Identifying Genetic Variations inemm89Streptococcus pyogenesAssociated with Severe Invasive Infections

Streptococcus pyogenescauses 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 ofemm89S. pyogenesstrains to comprehensively identify pathology-related bacterial genetic factors (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 1,075 SNPs/indels and 2 and 169 genes, respectively, that displayed associations with invasiveness. We validated one of them, a non-invasiveness-related point mutation,fhuBT218C, 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 convertemm89S. pyogenesto an invasive phenotype and a platform for establishing novel treatments and prevention strategies.