Dengue Host–Virus Co-genomics: Genetic Interactions that Drive Disease Severity (360G-Wellcome-338487_Z_25_Z)

Dengue virus (DENV) is a major, expanding global health threat, yet the factors determining progression to severe dengue (SD) remain poorly understood. Current immunological models are incomplete, and while both host and viral genetics are known to influence outcomes, they have been critically understudied and investigated in isolation. This programme hypothesises that heterogeneity in dengue outcomes is driven by host-virus genetic interactions that modulate viral replication, immune, and endothelial responses. To test this, we will pioneer a Host-Virus Co-Genomics framework, establishing the largest resource of ~5,000 paired host and viral genomes from a deeply- phenotyped Vietnamese clinical cohort. Using this unique dataset, we will first identify separate host (host-GWAS) and viral (viral-GWAS) genetic factors associated with disease phenotypes across all four serotypes. We will then build on this to test our central hypothesis: defining how host genomic pressures drive DENV evolution and, crucially, identifying the specific host- virus genetic combinations that jointly determine disease outcomes. Finally, we will translate these population-level genetic interactions into cellular mechanisms of pathogenesis using single-cell transcriptomics on a prospectively recruited case-control cohort. This research will link host–virus genetic interactions to endothelial and immune dysfunction, define biomarkers that predict severe disease, and nominate tractable pathways for intervention.