Identifying genetic variations in emm89 Streptococcus pyogenes associated with severe invasive infections

Streptococcus pyogenes causes mild human infections as well as life-threatening invasive diseases. Since the mutations known to enhance virulence to date account for only half of the severe invasive infections, additional mechanisms/mutations need to be identified. Here, we conducted a genome-wide association study of emm89 S. pyogenes strains to comprehensively identify pathology-related bacterial genetic factors (single-nucleotide polymorphisms [SNPs], indels, genes, or k-mers). Japanese (n = 311) and global (n = 666) cohort studies of strains isolated from invasive or non-invasive infections revealed 17 and 1075 SNPs/indels and 2 and 169 genes, respectively, that displayed associations with invasiveness. We validated one of them, a non-invasiveness-related point mutation, fhuB T218C, by structure predictions and introducing it into a severe invasive strain and confirmed that the mutant showed slower growth in human blood. Thus, we report novel mechanisms that convert emm89 S. pyogenes to an invasive phenotype and a platform for establishing novel treatments and prevention strategies.