Human genetic determinants of invasive group A streptococcal host-pathogen interactions

Group A streptococcus (GAS) is a major, human specific, bacterial pathogen. Most people suffer from mild infections, while only a few develop invasive GAS (iGAS) infections. These cases of iGAS infections are unexplained as they strike otherwise healthy people. The human specificity of GAS and the interindividual variability upon infection with GAS are poorly understood.

My proposal aims to close both knowledge gaps: I hypothesize that single-gene defects of antistreptococcal immunity increase susceptibility to human-specific GAS virulence factors in some people, thereby underlying their iGAS infections.

I propose an innovative framework to unravel iGAS pathophysiology in humans, by applying a strategy to integrate the studies of human genetics and host-pathogen interactions at the molecular level. This project focuses on patients suffering from iGAS infections. Most patients have been enrolled, sampled, and whole exome sequencing (WES) performed.

Additional patients will be recruited. The human gene(s) underlying iGAS infections will be identified using complementary WES-based approaches.

The discovered inborn error(s) of immunity to GAS and the host-pathogen interactions will be dissected at the molecular, cellular, tissue, and whole-organismal levels, including with patients’ cells and clinical GAS strains.The immediate availability of patients’ genetic data provides a secure starting point for an efficient implementation of this proposal.

Preliminary analyses have yielded two promising candidate genes.

Access to patients’ specimens and clinical GAS isolates offers an exceptional opportunity to characterize patient-specific host-pathogen interactions.

Thus, we are in a unique position to discover the first human genetic determinant(s) of iGAS host-pathogen interactions.

This project may uncover the role of genes in human physiology beyond the infectious phenotype and accelerate the development of preventative strategies against GAS infections.