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Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.

ABSTRACT: Streptococcus pyogenes causes 700 million human infections annually worldwide, yet, despite a century of intensive effort, there is no licensed vaccine against this bacterium. Although a number of large-scale genomic studies of bacterial pathogens have been published, the relationships among the genome, transcriptome, and virulence in large bacterial populations remain poorly understood. We sequenced the genomes of 2,101 emm28 S. pyogenes invasive strains, from which we selected 492 phylogenetically diverse strains for transcriptome analysis and 50 strains for virulence assessment. Data integration provided a novel understanding of the virulence mechanisms of this model organism. Genome-wide association study, expression quantitative trait loci analysis, machine learning, and isogenic mutant strains identified and confirmed a one-nucleotide indel in an intergenic region that significantly alters global transcript profiles and ultimately virulence. The integrative strategy that we used is generally applicable to any microbe and may lead to new therapeutics for many human pathogens.

SUBMITTER: Kachroo P

PROVIDER: S-EPMC8547240 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.

Kachroo Priyanka P Eraso Jesus M JM Beres Stephen B SB Olsen Randall J RJ Zhu Luchang L Nasser Waleed W Bernard Paul E PE Cantu Concepcion C CC Saavedra Matthew Ojeda MO Arredondo María José MJ Strope Benjamin B Do Hackwon H Kumaraswami Muthiah M Vuopio Jaana J Gröndahl-Yli-Hannuksela Kirsi K Kristinsson Karl G KG Gottfredsson Magnus M Pesonen Maiju M Pensar Johan J Davenport Emily R ER Clark Andrew G AG Corander Jukka J Caugant Dominique A DA Gaini Shahin S Magnussen Marita Debess MD Kubiak Samantha L SL Nguyen Hoang A T HAT Long S Wesley SW Porter Adeline R AR DeLeo Frank R FR Musser James M JM

Nature genetics 20190218 3

Streptococcus pyogenes causes 700 million human infections annually worldwide, yet, despite a century of intensive effort, there is no licensed vaccine against this bacterium. Although a number of large-scale genomic studies of bacterial pathogens have been published, the relationships among the genome, transcriptome, and virulence in large bacterial populations remain poorly understood. We sequenced the genomes of 2,101 emm28 S. pyogenes invasive strains, from which we selected 492 phylogenetic ...[more]

PMID: 30778225

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Project description:UnlabelledThe two-component control of virulence (Cov) regulator (R)-sensor (S) (CovRS) regulates the virulence of Streptococcus pyogenes (group A Streptococcus [GAS]). Inactivation of CovS during infection switches the pathogenicity of GAS to a more invasive form by regulating transcription of diverse virulence genes via CovR. However, the manner in which CovRS controls virulence through expression of extended gene families has not been fully determined. In the current study, the CovS-regulated gene expression profiles of a hypervirulent emm23 GAS strain (M23ND/CovS negative [M23ND/CovS(-)]) and a noninvasive isogenic strain (M23ND/CovS(+)), under different growth conditions, were investigated. RNA sequencing identified altered expression of ∼ 349 genes (18% of the chromosome). The data demonstrated that M23ND/CovS(-) achieved hypervirulence by allowing enhanced expression of genes responsible for antiphagocytosis (e.g., hasABC), by abrogating expression of toxin genes (e.g., speB), and by compromising gene products with dispensable functions (e.g., sfb1). Among these genes, several (e.g., parE and parC) were not previously reported to be regulated by CovRS. Furthermore, the study revealed that CovS also modulated the expression of a broad spectrum of metabolic genes that maximized nutrient utilization and energy metabolism during growth and dissemination, where the bacteria encounter large variations in available nutrients, thus restructuring metabolism of GAS for adaption to diverse growth environments. From constructing a genome-scale metabolic model, we identified 16 nonredundant metabolic gene modules that constitute unique nutrient sources. These genes were proposed to be essential for pathogen growth and are likely associated with GAS virulence. The genome-wide prediction of genes associated with virulence identifies new candidate genes that potentially contribute to GAS virulence.ImportanceThe CovRS system modulates transcription of ∼ 18% of the genes in the Streptococcus pyogenes genome. Mutations that inactivate CovR or CovS enhance the virulence of this bacterium. We determined complete transcriptomes of a naturally CovS-inactivated invasive deep tissue isolate of an emm23 strain of S. pyogenes (M23ND) and its complemented avirulent variant (CovS(+)). We identified diverse virulence genes whose altered expression revealed a genetic switching of a nonvirulent form of M23ND to a highly virulent strain. Furthermore, we also systematically uncovered for the first time the comparative levels of expression of a broad spectrum of metabolic genes, which reflected different metabolic needs of the bacterium as it invaded deeper tissue of the human host.

Dataset Information

Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.

Publications

Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.

Similar Datasets

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