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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.101938.3

Preprint — published as 10.7554/elife.101938 · Paper page

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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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Research works printed but not linked: 78

  1. Beall, 1998, Streptococcal emm types associated with T-agglutination types and the use of conserved emm gene restriction fragment patterns for subtyping group A streptococci, Journal of Medical Microbiology, 47, 893, 10.1099/00222615-47-10-893 · DOI
  2. Berbel, 2021, Deciphering mobile genetic elements disseminating macrolide resistance in Streptococcus pyogenes over a 21 year period in Barcelona, Spain, The Journal of Antimicrobial Chemotherapy, 76, 1991, 10.1093/jac/dkab130 · DOI
  3. Beres, 2016, Transcriptome remodeling contributes to epidemic disease caused by the human pathogen Streptococcus pyogenes, mBio, 7, 10.1128/mBio.00403-16 · DOI
  4. Beres, 2017, Genome sequence analysis of emm89 Streptococcus pyogenes strains causing infections in Scotland, 2010-2016, Journal of Medical Microbiology, 66, 1765, 10.1099/jmm.0.000622 · DOI
  5. Bessen, 2015, Molecular epidemiology and genomics of group A Streptococcus, Infection, Genetics and Evolution, 33, 393, 10.1016/j.meegid.2014.10.011 · DOI
  6. Bessen, 2018, Molecular epidemiology, ecology, and evolution of group a streptococci, Microbiology Spectrum, 6, 10.1128/microbiolspec.cpp3-0009-2018 · DOI
  7. Brouwer, 2023, Pathogenesis, epidemiology and control of group a streptococcus infection, Nature Reviews. Microbiology, 21, 431, 10.1038/s41579-023-00865-7 · DOI
  8. Carapetis, 2005, The global burden of group a streptococcal diseases, The Lancet. Infectious Diseases, 5, 685, 10.1016/S1473-3099(05)70267-X · DOI
  9. Chen, 2018, fastp: an ultra-fast all-in-one FASTQ preprocessor, Bioinformatics, 34, i884, 10.1093/bioinformatics/bty560 · DOI · Paper page
  10. Chochua, 2017, Population and whole genome sequence based characterization of invasive group a streptococci recovered in the United States during 2015, mBio, 8, 10.1128/mBio.01422-17 · DOI
  11. Cimen, 2008, Free radical metabolism in human erythrocytes, Clinica Chimica Acta; International Journal of Clinical Chemistry, 390, 1, 10.1016/j.cca.2007.12.025 · DOI
  12. Cole, 2011, Molecular insight into invasive group A streptococcal disease, Nature Reviews. Microbiology, 9, 724, 10.1038/nrmicro2648 · DOI
  13. Craik, 2022, Global disease burden of streptococcus pyogenes, 1
  14. Davies, 2019, Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics, Nature Genetics, 51, 1035, 10.1038/s41588-019-0417-8 · DOI
  15. de Avila E Silva, 2011, BacPP: bacterial promoter prediction--a tool for accurate sigma-factor specific assignment in enterobacteria, Journal of Theoretical Biology, 287, 92, 10.1016/j.jtbi.2011.07.017 · DOI
  16. Fay, 2021, Patterns of antibiotic nonsusceptibility among invasive group a streptococcus infections-United States, 2006-2017, Clinical Infectious Diseases, 73, 1957, 10.1093/cid/ciab575 · DOI
  17. Ge, 2018, iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data, BMC Bioinformatics, 19, 10.1186/s12859-018-2486-6 · DOI
  18. Hasegawa, 2017, Characterisation of clinically isolated Streptococcus pyogenes from balanoposthitis patients, with special emphasis on emm89 isolates, Journal of Medical Microbiology, 66, 511, 10.1099/jmm.0.000460 · DOI
  19. He, 2022, Immunization with the lipoprotein FtsB stimulates protective immunity against Streptococcus pyogenes infection in mice, Frontiers in Microbiology, 13, 10.3389/fmicb.2022.969490 · DOI
