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Regulatory Rewiring Confers Serotype-Specific Hyper-Virulence in the Human Pathogen Group A Streptococcus

ABSTRACT: We sequenced mRNA transcripts from three isogenic M3 serotype GAS strains, parental (MGAS10870), complement (10870::rocAM1), and deletion (10870ΔrocA). There were no significant changes between the parental and revertant strain. Comparison of the parental and complemented strain revealed several virulence factors were up-regulated in the parental strain where RocA function was diminished. We concluded that RocA, through direct or indirect mechanisms, is able to control numerous virulence genes and this lack of RocA regulation increases expression of virulence factors, which contributes to the hyper-virulent state of serotype M3 GAS.

ORGANISM(S): Streptococcus pyogenes

PROVIDER: GSE68277 | GEO | 2015/08/24

SECONDARY ACCESSION(S): PRJNA282372

REPOSITORIES: GEO

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Project description:Recent whole-genome sequencing of large populations of the same bacterial species has revealed significant disparity among genes in the frequency of single nucleotide polymorphisms (SNPs). For example, a previous analysis of invasive serotype M3 group A streptococci (GAS) found the highest frequency of SNPs in the gene (ropB) encoding the regulator of proteinase B (RopB). This finding led us to hypothesize that RopB polymorphisms contribute to altered GAS host-pathogen interactions. Sequencing of ropB in 171 invasive serotype M3 GAS strains from a surveillance study identified 19 distinct ropB alleles. Inactivation of the ropB gene in strains producing distinct RopB variants had dramatically different effects on GAS global gene expression. Further, analysis of laboratory-generated isoallelic GAS strains differing only by a single amino acid replacement in RopB confirmed that the variant protein affected the transcript level of the gene encoding streptococcal proteinase B, a major RopB-regulated virulence factor. Comparison of parental, RopB-inactivated, and RopB isoallelic strains in mouse infection models demonstrated that RopB polymorphisms significantly influence GAS virulence and disease manifestations. These studies detail a paradigm in which unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections. This study examined the effects of RopB inactivaiton on two distinct serotype M3 group A streptococcal strains with distinct forms of the RopB protein. RopB was inactivated in a strain with a wild-type RopB allele (strain MGAS10870) and in a strain with a RopB allele containing a C85Y polymorphism (strain MGAS9937). The wild-type and RopB inactivated strains were grown in duplicate to the early stationary growth phase in standard laboratory medium (THY). Total RNA was isolated, converted to cDNA, and hybridized to a custom-made Affymetrix GeneChip.

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Regulatory Rewiring Confers Serotype-Specific Hyper-Virulence in the Human Pathogen Group A Streptococcus

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