Characterisation of the immunological mechanisms that drive chronic chikungunya disease pathogenesis

Chikungunya virus (CHIKV) represents a widespread mosquito-transmitted, arthritogenic virus that causes chronic debilitating joint pain and arthritis in almost half of infected patients. Currently, no effective therapies or biomarkers predicting chronic disease exist, as the mechanisms driving chronic CHIKV symptoms remain elusive. The central hypothesis of our proposal is that dysregulated antibody responses modulate susceptibility to chronic chikungunya through impaired antiviral activity, as well as excessive and inappropriate activation of pro-inflammatory pathways. This hypothesis will be tested by the in-depth characterization of a unique cohort of chikungunya patients with resolved or chronic disease. We will comprehensively analyse the immune responses during the acute phase of CHIKV infection, aiming to identify the immune determinants of susceptibility to chronic chikungunya disease. We will additionally characterize the heterogeneity of humoral immune responses from patients with differential disease outcomes. Lastly, using novel mouse models of chikungyunya disease, we will investigate the immunopathogenic mechanisms of CHIKV infection, as well as determine the mechanisms by which antibodies modulate disease pathogenesis. These studies are expected to lead to the identification of the immune pathways and biomarkers that are associated with disease chronicity, guiding the development of novel vaccination and therapeutic strategies to prevent or treat chikungunya disease.