  20. Hirokawa, 1998, SOSUI: classification and secondary structure prediction system for membrane proteins, Bioinformatics, 14, 378, 10.1093/bioinformatics/14.4.378 · DOI
  21. Hirose, 2020, Genetic characterization of Streptococcus pyogenes emm89 strains isolated in Japan From 2011 to 2019, Infectious Microbes & Diseases, 2, 160, 10.1097/IM9.0000000000000038 · DOI
  22. Honda-Ogawa, 2013, Cysteine proteinase from Streptococcus pyogenes enables evasion of innate immunity via degradation of complement factors, The Journal of Biological Chemistry, 288, 15854, 10.1074/jbc.M113.469106 · DOI
  23. Ikebe, 2003, Changing prevalent T serotypes and emm genotypes of Streptococcus pyogenes isolates from streptococcal toxic shock-like syndrome (TSLS) patients in Japan, Epidemiology and Infection, 130, 569, 10.1017/S0950268803008331 · DOI
  24. Ikebe, 2010, Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates, PLOS Pathogens, 6, 10.1371/journal.ppat.1000832 · DOI
  25. Ikebe, 2021, Molecular characterization and antimicrobial resistance of group A streptococcus isolates in streptococcal toxic shock syndrome cases in Japan from 2013 to 2018, International Journal of Medical Microbiology, 311, 10.1016/j.ijmm.2021.151496 · DOI
  26. Jaillard, 2018, A fast and agnostic method for bacterial genome-wide association studies: bridging the gap between k-mers and genetic events, PLOS Genetics, 14, 10.1371/journal.pgen.1007758 · DOI
  27. Jain, 2020, The group A Streptococcus accessory protein RocA: regulatory activity, interacting partners and influence on disease potential, Molecular Microbiology, 113, 190, 10.1111/mmi.14410 · DOI
  28. Johnson, 1993, A review of the correlation of T-agglutination patterns and M-protein typing and opacity factor production in the identification of group A streptococci, Journal of Medical Microbiology, 38, 311, 10.1099/00222615-38-5-311 · DOI
  29. Jolley, 2010, BIGSdb: Scalable analysis of bacterial genome variation at the population level, BMC Bioinformatics, 11, 10.1186/1471-2105-11-595 · DOI
  30. Jolley, 2018, Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications, Wellcome Open Research, 3, 10.12688/wellcomeopenres.14826.1 · DOI · Paper page
  31. Kachroo, 2019, Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis, Nature Genetics, 51, 548, 10.1038/s41588-018-0343-1 · DOI
  32. Kalyaanamoorthy, 2017, ModelFinder: fast model selection for accurate phylogenetic estimates, Nature Methods, 14, 587, 10.1038/nmeth.4285 · DOI · Paper page
  33. Kapatai, 2017, Whole genome sequencing of group A Streptococcus: development and evaluation of an automated pipeline for emmgene typing, PeerJ, 5, 10.7717/peerj.3226 · DOI
  34. Katsukawa, 2002, M protein gene (emm) typing of Streptococcus pyogenes, Kansenshogaku Zasshi. The Journal of the Japanese Association for Infectious Diseases, 76, 238, 10.11150/kansenshogakuzasshi1970.76.238 · DOI
  35. Laabei, 2019, Catch me if you can: Streptococcus pyogenes complement evasion strategies, Journal of Innate Immunity, 11, 3, 10.1159/000492944 · DOI
  36. Lancefield, 1957, Differentiation of group A streptococci with a common R antigen into three serological types, with special reference to the bactericidal test, The Journal of Experimental Medicine, 106, 525, 10.1084/jem.106.4.525 · DOI
  37. Lees, 2018, pyseer: a comprehensive tool for microbial pangenome-wide association studies, Bioinformatics, 34, 4310, 10.1093/bioinformatics/bty539 · DOI
  38. Letunic, 2021, Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation, Nucleic Acids Research, 49, W293, 10.1093/nar/gkab301 · DOI
  39. Liao, 2014, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features, Bioinformatics, 30, 923, 10.1093/bioinformatics/btt656 · DOI · Paper page
