ArticlePLoS pathogens2018
Phosphatase activity of the control of virulence sensor kinase CovS is critical for the pathogenesis of group A streptococcus.
Article in PLoS pathogens, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 41 citations in OpenAlex.
- Constitutive activation of two-component systems reveals regulatory network interactions in Streptococcus agalactiae.Nature communications · 2024Article
- Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes.Journal of biomedical science · 2024Article
- Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci.mSystems · 2023Article
- Elucidation of independently modulated genes inmSystems · 2023Article
- Hyperphosphorylation of the Group A Streptococcal Control of Virulence Regulator Increases Promoter Occupancy Specifically at Virulence Factor-Encoding Genes.Journal of bacteriology · 2023Article
- A Novel CovS Variant Harbored by a Colonization Strain Reduces Streptococcus pyogenes Virulence.Journal of bacteriology · 2023Article
- Phosphorylation chemistry of the Bordetella PlrSR TCS and its contribution to bacterial persistence in the lower respiratory tract.Molecular microbiology · 2023Article
- Slipped-strand mispairing within a polycytidine tract in transcriptional regulatorFrontiers in microbiology · 2023Article
- Transcriptome and metabolome profiling to elucidate the mechanism underlying the poor growth ofFrontiers in veterinary science · 2023Article
- Article
- CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus.PLoS pathogens · 2022Article
- The CovR regulatory network drives the evolution of Group B Streptococcus virulence.PLoS genetics · 2021Article
- Article
- Genome-wide analysis of in vivo CcpA binding with and without its key co-factor HPr in the major human pathogen group A Streptococcus.Molecular microbiology · 2021Article
- Comparative genomics reveals an SNP potentially leading to phenotypic diversity ofMicrobial genomics · 2021Article
- Playing With Fire: Proinflammatory Virulence Mechanisms of Group AFrontiers in cellular and infection microbiology · 2021Review
- Incidence and Effects of Acquisition of the Phage-EncodedFrontiers in microbiology · 2021Article
- Single Amino Acid Replacements in RocA Disrupt Protein-Protein Interactions To Alter the Molecular Pathogenesis of Group AInfection and immunity · 2020Article
- Group A Streptococcus Infection of the Nasopharynx Requires Proinflammatory Signaling through the Interleukin-1 Receptor.Infection and immunity · 2020Article
- Article
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9 authors at 2 institutions in 1 country.
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Abstract
The control of virulence regulator/sensor kinase (CovRS) two-component system is critical to the infectivity of group A streptococcus (GAS), and CovRS inactivating mutations are frequently observed in GAS strains causing severe human infections. CovS modulates the phosphorylation status and with it the regulatory effect of its cognate regulator CovR via its kinase and phosphatase activity. However, the contribution of each aspect of CovS function to GAS pathogenesis is unknown. We created isoallelic GAS strains that differ only by defined mutations which either abrogate CovR phosphorylation, CovS kinase or CovS phosphatase activity in order to test the contribution of CovR phosphorylation levels to GAS virulence, emergence of hypervirulent CovS-inactivated strains during infection, and GAS global gene expression. These sets of strains were created in both serotype M1 and M3 backgrounds, two prevalent GAS disease-causing serotypes, to ascertain whether our observations were serotype-specific. In both serotypes, GAS strains lacking CovS phosphatase activity (CovS-T284A) were profoundly impaired in their ability to cause skin infection or colonize the oropharynx in mice and to survive neutrophil killing in human blood. Further, response to the human cathelicidin LL-37 was abrogated. Hypervirulent GAS isolates harboring inactivating CovRS mutations were not recovered from mice infected with M1 strain M1-CovS-T284A and only sparsely recovered from mice infected with M3 strain M3-CovS-T284A late in the infection course. Consistent with our virulence data, transcriptome analyses revealed increased repression of a broad array of virulence genes in the CovS phosphatase deficient strains, including the genes encoding the key anti-phagocytic M protein and its positive regulator Mga, which are not typically part of the CovRS transcriptome. Taken together, these data establish a key role for CovS phosphatase activity in GAS pathogenesis and suggest that CovS phosphatase activity could be a promising therapeutic target in GAS without promoting emergence of hypervirulent CovS-inactivated strains.
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