Host determinants of disease outcomes in arboviral infections (360G-Wellcome-206369_Z_17_Z)

Infections of animals or humans by viruses can result in many different clinical outcomes. Studying natural models of infection and disease can help us gain a full understanding of the mechanisms of viral pathogenesis, in the knowledge that this is influenced by virus-host co-evolution. In this proposal, we will study bluetongue, a vector-borne disease caused by bluetongue virus (BTV). Bluetongue is one of the major viral diseases of livestock. Essentially all domestic and wild ruminant are susceptible to BTV infection but the resulting clinical symptoms vary considerably (from mild fever to lethal haemorrhagic fever). In this proposal, we will address how a pathogenic virus renders some infected hosts seriously ill, whilst causing only mild/no disease in others, despite abundant viral replication in both. We will use in vitro and in vivo experiments to address our overarching hypothesis that the clinical fate of BTV infection is determined by the complex balance between virus replication in the face of the host’s innate and adaptive immune responses. The outcomes of this proposal will inform appropriate control strategies for this veterinary disease and generate an intellectual framework of value in understanding disease susceptibility in many other arboviral diseases of humans and animals.