Identifying Genetic Variations in emm89 Streptococcus pyogenes Associated with Severe Invasive Infections

• DOI: 10.7554/elife.101938.2
• Publication Date: 2025-05-20T15:30:08Z
• Authors: Masayuki Ono; Masaya Yamaguchi; Daisuke Motooka; Yujiro Hirose; Kotaro Higashi; Tomoko Sumitomo; Tohru Miyoshi-Aki...; Rumi Okuno; Takahiro Yamaguchi; Ryuji Kawahara; Hitoshi Otsuka; Noriko Nakanishi; Yu Kazawa; Chikara Nakagawa; Ryo Yamaguchi; Hiroo Sakai; Yuko Matsumoto; Tadayoshi Ikebe; Shigetada Kawabata

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.