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Hyperphosphorylation of the Group A Streptococcal Control of Virulence Regulator Increases Promoter Occupancy Specifically at Virulence Factor Encoding Genes

ABSTRACT: The control of virulence two-component gene regulatory system (CovRS) is critical to the pathogenesis of many medically important streptococci. In emm1 group A streptococci (GAS), CovR directly binds the promoters of numerous GAS virulence factor encoding genes. Elimination of CovS phosphatase activity increases CovR phosphorylation (CovR~P) levels and abrogates GAS virulence. Given the emm type-specific diversity of CovRS function, herein we used ChIP-seq to define global CovR DNA occupancy in the wild-type emm3 strain MGAS10870 (medium CovR~P) and its CovS phosphatase-negative derivative 10870-CovS-T284A (high CovR~P). In the wild-type emm3 strain, 89% of the previously identified emm1 CovR binding sites present in the emm3 genome were also enriched; additionally, we ascertained unique CovR binding, primarily to genes in mobile genetic elements and other sites of inter-strain chromosomal differences. Elimination of phosphatase activity specifically increased CovR occupancy at the promoters of a broad array of CovR repressed virulence factor encoding genes, including those encoding the key GAS regulator Mga and M protein. However, a limited number of promoters had augmented enrichment at low CovR~P levels. Differential motif searches using sequences enriched at high vs. low CovR~P levels revealed two distinct binding patterns. At high CovR~P, a pseudo-palindromic AT-rich consensus sequence consistent with CovR binding as a dimer was determined. Conversely, sequences specifically enriched at low CovR~P contained isolated “ATTARA” motifs suggesting an interaction with a monomer. These data extend understanding of global CovR DNA occupancy beyond emm1 GAS and provide a mechanism for previous observations regarding hypovirulence induced by CovS phosphatase abrogation.

ORGANISM(S): Streptococcus pyogenes

PROVIDER: GSE230870 | GEO | 2023/05/31

REPOSITORIES: GEO

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Project description:In bacteria, phenotypic heterogeneity rescues the need for diversity in isogenic populations and allow concomitant multiple survival strategies when choosing only one is too risky. This powerful tactic is exploited for competence in streptococci and results in a bimodal activation, where only a subset of the community triggers the system. Deciphering the mechanisms underlying this puzzling behavior has remained challenging, especially since its study has been mainly achieved in S. mutans, where two different but interconnected regulation networks control competence. In this work, we sought to determine the origin of bimodality associated to the ComRS system thanks to the simplified S. salivarius model that harbors no supplemental signaling system. Using a single cell fluorescence reporter system together with the overexpression of the main actors of the regulation network, we showed that the ComR intracellular concentration is directly linked to the proportion of competent cells in the population. We report that this type of activation requires a functional positive feedback loop acting on comS through Opp and a putative ComS exporter, PptAB. To determine the origin of the heterogeneity amplified by the loop, we developed a mathematical model suggesting that either noise on ComS or ComR abundance could explain bimodality. Because ComR abundance is central for competence bimodal activation, we conducted an in silico identification and a systematic deletion of all the Two Component Systems (TCS) present in S. salivarius and identified CovRS, a well described virulence regulator in GAS and GBS, as a repressor of comR transcription. In vitro direct binding of CovR with the promoter of comR and transcriptomics confirmed those data. As CovRS integrates environmental stimuli that control ComR intracellular concentration, it represents the missing puzzle piece bridging environmental conditions and competence (bimodal) activation in salivarius streptococci.

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Hyperphosphorylation of the Group A Streptococcal Control of Virulence Regulator Increases Promoter Occupancy Specifically at Virulence Factor Encoding Genes

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