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The Group A Streptococcus remains a significant human pathogen causing a wide array of disease ranging from self-limiting to life-threatening invasive infections. Epithelium (skin or throat) colonization with progression to the subepithelial tissues is the common step in all GAS infections. Here, we used transposon-sequencing (Tn-seq) to define the GAS 5448 genetic requirements for  in vivo  fitness in subepithelial tissue. A near-saturation transposon library of the M1T1 GAS 5448 strain was injected subcutaneously into mice, producing suppurative inflammation at 24 h that progressed to prominent abscesses with tissue necrosis at 48 h. The library composition was monitored  en masse  by Tn-seq and ratios of mutant abundance comparing the output (12, 24 and 48 h) versus input (T 0 ) mutant pools were calculated for each gene. We identified a total of 273  s ub c utaneous  f itness ( scf ) genes with 147 genes (55 of unknown function) critical for the M1T1 GAS 5448 fitness  in vivo ; and 126 genes (53 of unknown function) potentially linked to  in vivo  fitness advantage. Selected  scf  genes were validated in competitive subcutaneous infection with parental 5448. Two uncharacterized genes,  scfA  and  scfB , encoding putative membrane-associated proteins and conserved among Gram-positive pathogens, were further characterized. Defined  scfAB  mutants in GAS were outcompeted by wild type 5448  in vivo , attenuated for lesion formation in the soft tissue infection model and dissemination to the bloodstream. We hypothesize that  scfAB  play an integral role in enhancing adaptation and fitness of GAS during localized skin infection, and potentially in propagation to other deeper host environments.

Genome-wide discovery of novel M1T1 group A streptococcal determinants important for fitness and virulence during soft-tissue infection