The use of novel host-specific models to determine infection mechanisms of the human pathogen Streptococcus pyogenes

The human bacterial pathogen Streptococcus pyogenes is responsible for a substantial global infection burden, with >300,000 deaths annually due to the post-infection condition of rheumatic heart disease (RHD) alone. Infection burden is highest in low- and middle-income countries (LMICs) and a vaccine is urgently needed, particularly to prevent primary throat or skin infections which may lead to RHD. Currently there are significant barriers to vaccine success in the form of 1) the lack of knowledge regarding S. pyogenes:host interactions at primary infection sites, and 2) extremely limited information on streptococcal molecular epidemiology and biology in LMICs; available data shows much higher diversity in these countries. We will address these barriers with our unique tissue-engineered human tonsil and human skin infection models for comprehensive study of S. pyogenes:host interactions. We will perform extensive functional genomic analysis of skin and throat isolates collected in the UK (a high-income country) and in The Gambia (a low-income country), alongside bacterial genome-wide transcriptomics and mutagenesis in the context of our human-relevant infection models. This innovative combination of research approaches will elucidate infection determinants and tissue-tropisms of high-income and low-income country isolates, transforming our understanding of global streptococcal biology and directly supporting vaccine development.