Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage

ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully und...

Full description

Saved in:
Bibliographic Details
Main Authors: Johanna Richter, Amanda J. Cork, Yvette Ong, Nadia Keller, Andrew J. Hayes, Mark A. Schembri, Amy V. Jennison, Mark R. Davies, Kate Schroder, Mark J. Walker, Stephan Brouwer
Format: Article
Language:English
Published: American Society for Microbiology 2025-02-01
Series:mBio
Subjects:
Online Access:https://journals.asm.org/doi/10.1128/mbio.03366-24
Tags: Add Tag
No Tags, Be the first to tag this record!
_version_ 1832096530653249536
author Johanna Richter
Amanda J. Cork
Yvette Ong
Nadia Keller
Andrew J. Hayes
Mark A. Schembri
Amy V. Jennison
Mark R. Davies
Kate Schroder
Mark J. Walker
Stephan Brouwer
author_facet Johanna Richter
Amanda J. Cork
Yvette Ong
Nadia Keller
Andrew J. Hayes
Mark A. Schembri
Amy V. Jennison
Mark R. Davies
Kate Schroder
Mark J. Walker
Stephan Brouwer
author_sort Johanna Richter
collection DOAJ
description ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence.
format Article
id doaj-art-a8014e835c654758b70a3282d1209a92
institution Kabale University
issn 2150-7511
language English
publishDate 2025-02-01
publisher American Society for Microbiology
record_format Article
series mBio
spelling doaj-art-a8014e835c654758b70a3282d1209a922025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03366-24Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineageJohanna Richter0Amanda J. Cork1Yvette Ong2Nadia Keller3Andrew J. Hayes4Mark A. Schembri5Amy V. Jennison6Mark R. Davies7Kate Schroder8Mark J. Walker9Stephan Brouwer10Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaPublic and Environmental Health, Pathology Queensland, Queensland Health, Coopers Plains, Queensland, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, AustraliaInstitute for Molecular Bioscience, Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence.https://journals.asm.org/doi/10.1128/mbio.03366-24Streptococcus pyogenestwo-component systemCovRSSNPtranscriptional regulationSLO
spellingShingle Johanna Richter
Amanda J. Cork
Yvette Ong
Nadia Keller
Andrew J. Hayes
Mark A. Schembri
Amy V. Jennison
Mark R. Davies
Kate Schroder
Mark J. Walker
Stephan Brouwer
Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
mBio
Streptococcus pyogenes
two-component system
CovRS
SNP
transcriptional regulation
SLO
title Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
title_full Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
title_fullStr Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
title_full_unstemmed Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
title_short Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
title_sort characterization of a novel covs snp identified in australian group a streptococcus isolates derived from the m1uk lineage
topic Streptococcus pyogenes
two-component system
CovRS
SNP
transcriptional regulation
SLO
url https://journals.asm.org/doi/10.1128/mbio.03366-24
work_keys_str_mv AT johannarichter characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT amandajcork characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT yvetteong characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT nadiakeller characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT andrewjhayes characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT markaschembri characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT amyvjennison characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT markrdavies characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT kateschroder characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT markjwalker characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage
AT stephanbrouwer characterizationofanovelcovssnpidentifiedinaustraliangroupastreptococcusisolatesderivedfromthem1uklineage