Signaling by a Conserved Quorum Sensing Pathway Contributes to Growth
            <i>Ex Vivo</i>
            and Oropharyngeal Colonization of Human Pathogen Group A Streptococcus

Makthal, Nishanth; Do, Hackwon; VanderWal, Arica R.; Olsen, Randall J.; Musser, James M.; Kumaraswami, Muthiah

doi:10.1128/iai.00169-18

Cited by 15 publications

(17 citation statements)

References 61 publications

(84 reference statements)

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“…SpeB is one of the most extensively characterized GAS virulence factor for its role in disease pathogenesis 25–32 . SpeB is produced during human infection and crucial for GAS virulence in several animal models of infection 26–28,33–35 . Proteolytic cleavage of host and bacterial proteins by SpeB contributes significantly to host tissue damage and disease dissemination 25 .…”

Section: Introductionmentioning

confidence: 99%

“…Proteolytic cleavage of host and bacterial proteins by SpeB contributes significantly to host tissue damage and disease dissemination 25 . Consistent with its contribution to pathogenesis, GAS employs elaborate transcriptional and post-transcriptional regulatory mechanisms to control spatiotemporal production of SpeB 25,30,31,35–39 .…”

Section: Introductionmentioning

confidence: 99%

“…1a). Each component of the SIP signaling pathway must be functional for a wild-type virulence phenotype 35,37,43 . Thus, the SIP regulatory circuit is the primary signaling mechanism controlling speB transcription in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

Makthal

VanderWal

et al. 2019

Nat Commun

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Bacteria control gene expression in concert with their population density by a process called quorum sensing, which is modulated by bacterial chemical signals and environmental factors. In the human pathogen Streptococcus pyogenes , production of secreted virulence factor SpeB is controlled by a quorum-sensing pathway and environmental pH. The quorum-sensing pathway consists of a secreted leaderless peptide signal (SIP), and its cognate receptor RopB. Here, we report that the SIP quorum-sensing pathway has a pH-sensing mechanism operative through a pH-sensitive histidine switch located at the base of the SIP-binding pocket of RopB. Environmental acidification induces protonation of His144 and reorganization of hydrogen bonding networks in RopB, which facilitates SIP recognition. The convergence of two disparate signals in the SIP signaling pathway results in induction of SpeB production and increased bacterial virulence. Our findings provide a model for investigating analogous crosstalk in other microorganisms.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

Makthal

VanderWal

et al. 2019

Nat Commun

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“…Although the phosphorylation level of CovR was decreased in both the covS and rocA mutants, Jain et al ( 10 ) showed that the rocA mutant outcompeted the covS mutant in the competition assay of the ex vivo respiratory tract infection model. The importance of the cysteine protease SpeB in pharyngeal colonization was recently demonstrated ( 23 ). Therefore, these results suggest that the ability of the rocA mutant to phosphorylate CovR and secrete SpeB protease could be crucial for GAS to establish infections in the respiratory tract.…”

Section: Discussionmentioning

confidence: 97%

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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“…The expression pattern of the cysteine protease SpeB is typically inversely related to CovR-repressed genes and its impact on GAS survival during skin and soft tissue infections is well-documented (Johansson et al, 2010; Mayfield et al, 2014; Brouwer et al, 2018). The importance of SpeB in pharyngeal colonization, along with the RopB-SIP quorum sensing system that regulates speB expression, was recently tested (Makthal et al, 2018). Deletions of speB, ropB , or the small open reading frame encoding the SIP pheromone each led to decreased colonization of the mouse oropharynx when examined via cultured throat swabs over a period of 7 days.…”

Section: The Murine Pharyngeal Colonization Modelmentioning

confidence: 99%

Modeling Streptococcus pyogenes Pharyngeal Colonization in the Mouse

Gogos

Federle

2019

Front. Cell. Infect. Microbiol.

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Streptococcus pyogenes , or Group A Streptococcus (GAS), is a human-restricted pathogen most commonly found in the posterior oropharynx of the human host. The bacterium is responsible for 600 million annual cases of pharyngitis globally and has been found to asymptomatically colonize the pharynxes of 4–30% of the population. As such, many studies have utilized animals as models in order to decipher bacterial and host elements that contribute to the bacterial-pharyngeal interaction and determine differences between acute infection and asymptomatic colonization. The aim of this review is to first describe both bacterial and host factors that are important for the pharyngeal persistence of GAS in humans, then to detail the bacterial and host factors that are important for colonization in murine model, and finally to compare the two in order to evaluate the strength of murine pharyngeal colonization as a model for the human-GAS pharyngeal interaction.

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Signaling by a Conserved Quorum Sensing Pathway Contributes to Growth Ex Vivo and Oropharyngeal Colonization of Human Pathogen Group A Streptococcus

Cited by 15 publications

References 61 publications

Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

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

Modeling Streptococcus pyogenes Pharyngeal Colonization in the Mouse

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