Phenotypic Variation in the Group A
            <i>Streptococcus</i>
            Due to Natural Mutation of the Accessory Protein-Encoding Gene
            <i>rocA</i>

Sarkar, Poulomee; Danger, Jessica L.; Jain, Ira; Meadows, Laura A.; Beam, Christopher R.; Medicielo, Josette; Burgess, Cameron; Musser, James M.; Sumby, Paul

doi:10.1128/msphere.00519-18

Cited by 8 publications

(5 citation statements)

References 65 publications

(117 reference statements)

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“…RocA has homology to membrane‐spanning sensor kinases, although it is unclear whether RocA has kinase activity or rather is a pseudokinase (Lynskey et al , ; Jain et al ., ; Sarkar et al , ). The regulatory activity of RocA occurs through its ability to enhance CovR/S system function (Miller et al , ).…”

Section: Introductionmentioning

confidence: 98%

The group A Streptococcus accessory protein RocA: regulatory activity, interacting partners and influence on disease potential

Jain

Danger

Burgess

et al. 2019

Molecular Microbiology

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The group A Streptococcus (GAS) causes diseases that range from mild (e.g. pharyngitis) to severely invasive (e.g. necrotizing fasciitis). Strain-and serotypespecific differences influence the ability of isolates to cause individual diseases. At the center of this variability is the CovR/S two-component system and the accessory protein RocA. Through incompletely defined mechanisms, CovR/S and RocA repress the expression of more than a dozen immunomodulatory virulence factors. Alleviation of this repression is selected for during invasive infections, leading to the recovery of covR, covS or rocA mutant strains. Here, we investigated how RocA promotes CovR/S activity, identifying that RocA is a pseudokinase that interacts with CovS. Disruption of CovS kinase or phosphatase activities abolishes RocA function, consistent with RocA acting through the modulation of CovS activity. We also identified, in conflict with a previous study, that the RocA regulon includes the secreted protease-encoding gene speB. Finally, we discovered an inverse correlation between the virulence of wild-type, rocA mutant, covS mutant and covR mutant strains during invasive infection and their fitness in an ex vivo upper respiratory tract model. Our data inform on mechanisms that control GAS disease potential and provide an explanation for observed strain-and serotype-specific variability in RocA function.

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Section: Introductionmentioning

confidence: 98%

The group A Streptococcus accessory protein RocA: regulatory activity, interacting partners and influence on disease potential

Jain

Danger

Burgess

et al. 2019

Molecular Microbiology

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“…45 Our interest in RocA is based on serotype M28 GAS whole-genome sequencing studies of strains collected from human invasive infections. 43,46 Although previous molecular pathogenesis studies bearing on RocA have investigated strains with laboratory-generated gene deletions and protein truncations, 39e44, 47 we discovered that the number of missense (amino acidealtering) and nonsense (protein-truncating) polymorphisms in rocA within the M28 population studied was higher than expected ( Figure 1A). 43,46 We hypothesized that naturally occurring polymorphisms in rocA result in altered RocA function and contribute to the molecular pathogenesis of serotype M28 GAS invasive infections.…”

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confidence: 63%

“…43 Although rocA polymorphisms in other GAS serotype strains result in increased ska transcript and SKA protein levels, rocA polymorphisms in M28 GAS strains cause decreased ska transcript levels and secreted SKA activity ( Supplemental Table S6 and Figure 4). 40,43,44,47 The ska gene is regulated by the FasBCA/fasX and CovRS systems, 21,22,29e31,33,37,55,86 and decreased fasX transcripts in the isogenic RocA T442P mutant strain likely resulted in a more severely decreased SKA activity phenotype (Figure 4). Our data suggest that RocA may interact, either directly or indirectly, with the FasBCA/fasX system to alter SKA activity.…”

