Mucosal delivery of interferon-? Alters the local cytokine environment to inhibit hyperinflammation and boost immunity to HSV-2 infection 3012

Abstract Description Proper regulation of inflammatory immune responses to viral infections is critical to the survival of a host. Type III interferons (IFN-λ) are cytokines known for their ability to inhibit viral replication and are an effective therapeutic intervention for viral infections. However, its mechanism of action is poorly defined and, until recently, believed to be independent of an ability to regulate immune responses. In this study, we explore whether IFN-λ can directly inhibit development of immunopathological events to protect against severe viral infections. To model the role of ΙFN-λ during mucosal viral infection, we infect mice intravaginally with HSV-2. We demonstrate that intravaginal administration of IFN-λ alters the cytokine milieu to promote the development of long-lived protective immune responses that limit neurodissemination and reduce mortality following HSV-2 infection. Furthermore, we find that IFN-λ treatment reduced the severity of immune-driven vaginal tissue pathology and can directly regulate the drivers of cytokine-driven hyperinflammation. Overall, we find that type III IFNs drive immune responses that prevent the dissemination of the HSV-2 virus. Simulataneously, we find that type III IFNs play an active role in inhibiting hyperinflammation. Our findings ultimately contribute to a better understanding of the multifaceted role of type III interferons during viral infection and their potential as a therapeutic intervention. Funding Sources Supported by the Canadian Institute of Health Research (CIHR) Canadian Graduate Scholarship Doctoral Award, and a CIHR Project Grant. Topic Categories Viral Immunology (VIR)