Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus

Bernard, Paul E.; Kachroo, Priyanka; Eraso, Jesus M.; Zhu, Luchang; Madry, Jessica E.; Linson, Sarah E.; Saavedra, Matthew Ojeda; Cantu, Concepcion; Musser, James M.; Olsen, Randall J.

doi:10.1016/j.ajpath.2019.06.009

Cited by 7 publications

(3 citation statements)

References 117 publications

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“…Our finding that the emm 28 strain had lower baseline CovR~P levels relative to emm 87, emm 89, and emm 1 strains adds to growing information regarding the apparently atypical nature of the CovRS system in this particular emm type ( 44 ). Bernard et al noted that emm 28 strains have an unusually high number of RocA polymorphisms relative to other emm types and demonstrated a dramatic impact of RocA on the emm 28 transcriptome ( 85 ). Moreover, an analysis of over 2,000 emm 28 strains identified numerous CovRS polymorphisms that were associated with a markedly altered transcriptome and increased virulence in a mouse necrotizing fasciitis model ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci

DebRoy,

Shropshire,

Vega

et al. 2023

mSystems

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Group A streptococcal (GAS) strains causing severe, invasive infections often have mutations in the control of virulence two-component regulatory system (CovRS) which represses capsule production, and high-level capsule production is considered critical to the GAS hypervirulent phenotype. Additionally, based on studies in emm1 GAS, hyperencapsulation is thought to limit transmission of CovRS-mutated strains by reducing GAS adherence to mucosal surfaces. It has recently been identified that about 30% of invasive GAS strains lacks capsule, but there are limited data regarding the impact of CovS inactivation in such acapsular strains. Using publicly available complete genomes ( n = 2,455) of invasive GAS strains, we identified similar rates of CovRS inactivation and limited evidence for transmission of CovRS-mutated isolates for both encapsulated and acapsular emm types. Relative to encapsulated GAS, CovS transcriptomes of the prevalent acapsular emm types emm28 , emm87 , and emm89 revealed unique impacts such as increased transcript levels of genes in the emm /mga region along with decreased transcript levels of pilus operon-encoding genes and the streptokinase-encoding gene ska . CovS inactivation in emm87 and emm89 strains, but not emm28 , increased GAS survival in human blood. Moreover, CovS inactivation in acapsular GAS reduced adherence to host epithelial cells. These data suggest that the hypervirulence induced by CovS inactivation in acapsular GAS follows distinct pathways from the better studied encapsulated strains and that factors other than hyperencapsulation may account for the lack of transmission of CovRS-mutated strains. IMPORTANCE Devastating infections due to group A streptococci (GAS) tend to occur sporadically and are often caused by strains that contain mutations in the control of virulence regulatory system (CovRS). In well-studied emm1 GAS, the increased production of capsule induced by CovRS mutation is considered key to both hypervirulence and limited transmissibility by interfering with proteins that mediate attachment to eukaryotic cells. Herein, we show that the rates of covRS mutations and genetic clustering of CovRS-mutated isolates are independent of capsule status. Moreover, we found that CovS inactivation in multiple acapsular GAS emm types results in dramatically altered transcript levels of a diverse array of cell-surface protein-encoding genes and a unique transcriptome relative to encapsulated GAS. These data provide new insights into how a major human pathogen achieves hypervirulence and indicate that factors other than hyperencapsulation likely account for the sporadic nature of the severe GAS disease.

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Section: Discussionmentioning

confidence: 99%

Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci

DebRoy,

Shropshire,

Vega

et al. 2023

mSystems

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“…These results suggest that the difference between emm 1 and emm 3 strains would be caused, at least partially, by the truncation of the rocA allele in the emm 3 strains. The truncated rocA alleles were found in the emm 3 and emm 18 isolates; in addition, the variations in the amino acid sequence of RocA among the emm 28 isolates and in the number of tandem repeats in the promoter regions of rocA gene found in different emm 89 isolates are associated with the changes of the regulatory activity of RocA and the expression level of rocA , respectively ( 24 – 26 ). These changes would result in the diverse responses when GAS invades into a niche with neutral pH conditions (e.g., blood) during infection and could be significantly associated with bacterial invasiveness.…”

Section: Discussionmentioning

confidence: 99%

RocA Regulates Phosphatase Activity of Virulence Sensor CovS of Group A Streptococcus in Growth Phase- and pH-Dependent Manners

Chiang-Ni

Chiou

Tseng

et al. 2020

mSphere

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The control of the virulence response regulator and sensor (CovR-CovS) two-component regulatory system in group A Streptococcus (GAS) strains regulates more than 15% of gene expression and has critical roles in invasive GAS infection. The membrane-embedded CovS has kinase and phosphatase activities, and both are required for modulating the phosphorylation level of CovR. Regulator of Cov (RocA) is a positive regulator of covR and also been shown to be a pseudokinase that interacts with CovS to enhance the phosphorylation level of CovR; however, how RocA modulates the activity of CovS has not been determined conclusively. Although the phosphorylation level of CovR was decreased in the rocA mutant in the exponential phase, the present study shows that phosphorylated CovR in the rocA mutant increased to levels similar to those in the wild-type strain in the stationary phase of growth. In addition, acidic stress, which is generally present in the stationary phase, enhanced the phosphorylation level of CovR in the rocA mutant. The phosphorylation levels of CovR in the CovS phosphatase-inactivated mutant and its rocA mutant were similar under acidic stress and Mg2+ (the signal that inhibits CovS phosphatase activity) treatments, suggesting that the phosphatase activity, but not the kinase activity, of CovS is required for RocA to modulate CovR phosphorylation. The phosphorylation level of CovR is crucial for GAS strains to regulate virulence factor expression; therefore, the growth phase- and pH-dependent RocA activity would contribute significantly to GAS pathogenesis. IMPORTANCE The emergence of invasive group A streptococcal infections has been reported worldwide. Clinical isolates that have spontaneous mutations or a truncated allele of the rocA gene (e.g., emm3-type isolates) are considered to be more virulent than isolates with the intact rocA gene (e.g., emm1-type isolates). RocA is a positive regulator of covR and has been shown to enhance the phosphorylation level of intracellular CovR regulator through the functional CovS protein. CovS is the membrane-embedded sensor and modulates the phosphorylation level of CovR by its kinase and phosphatase activities. The present study shows that the enhancement of CovR phosphorylation is mediated via the repression of CovS’s phosphatase activity by RocA. In addition, we found that RocA acts dominantly on modulating CovR phosphorylation under neutral pH conditions and in the exponential phase of growth. The phosphorylation level of CovR is crucial for group A Streptococcus species to regulate virulence factor expression and is highly related to bacterial invasiveness; therefore, growth phase- and pH-dependent RocA activity and the sequence polymorphisms of rocA gene would contribute significantly to bacterial phenotype variations and pathogenesis.

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“…Quantitative RT-PCR analysis of emm28 expression was performed according to previous descriptions. 46,47 Briefly, GAS strains were grown in quadruplicate in THY broth to midexponential phase (OD600 Z 0.5). RNA was extracted from GAS culture using the RNeasy kit (Qiagen, Hilden, Germany).…”

Section: Quantitative Rt-pcr Analysismentioning

confidence: 99%

Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence

Zhu

Olsen

Beres

et al. 2020

The American Journal of Pathology

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Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus

Cited by 7 publications

References 117 publications

Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci

Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci

RocA Regulates Phosphatase Activity of Virulence Sensor CovS of Group A Streptococcus in Growth Phase- and pH-Dependent Manners

Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence

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