Section: Discussionmentioning

confidence: 99%

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

Bernard

Kachroo

Eraso

et al. 2019

The American Journal of Pathology

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Two-component systems (TCSs) are signal transduction proteins that enable bacteria to respond to external stimuli by altering the global transcriptome. Accessory proteins interact with TCSs to fine-tune their activity. In group A Streptococcus (GAS), regulator of Cov (RocA) is an accessory protein that functions with the control of virulence regulator/sensor TCS, which regulates approximately 15% of the GAS transcriptome. Whole-genome sequencing analysis of serotype M28 GAS strains collected from invasive infections in humans identified a higher number of missense (amino acidealtering) and nonsense (protein-truncating) polymorphisms in rocA than expected. We hypothesized that polymorphisms in RocA alter the global transcriptome and virulence of serotype M28 GAS. We used naturally occurring clinical isolates with rocA polymorphisms (n Z 48), an isogenic rocA deletion mutant strain, and five isogenic rocA polymorphism mutant strains to perform genome-wide transcript analysis (RNA sequencing), in vitro virulence factor assays, and mouse and nonhuman primate pathogenesis studies to test this hypothesis. Results demonstrated that polymorphisms in rocA result in either a subtle transcriptome change, causing a wild-typeelike virulence phenotype, or a substantial transcriptome change, leading to a significantly increased virulence phenotype. Each polymorphism had a unique effect on the global GAS transcriptome. Taken together, our data show that naturally occurring polymorphisms in one gene encoding an accessory protein can significantly alter the global transcriptome and virulence phenotype of GAS, an important human pathogen.

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“…These data are summarized in Table 4 , and the mga polymorphisms at the polycytidine tract and base 1657 of 106 M12 genomes are listed in Supplementary Table S2 . It is interesting that two of the three strains with nonfunctional c.1574C[7]/1657G mga variant 1, ATCC 11434 ( Tanaka et al, 2020 ) and MGAS2096 ( Sarkar et al, 2018 ), were isolated from patients with acute poststreptococcal glomerulonephritis, and the infection nature of the third strain, NCTC8300, is not known. The data indicate that the length polymorphism of Mga is caused through arising the nonfunctional c.1574C[7]/1657G mga variant and restoring the function of the nonfunctional c.1574C[7]/1657G mga variant by the additional C deletion at the c.1574C[7] tract or the G-to-A mutation at base 1657.…”

Section: Resultsmentioning

confidence: 99%

Section: Polymorphisms Of the Polycytidine Tract Of Mga-1 In Sequence...mentioning

confidence: 99%

Slipped-strand mispairing within a polycytidine tract in transcriptional regulator mga leads to M protein phase variation and Mga length polymorphism in Group A Streptococcus

et al. 2023

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The M protein, a major virulence factor of Group A Streptococcus (GAS), is regulated by the multigene regulator Mga. An unexplained phenomena frequently occurring with in vitro genetic manipulation or culturing of M1T1 GAS strains is the loss of M protein production. This study was aimed at elucidating the basis for the loss of M protein production. The majority of M protein-negative (M−) variants had one C deletion at a tract of 8 cytidines starting at base 1,571 of the M1 mga gene, which is designated as c.1571C[8]. The C deletion led to a c.1571C[7] mga variant that has an open reading frame shift and encodes a Mga-M protein fusion protein. Transformation with a plasmid containing wild-type mga restored the production of the M protein in the c.1571C[7] mga variant. Isolates producing M protein (M+) were recovered following growth of the c.1571C[7] M protein-negative variant subcutaneously in mice. The majority of the recovered isolates with reestablished M protein production had reverted back from c.1571C[7] to c.1571C[8] tract and some M+ isolates lost another C in the c.1571C[7] tract, leading to a c.1571C[6] variant that encodes a functional Mga with 13 extra amino acid residues at the C-terminus compared with wild-type Mga. The nonfunctional c.1571C[7] and functional c.1571C[6] variants are present in M1, M12, M14, and M23 strains in NCBI genome databases, and a G-to-A nonsense mutation at base 1,657 of M12 c.1574C[7] mga leads to a functional c.1574C[7]/1657A mga variant and is common in clinical M12 isolates. The numbers of the C repeats in this polycytidine tract and the polymorphism at base 1,657 lead to polymorphism in the size of Mga among clinical isolates. These findings demonstrate the slipped-strand mispairing within the c.1574C[8] tract of mga as a reversible switch controlling M protein production phase variation in multiple GAS common M types.

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Phenotypic Variation in the Group A Streptococcus Due to Natural Mutation of the Accessory Protein-Encoding Gene rocA

Cited by 8 publications

References 65 publications

The group A Streptococcus accessory protein RocA: regulatory activity, interacting partners and influence on disease potential

The group A Streptococcus accessory protein RocA: regulatory activity, interacting partners and influence on disease potential

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

Slipped-strand mispairing within a polycytidine tract in transcriptional regulator mga leads to M protein phase variation and Mga length polymorphism in Group A Streptococcus

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