  40. Lin, 2009, Streptolysin S inhibits neutrophil recruitment during the early stages of Streptococcus pyogenes infection, Infection and Immunity, 77, 5190, 10.1128/IAI.00420-09 · DOI
  41. Maiden, 2013, MLST revisited: the gene-by-gene approach to bacterial genomics, Nature Reviews. Microbiology, 11, 728, 10.1038/nrmicro3093 · DOI
  42. Martinez, 2024, CDBProm: the comprehensive directory of bacterial promoters, NAR Genomics and Bioinformatics, 6, 10.1093/nargab/lqae018 · DOI
  43. McShan, 2019, The bacteriophages of Streptococcus pyogenes, Microbiology Spectrum, 7, 10.1128/microbiolspec.GPP3-0059-2018 · DOI
  44. Nguyen, 2015, IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies, Molecular Biology and Evolution, 32, 268, 10.1093/molbev/msu300 · DOI · Paper page
  45. Nguyen, 2016, Lipoproteins of gram-positive bacteria: key players in the immune response and virulence, Microbiology and Molecular Biology Reviews, 80, 891, 10.1128/MMBR.00028-16 · DOI
  46. Ondov, 2016, Mash: fast genome and metagenome distance estimation using MinHash, Genome Biology, 17, 10.1186/s13059-016-0997-x · DOI · Paper page
  47. Page, 2015, Roary: rapid large-scale prokaryote pan genome analysis, Bioinformatics, 31, 3691, 10.1093/bioinformatics/btv421 · DOI · Paper page
  48. Paul, 2024, MLDSPP: bacterial promoter prediction tool using DNA structural properties with machine learning and explainable AI, Journal of Chemical Information and Modeling, 64, 2705, 10.1021/acs.jcim.3c02017 · DOI
  49. Ribardo, 2006, Defining the Mga regulon: Comparative transcriptome analysis reveals both direct and indirect regulation by Mga in the group A streptococcus, Molecular Microbiology, 62, 491, 10.1111/j.1365-2958.2006.05381.x · DOI
  50. Rice, 2000, EMBOSS: the european molecular biology open software suite, Trends in Genetics, 16, 276, 10.1016/s0168-9525(00)02024-2 · DOI · Paper page
  51. Seemann, 2014, Prokka: rapid prokaryotic genome annotation, Bioinformatics, 30, 2068, 10.1093/bioinformatics/btu153 · DOI
  52. Souvorov, 2018, SKESA: strategic k-mer extension for scrupulous assemblies, Genome Biology, 19, 10.1186/s13059-018-1540-z · DOI
  53. Stevens, 2014, Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America, Clinical Infectious Diseases, 59, 147, 10.1093/cid/ciu296 · DOI
  54. Stevens, 2016, Severe group a streptococcal infections
  55. Sumby, 2006, Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity, PLOS Pathogens, 2, 10.1371/journal.ppat.0020005 · DOI
  56. Sumitomo, 2011, Streptolysin S contributes to group a streptococcal translocation across an epithelial barrier, Journal of Biological Chemistry, 286, 2750, 10.1074/jbc.M110.171504 · DOI
  57. Takamatsu, 2001, Thermosensitive suicide vectors for gene replacement in Streptococcus suis, Plasmid, 46, 140, 10.1006/plas.2001.1532 · DOI
  58. Takemura, 2022, Pneumococcal bgaa promotes host organ bleeding and coagulation in a mouse sepsis model, Frontiers in Cellular and Infection Microbiology, 12, 10.3389/fcimb.2022.844000 · DOI
  59. Tanaka, 2016, Molecular epidemiology, antimicrobial susceptibility, and characterization of macrolide-resistant Streptococcus pyogenes in Japan, Journal of Infection and Chemotherapy, 22, 727, 10.1016/j.jiac.2016.06.013 · DOI
  60. Tatara, 2020, Molecular epidemiology, antimicrobial susceptibility, and characterization of fluoroquinolone non-susceptible Streptococcus pyogenes in Japan, Journal of Infection and Chemotherapy, 26, 280, 10.1016/j.jiac.2019.10.004 · DOI
  61. Terao, 2008, Group A Streptococcal cysteine protease degrades C3 (C3b) and contributes to evasion of innate immunity, Journal of Biological Chemistry, 283, 6253, 10.1074/jbc.M704821200 · DOI
  62. Turner, 2015, Emergence of a new highly successful acapsular group A Streptococcus Clade of Genotype emm89 in the United Kingdom, mBio, 6, 10.1128/mBio.00622-15 · DOI
