The role of innate immune regulation in viral pathogenesis and the development of anti-viral T cell memory (360G-Wellcome-207503_Z_17_Z)

Immune mechanisms that regulate antiviral immune responses determine whether the host can control pathogen replication and virus-induced immunopathology. The pathogenic human cytomegalovirus (HCMV) establishes chronicity and induces inflammation-associated pathologies. Cytomegalovirus (CMV) also induces the largest known expansion of T cells, and thus represents an important tool for identifying mechanisms inducing robust T cell immunity. CMV may also be exploited as an attenuated vaccine vector. Using a CMV model of viral pathogenesis, I identified that immune regulation during initial infection determines the extent of virus-induced inflammation and development of long- lived virus-specific immunity. The key goals of this proposal are: - Identify innate immune components that mediate viral pathogenesis and understand how they are controlled - Test whether innate immune pathways can be a) safely targeted therapeutically to treat viral disease and/or b) used to predict genetic risk of CMV pathogenesis - Identify the early immunological events that promote CMV-specific T cell memory development, and elucidate whether regulatory pathways controlling these factors can be harnessed to enhance virus-driven memory T cell formation induced by attenuated viral vectors This research will determine whether innate immune activation can be exploited to: 1) safely treat viral pathogenesis and/or 2) enhance virus-induced T cell memory responses.