Genetic heterogeneity of the Spy1336/R28 – Spy1337 Virulence Axis in Streptococcus pyogenes and Effect on Gene Transcript Levels and Pathogenesis
Genetic heterogeneity of the Spy1336/R28 – Spy1337 Virulence Axis in Streptococcus pyogenes and Effect on Gene Transcript Levels and Pathogenesis
ABSTRACT Streptococcus pyogenes is a strict human pathogen responsible for more than 700 million infections annually worldwide. Strains of serotype M28 S. pyogenes are typically among the five more abundant types causing invasive infections and pharyngitis in adults and children. Type M28 strains also have an unusual propensity to cause puerperal sepsis and neonatal disease. We recently discovered that a one-nucleotide indel in an intergenic homopolymeric tract located between genes Spy1336/R28 and Spy1337 altered virulence in a mouse model of infection. In the present study, we analyzed size variation in this homopolymeric tract and determined the extent of heterogeneity in the number of tandemly-repeated 79-amino acid domains in the coding region of Spy1336/R28 in large samples of strains recovered from humans with invasive infections. Both repeat sequence elements are highly polymorphic in natural populations of M28 strains. Variation in the homopolymeric tract results in (i) changes in transcript levels of Spy1336/R28 and Spy1337 in vitro, (ii) differences in virulence in a mouse model of necrotizing myositis, and (iii) global transcriptome changes as shown by RNAseq analysis of isogenic mutant strains. Variation in the number of tandem repeats in the coding sequence of Spy1336/R28 is responsible for size variation of R28 protein in natural populations. Isogenic mutant strains in which genes encoding R28 or transcriptional regulator Spy1337 are inactivated are significantly less virulent in a nonhuman primate model of necrotizing myositis. Our findings provide impetus for additional studies addressing the role of R28 and Spy1337 variation in pathogen-host interactions.
Badu Traci、Kachroo Priyanka、Musser James M.、Kubiak Samantha L.、DeLeo Frank R.、Saavedra Matthew Ojeda、Shannon Sydney、Porter Adeline R.、Olsen Randall J.、Cantu Concepcion C.、Zhu Luchang、Beres Stephen B.、Eraso Jesus M.
Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital||Macalester College, Neuroscience DepartmentCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist HospitalCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital||Departments of Pathology and Laboratory Medicine, and Microbiology and Immunology, Weill Cornell Medical CollegeCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital||University of North Texas Health Science Center, School of Health ProfessionsLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist HospitalCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital||University of Rochester, Biomedical Engineering DepartmentLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital||Departments of Pathology and Laboratory Medicine, and Microbiology and Immunology, Weill Cornell Medical CollegeCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist HospitalCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist HospitalCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist HospitalCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital
基础医学微生物学遗传学
Badu Traci,Kachroo Priyanka,Musser James M.,Kubiak Samantha L.,DeLeo Frank R.,Saavedra Matthew Ojeda,Shannon Sydney,Porter Adeline R.,Olsen Randall J.,Cantu Concepcion C.,Zhu Luchang,Beres Stephen B.,Eraso Jesus M..Genetic heterogeneity of the Spy1336/R28 – Spy1337 Virulence Axis in Streptococcus pyogenes and Effect on Gene Transcript Levels and Pathogenesis[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/777987.点此复制
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