Natural EBV infection in humans induces an expression profile similar to cytokine storm illnesses that is unique from other acute viral infections

Abstract Herpesvirus infections are common in humans, and while generally not lethal, lead to lifelong infection associated with cancer and autoimmune disease. To better understand immunity to persistent viral infection, we performed a prospective study in otherwise healthy college students of naturally acquired infection by the gamma herpesvirus, Epstein Barr virus (EBV). Transcriptome analysis defined a striking and reproducible profile during acute infection regardless of disease severity and included genes related to cell cycle, interferon response, and immune function. Even with the highly sensitive approach taken, however, no lasting gene changes were apparent during latent infection. Comparing the EBV response profile to multiple other acute viral infections revealed similarity only to Dengue virus. The signature shared by EBV and Dengue was also present in inflammatory syndrome patients. Interestingly, while EBV induced a type I interferon response, a subset of interferon induced genes, including MX1 and OAS1, were not upregulated, despite these genes being conventional contributors in a type I interferon response. Furthermore, IL1B was downregulated, together suggesting potential mechanisms of viral antagonism. These data provide an important first description of the response to natural herpesvirus infection in humans during multiple stages of infection.