gut permeability was measured by tracking orally administered dextrans in the bloodstream. The role of gut microbes was also examined in a germ-free mouse model. Blocking type I interferon (IFN) responses increased WNV infection in the GI epithelial cells, leading to heightened gut and blood-brain barrier permeability, elevated cytokine levels, and worsened disease. This effect was microbiota-dependent and absent in germ-free mice. Moreover, severe WNV cases in humans had higher levels of auto-antibodies against IFN-α2 or IFN-ω, and serum samples from these individuals enhanced viral infection in organoids. Our findings highlight the microbiota’s role in driving pro-inflammatory signals that impact barrier permeability and suggest that auto-antibodies against type I IFN are associated with more severe WNV outcomes. Funding Sources The studies were supported by NIH grants R01AI073755 and R01DK122790 (awarded to M.S.D.), and K23AI057341 and R01AI091816 (awarded to K.O.M.). S-C.L. was supported by NIDDK RC2 grant GR0009021 003054 28480. F.R.Z. was supported by a Rheumatology Research Foundation Scientist Development Award.