Identifying Genetic Variations in emm89 Streptococcus pyogenes Linked to Severe Invasive Infections
Ono, M.; Yamaguchi, M.; Motooka, D.; Hirose, Y.; Higashi, K.; Sumitomo, T.; Miyoshi-Akiyama, T.; Okuno, R.; Yamaguchi, T.; Kawahara, R.; Otsuka, H.; Nakanishi, N.; Kazawa, Y.; Nakagawa, C.; Yamaguchi, R.; Sakai, H.; Matsumoto, Y.; Ikebe, T.; Kawabata, S.
Show abstract
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 (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, 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.
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