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

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Ono, Masayuki, Yamaguchi, Masaya, Motooka, Daisuke, Hirose, Yujiro, Higashi, Kotaro, Sumitomo, Tomoko, Miyoshi-Akiyama, Tohru, Okuno, Rumi, Yamaguchi, Takahiro, Kawahara, Ryuji, Otsuka, Hitoshi, Nakanishi, Noriko, Kazawa, Yu, Nakagawa, Chikara, Yamaguchi, Ryo, Sakai, Hiroo, Matsumoto, Yuko, Ikebe, Tadayoshi, Kawabata, Shigetada·2025·eLife
DOI 10.7554/elife.101938PMC PMC12289306

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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 emm 89 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 emm 89 S. pyogenes to an invasive phenotype and a platform for establishing novel treatments and prevention strategies.

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Metadata

Authors
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.
Affiliations
  • The University of Osaka (JP)
  • National Institute of Biomedical Innovation, Health and Nutrition (JP)
  • Institute for Open and Transdisciplinary Research Initiatives (JP)
  • Tokushima University (JP)
  • Pathogenic Microbe Laboratory, Department of Infectious Diseases, National Center for Global Health and Medicine
  • Tokyo Metropolitan Institute of Public Health (JP)
  • Osaka Institute of Public Health (JP)
  • Yamaguchi Prefectural Institute of Public Health and Environment (JP)
  • Kobe Institute of Health (JP)
  • Fukushima Prefectural Institute for Public Health Ken-chu Branch Office
  • Kyoto City Institute of Health and Environmental Sciences (JP)
  • Sapporo Public Health Office
  • Niigata City Institute of Public Health and Environment (JP)
  • Yokohama City Institute of Public Health (JP)
  • National Institute of Infectious Diseases (JP)
  • Center for Infectious Disease Education and Research, The University of Osaka (JP)
Corresponding author
Yamaguchi, Masaya
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-07-24
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.101938
PMC
PMC12289306
OpenAlex
W4406027527
Cited by
4
References
4
Citations by year
2026: 2 · 2025: 2
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for the Promotion of Science (20KK0210, 22H03262, 22K19618, 22K19619, 23H03073, 23K19687, 24K19854)
  • Joint Research Program of the Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University (2022B05, 2025B01, 2025B13)
  • Japan Science and Technology Agency SPRING (JPMJSP2138)
  • AMED (JP17fk0108044, JP20fk0108130, JP20wm0325001, JP243fa727001h)
  • Joint Usage/Research Center for Interdisciplinary Large-scale Information Infrastructures (EX22701, jh230035, jh240003, jh250016)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Streptococcal Infections and Treatments
  • Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
  • Life Sciences › Immunology and Microbiology › Microbiology › Microbial infections and disease research
Keywords
Streptococcus pyogenes, emm89, invasive streptococcal infection, virulence factors, genome-wide association study, single nucleotide polymorphisms, indels, bacterial adhesion, virulence genes, Japanese isolates
MeSH terms
Humans, Streptococcal Infections, Streptococcus pyogenes, Genetic Variation, Virulence, Polymorphism, Single Nucleotide, INDEL Mutation, Genome-Wide Association Study

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