CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus

Horstmann, Nicola; Myers, Kevin S.; Tran, Chau Nguyen; Flores, Anthony R.; Shelburne III, Samuel A.

doi:10.1371/journal.ppat.1010341

Title: CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus

Journal Article · 17 February 2022 · PLoS Pathogens

DOI: https://doi.org/10.1371/journal.ppat.1010341 · OSTI ID:1904236

Horstmann, Nicola ^[1]; Myers, Kevin S. ^[2]; Tran, Chau Nguyen ^[3]; Flores, Anthony R. ^[3];

^[3]

University of Texas, Houston, TX (United States); Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center
University of Wisconsin, Madison, WI (United States)
University of Texas, Houston, TX (United States)

The control of virulence gene regulator (CovR), also called caspsule synthesis regulator (CsrR), is critical to how the major human pathogen group A Streptococcus fine-tunes virulence factor production. CovR phosphorylation (CovR~P) levels are determined by its cognate sensor kinase CovS, and functional abrogating mutations in CovS can occur in invasive GAS isolates leading to hypervirulence. Presently, the mechanism of CovR-DNA binding specificity is unclear, and the impact of CovS inactivation on global CovR binding has not been assessed. Thus, we performed CovR chromatin immunoprecipitation sequencing (ChIP-seq) analysis in the emm1 strain MGAS2221 and its CovS kinase deficient derivative strain 2221-CovS-E281A. We identified that CovR bound in the promoter regions of nearly all virulence factor encoding genes in the CovR regulon. Additionally, direct CovR binding was observed for numerous genes encoding proteins involved in amino acid metabolism, but we found limited direct CovR binding to genes encoding other transcriptional regulators. The consensus sequence AATRANAAAARVABTAAA was present in the promoters of genes directly regulated by CovR, and mutations of highly conserved positions within this motif relieved CovR repression of the hasA and MGAS2221_0187 promoters. Analysis of strain 2221-CovS-E281A revealed that binding of CovR at repressed, but not activated, promoters is highly dependent on CovR~P state. CovR repressed virulence factor encoding genes could be grouped dependent on how CovR~P dependent variation in DNA binding correlated with gene transcript levels. Taken together, the data show that CovR repression of virulence factor encoding genes is primarily direct in nature, involves binding to a newly-identified DNA binding motif, and is relieved by CovS inactivation. These data provide new mechanistic insights into one of the most important bacterial virulence regulators and allow for subsequent focused investigations into how CovR-DNA interaction at directly controlled promoters impacts GAS pathogenesis.

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Research Organization:: University of Wisconsin, Madison, WI (United States)

Sponsoring Organization:: National Institute of Allergy and Infectious Diseases; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0018409

OSTI ID:: 1904236

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 2 Vol. 18; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA
DNA-binding proteins
gene expression
gene regulation
promoter regions
regulator genes
sequence motif analysis
virulence factors

Title: CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus

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