TY - JOUR
T1 - Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis
AU - Kachroo, Priyanka
AU - Eraso, Jesus M.
AU - Beres, Stephen B.
AU - Olsen, Randall J.
AU - Zhu, Luchang
AU - Nasser, Waleed
AU - Bernard, Paul E.
AU - Cantu, Concepcion C.
AU - Saavedra, Matthew Ojeda
AU - Arredondo, María José
AU - Strope, Benjamin
AU - Do, Hackwon
AU - Kumaraswami, Muthiah
AU - Vuopio, Jaana
AU - Gröndahl-Yli-Hannuksela, Kirsi
AU - Kristinsson, Karl G.
AU - Gottfredsson, Magnus
AU - Pesonen, Maiju
AU - Pensar, Johan
AU - Davenport, Emily R.
AU - Clark, Andrew G.
AU - Corander, Jukka
AU - Caugant, Dominique A.
AU - Gaini, Shahin
AU - Magnussen, Marita Debess
AU - Kubiak, Samantha L.
AU - Nguyen, Hoang A.T.
AU - Long, S. Wesley
AU - Porter, Adeline R.
AU - DeLeo, Frank R.
AU - Musser, James M.
N1 - Funding Information:
This study was supported in part by the Fondren Foundation, Houston Methodist Hospital and Research Institute (to J.M.M.), the Academy of Finland (grant 255636 to J.V.), a European Research Council grant (number 742158 to J.C.), and a National Institutes of Health grant (1R01AI109096-01A1 to M.K.). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health (to F.R.D.). We thank N. Copeland, N. Jenkins, and D. Ginsburg for critical comments and suggestions to improve the manuscript; K. Stockbauer for critical comments and editorial assistance; E. Graviss, H. Erlendsdottir, W. Hong, and S. Linson for technical assistance; H.-L. Hyyryläinen, J. Jalava, and the Finnish clinical microbiology laboratories; A. A. Shishkin for helpful suggestions regarding the RNAtag-seq protocol; M. Todorovic and J. Jonsdottir Nielsen for banking strains from the Faroe Islands; A. McGeer for Ontario strains; C. Van Beneden, B. Beall, and the Active Bacterial Core Surveillance of the CDC’s Emerging Infections Programs network; A. Ramstad Alme and A. Witsø for technical assistance; and M. Steinbakk (Norwegian Laboratory for Streptococci) for support.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-018-0343-1
DO - 10.1038/s41588-018-0343-1
M3 - Article
C2 - 30778225
AN - SCOPUS:85060887096
SN - 1061-4036
VL - 51
SP - 548
EP - 559
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -