PROJECT SUMMARY The goal of this grant is to understand how bystander infections alter chronic infection with γ- herpesviruses. This is important because herpesviruses infect virtually all people and persist for the life of the host. This means that herpesvirus infection is potentially altered by exposure to bystander infections. Even though herpesvirus infections are chronic, these viruses do not persistently replicate in a healthy host. Instead, they establish a quiescent infection, termed latency. This latent infection with herpesviruses is tightly controlled by the host immune system, and changes in the immune system modulate the state of herpesvirus infection, leading to virus reactivation from latency. We found that co-infection with an intestinal helminth parasite induced γ-herpesvirus reactivation. We identified the host cytokines, interleukin (IL)-4 and IL-13 that are produced during helminth infection to be critical for γ-herpesvirus reactivation. We also identified a viral promoter that is directly regulated by IL-4/IL-13 signaling. However, the mechanisms for helminth-mediated herpesvirus reactivation in vivo are still incompletely understood. We will leverage our unique experimental systems of herpesvirus-helminth co-infection to explore these mechanisms in the mouse. We hypothesize that parasite infection has multiple effects of γ-herpesvirus infection that are dependent on the timing or order of the dual infections. We propose to further detail the requirements for IL-4/IL-13 signaling in herpesvirus- helminth co-infection, and to define the contribution of infection timing to the phenotypes observed. This proposal will increase our understanding of host regulation of herpesvirus latency and the role bystander infections play in herpesvirus infection. This is critical to understanding how these viruses drive pathologies and alter the host immune system.