Gamma Herpesvirus manipulates HVEM regulated IL-1β pathway to evade immune responses

Abstract

Abstract The herpes virus entry mediator (HVEM) a member of the TNFR superfamily, is a key immunoregulator with both proinflammatory and inhibitory signaling functions. Both α and β-herpes viruses exploit HVEM to establish persistent infections, however little is known about whether the oncogenic γ-herpesviruses modulate HVEM. Here, we investigate the role of HVEM in a mouse model of γ-herpesvirus (MHV68) infection. Control C57BL/6 and HVEM-deficient (Tnfrsf14−/−) mice were intranasally infected with MHV68. We found that virus replication in the lungs of Tnfrsf14−/− mice increased significantly indicating HVEM expression is required to control MHV68 infection. We found that alveolar macrophages were drastically reduced in Tnfrsf14−/− mice compared to C57/BL6 controls suggesting their survival requires HVEM signaling. Importantly, we showed that IL-1β levels in the lungs of MHV68 infected Tnfrsf14−/−mice were significantly higher than C57BL/6 controls. Bone marrow-derived macrophage from Tnfrsf14−/− showed that HVEM is necessary to prevent IL-1β production in response to inflammasome activator. Antibodies that block IL-1R or IL-1β drastically increased the viral load in the lungs suggested that IL-1β is necessary to control viral replication. Taken together, our results highlight the role for HVEM in innate immune response evasion of MHV68 that could involve the inflammasome.