Of the over 500,000 annual deaths due to complications of Group A streptococcal (GAS) infections, well over two-third are attributed to rheumatic heart disease (RHD). Acute rheumatic fever (ARF) and RHD, which are autoimmune sequelae of GAS pharyngitis and/or pyoderma, continue to be a significant health problem.
As ARF/RHD are uniquely human diseases, there is an urgent need to develop and characterise reliable small animal models that mimic the cardinal features of these complications to develop specific treatment and prevention strategies. The rat autoimmune valvulitis (RAV) model of RHD that we have characterised reflects both the early and late clinical features of RHD. Cardiac functional and neurobehavioral tests were conducted before and after injections of Lewis rats with recombinant GAS M5. ELISAs were carried out on sera to determine cross-reactivity with tissue proteins. Adoptive transfer studies were also carried out to determine the role of both T-cells and antibodies in the development of both cardiac and neurological changes.
Rats injected with GAS M proteins developed cardiac functional and neurobehavioral abnormalities with antibodies against GAS M proteins cross-reacting with purified cardiac, connective, and neuronal proteins. We found that GAS initiates interleukin 17A/interferon γ-induced myocarditis and valvulitis. Our ex vivo studies have demonstrated that M protein specific antibodies and T-cells independently induced upregulation of the endothelial cell adhesion molecules facilitating T-cell transmigration.
We have identified the early events that lead to cardiac and neurobehavioral changes at different stages of the disease process. This model is currently being used in multidisciplinary translational research to (1) assess the safety of anti-streptococcal vaccine candidates; (2) identify specific biomarkers that can be used as point-of-care screening tests and (3) develop next-generation immunotherapies.