The strictly human pathogen Streptococcus pyogenes, Group A Streptococcus (GAS), is a Gram-positive bacterium responsible for non-invasive and invasive infections and post streptococcal sequelae, leading altogether to over 500,000 deaths yearly. Fatty acids are main constituents of membrane phospholipids, which in turn determine bacterial functions and interactions with the environment. FabT is the transcriptional repressor of the Fatty Acid Synthesis pathway (FASII) in numerous Streptococcaceae. In GAS, fabT mutants, which may arise naturally, display attenuated virulence, as revealed in a non-human primate model of necrotizing fasciitis. We hypothesized that disrupting membrane homeostasis through fatty acid reprogramming leads to this virulence defect.
Our goal is to decipher the mechanistic link between FabT and virulence. We performed comparative transcriptional profiles, and membrane lipid and protein identification on GAS wild type and fabT mutant strains, under different culture conditions. We then compared the capacity of these strains to adhere and grow in the presence of human cells. The fabT mutant showed defects in both properties. In GAS, FabT inactivation leads to changes in cell-envelope composition that impacts the bacterial adaptation to its environment.
We are currently investigating two non-exclusive hypotheses: i) FabT feedback repression of FASII prevents futile activity when fatty acids are available and/or ii) fabT mutant variants are unable to transport or use cell-secreted nutriments. Hypothesis ii) is being tested by growth in minimal media and by a metabolomic approach. Our results will allow us to pinpoint how FabT is implicated in virulence.