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Nat Genet. 2019 Mar;51(3):548-559. doi: 10.1038/s41588-018-0343-1. Epub 2019 Feb 18.

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

Author information

1
Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA.
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
3
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
4
Institute of Biomedicine, Medical Microbiology and Immunology, University of Turku, Turku, Finland.
5
National Institute for Health and Welfare, Helsinki, Finland.
6
Department of Clinical Microbiology, Landspitali University Hospital, Reykjavik, Iceland.
7
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
8
Department of Infectious Diseases, Landspitali University Hospital, Reykjavik, Iceland.
9
Helsinki Institute of Information Technology, Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
10
Department of Computer Science, Aalto University, Espoo, Finland.
11
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
12
Department of Biostatistics, University of Oslo, Oslo, Norway.
13
Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
14
Medical Department, Infectious Diseases Division, National Hospital of the Faroe Islands, Tórshavn, Denmark.
15
Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.
16
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
17
Department of Science and Technology, Centre of Health Research, University of the Faroe Islands, Tórshavn, Denmark.
18
Thetis, Food and Environmental Laboratory, Torshavn, Denmark.
19
Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
20
Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA. JMMusser@houstonmethodist.org.
21
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. JMMusser@houstonmethodist.org.
22
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA. JMMusser@houstonmethodist.org.

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.

PMID:
30778225
DOI:
10.1038/s41588-018-0343-1
[Indexed for MEDLINE]

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