title: Transcriptome Remodeling Contributes to Epidemic Disease Caused by the Human Pathogen Streptococcus pyogenes.
abstract: For over a century, a fundamental objective in infection biology research has been to understand the molecular processes contributing to the origin and perpetuation of epidemics. Divergent hypotheses have emerged concerning the extent to which environmental events or pathogen evolution dominates in these processes. Remarkably few studies bear on this important issue. Based on population pathogenomic analysis of 1,200 Streptococcus pyogenes type emm89 infection isolates, we report that a series of horizontal gene transfer events produced a new pathogenic genotype with increased ability to cause infection, leading to an epidemic wave of disease on at least two continents. In the aggregate, these and other genetic changes substantially remodeled the transcriptomes of the evolved progeny, causing extensive differential expression of virulence genes and altered pathogen-host interaction, including enhanced immune evasion. Our findings delineate the precise molecular genetic changes that occurred and enhance our understanding of the evolutionary processes that contribute to the emergence and persistence of epidemically successful pathogen clones. The data have significant implications for understanding bacterial epidemics and for translational research efforts to blunt their detrimental effects.
  
  
  
  The confluence of studies of molecular events underlying pathogen strain emergence, evolutionary genetic processes mediating altered virulence, and epidemics is in its infancy. Although understanding these events is necessary to develop new or improved strategies to protect health, surprisingly few studies have addressed this issue, in particular, at the comprehensive population genomic level. Herein we establish that substantial remodeling of the transcriptome of the human-specific pathogen Streptococcus pyogenes by horizontal gene flow and other evolutionary genetic changes is a central factor in precipitating and perpetuating epidemic disease. The data unambiguously show that the key outcome of these molecular events is evolution of a new, more virulent pathogenic genotype. Our findings provide new understanding of epidemic disease.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beres
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kachroo
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Waleed
authors.initials: W
authors.lastname: Nasser
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA Departments of Pathology and Laboratory Medicine and Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Luchang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Flores
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: de la Riva
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Paez-Mayorga
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Jimenez
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Cantu
authors.affiliation: Department of Medical Microbiology and Immunology, Medical Faculty, University of Turku, Turku, Finland Department of Infectious Diseases, National Institute for Health and Welfare, Turku, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Vuopio
authors.affiliation: Department of Infectious Diseases, National Institute for Health and Welfare, Turku, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Jalava
authors.affiliation: Departments of Clinical Microbiology and Infectious Diseases, Landspitali University Hospital, Reykjavik, Iceland Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Kristinsson
authors.affiliation: Departments of Clinical Microbiology and Infectious Diseases, Landspitali University Hospital, Reykjavik, Iceland Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gottfredsson
authors.affiliation: Department of Biostatistics, University of Oslo, Oslo, Norway, and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Corander
authors.affiliation: Public Health Ontario, and Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nahuel
authors.initials: N
authors.lastname: Fittipaldi
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Di Luca
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Dezemona
authors.initials: D
authors.lastname: Petrelli
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Vitali
authors.affiliation: Comparative Medicine Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Annessa
authors.initials: A
authors.lastname: Raiford
authors.affiliation: Comparative Medicine Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Jenkins
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, and Houston Methodist Hospital, Houston, Texas, USA Departments of Pathology and Laboratory Medicine and Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA jmmusser@houstonmethodist.org.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics*; D058872:Epidemics / Q000517:prevention & control; D019143:Evolution, Molecular; D022761:Gene Transfer, Horizontal; D016680:Genome, Bacterial; D005838:Genotype; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D013290:Streptococcal Infections / Q000453:epidemiology* / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D059467:Transcriptome; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors