Defining viral and human determinants of Dengue virus susceptibility

Dengue virus (DNV) is the world leading mosquito-borne virus and a WHO- priority. With 390 million annual infections, climate change risks infections of naïve populations and spillovers from their macaque natural reservoir. Yet no effective treatments are available. DNV infection causes asymptomatic to severe outcomes with 20% mortality. However, the viral and cellular determinants of dengue outcome remain poorly understood. Restriction factors are proteins that constitute the first line of antiviral defense with major roles in health and disease. In this award, I hypothesize that restriction factors are major determinants of dengue outcome and host range. My preliminary data revealed that 264 restriction factors execute DNV antiviral control in primary human immune cells. We will now 1) Investigate how these restriction factors control DNV replication using computational, virological, and biochemical assays, 2) Identify viral signatures of pathogenicity that enable restriction factor evasion, 3) Define genetic variants in restriction factors present in active cohorts of mild and severe dengue patients, and 4) Identify restriction factors that influence DNV host range using human and macaque ex vivo models. These results will lead to a significant shift in our understanding of DNV immunopathogenesis to inform biomarkers of severity, surveillance, and much needed therapeutics.