  63. Turner, 2019, The emergence of successful Streptococcus pyogenes lineages through convergent pathways of capsule loss and recombination directing high toxin expression, mBio, 10, 10.1128/mBio.02521-19 · DOI
  64. Ubukata, 2020, Changes in epidemiologic characteristics and antimicrobial resistance of Streptococcus pyogenes isolated over 10 years from Japanese children with pharyngotonsillitis, Journal of Medical Microbiology, 69, 443, 10.1099/jmm.0.001158 · DOI
  65. Vega, 2016, Virulence-Related Transcriptional Regulators of Streptococcus pyogenes
  66. Wajima, 2014, Prevalence of macrolide resistance among group A streptococci isolated from pharyngotonsillitis, Microbial Drug Resistance, 20, 431, 10.1089/mdr.2013.0213 · DOI
  67. Walker, 2007, DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection, Nature Medicine, 13, 981, 10.1038/nm1612 · DOI
  68. Wickham, 2016, Ggplot2: Elegant Graphics for Data Analysis, 10.1007/978-3-319-24277-4_9 · DOI
  69. Yamaguchi, 2013, Streptococcus pneumoniae invades erythrocytes and utilizes them to evade human innate immunity, PLOS ONE, 8, 10.1371/journal.pone.0077282 · DOI
  70. Yamaguchi, 2019, Identification of evolutionarily conserved virulence factor by selective pressure analysis of Streptococcus pneumoniae, Communications Biology, 2, 10.1038/s42003-019-0340-7 · DOI
  71. Zhu, 2015, A molecular trigger for intercontinental epidemics of group A Streptococcus, The Journal of Clinical Investigation, 125, 3545, 10.1172/JCI82478 · DOI
  72. Zhu, 2015, Trading capsule for increased cytotoxin production: contribution to virulence of a newly emerged clade of emm89 Streptococcus pyogenes, mBio, 6, 10.1128/mBio.01378-15 · DOI
  73. Ono M, Yamaguchi M, Kawabata S. 2025. Illumina NovaSeq 6000 paired end sequencing of KB01. NCBI Sequence Read Archive. https://www.ncbi.nlm.nih.gov/sra/DRR511668. DRR511668.
  74. Ono M, Yamaguchi M, Kawabata S. 2025. llumina NovaSeq 6000 paired end sequencing of TK124. NCBI Sequence Read Archive. https://www.ncbi.nlm.nih.gov/sra/DRR511874. DRR511874.
  75. Hirose Y, Yamaguchi M, Takemoto N, Miyoshi-Akiyama T, Sumitomo T, Nakata M, Ikebe T, Hanada T, Yamaguchi T, Kawahara R. 2020. Genetic characterization of recently emerged clade of emm 89 Streptococcus pyogenes, Japan, 2011-2019. NCBI BioProject. https://www.ncbi.nlm.nih.gov/bioproject/PRJDB8877. PRJDB8877.
  76. Chochua S, Metcalf BJ, Li Z, Rivers J, Mathis S, Jackson D, Gertz RE, Srinivasan V, Lynfield R, Van Beneden C. 2017. WGS of the United States invasive Streptococcus pyogenes isolates. NCBI BioProject. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA395240. PRJNA395240.
  77. Davies MR, McIntyre L, Mutreja A, Lacey JA, Lees JA, Towers RJ, Smeesters PR, Frost HR, Price DJ, Holden MT G. 2019. Complete genomes of 30 globally distributed Group A Streptococcus isolates. NCBI BioProject. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA454341. PRJNA454341.
  78. Beres SB, Olsen RJ, Saavedra MO, Ure R, Reynolds A, Lindsay DSJ, Smith AJ, Musser JM. 2017. Scotland Streptococcus pyogenes emm89 strains, 2010-2016. NCBI BioProject. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA387243. PRJNA387243.

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)
  • 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)
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.101938.3
OpenAlex
W4400377935
Cited by
0
References
5
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
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, invasive streptococcal infection, virulence factors, genetic variation, single nucleotide polymorphisms, indels, bacterial adhesion, genome-wide association study, virulence genes

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