title: Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes.
abstract: Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown.
  
  
  
  To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses.
  
  
  
  Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors. We subjected these strains to whole-genome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility.
  
  
  
  We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis.
  
  
  
  In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro.
authors.affiliation: 1 National Institute for Public Health and the Environment, Bilthoven, the Netherlands.|2 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|3 ICVS/3B's Research Group, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Hanna
authors.initials: H
authors.lastname: Nebenzahl-Guimaraes
authors.affiliation: 4 Department of Internal Medicine and Radboud Center for Infectious Diseases.
authors.forename: Arjan
authors.identifier: 0000-0002-6607-4075
authors.initials: A
authors.lastname: van Laarhoven
authors.affiliation: 5 Pulmonary and Critical Care Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maha R
authors.initials: MR
authors.lastname: Farhat
authors.affiliation: 4 Department of Internal Medicine and Radboud Center for Infectious Diseases.
authors.forename: Valerie A C M
authors.identifier: 0000-0002-5783-9013
authors.initials: VACM
authors.lastname: Koeken
authors.affiliation: 6 University of Wageningen, Wageningen, the Netherlands.
authors.forename: Jornt J
authors.identifier: 0000-0002-1718-6599
authors.initials: JJ
authors.lastname: Mandemakers
authors.affiliation: 7 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, and.|8 Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
authors.forename: Aldert
authors.initials: A
authors.lastname: Zomer
authors.affiliation: 7 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, and.
authors.forename: Sacha A F T
authors.initials: SAFT
authors.lastname: van Hijum
authors.affiliation: 4 Department of Internal Medicine and Radboud Center for Infectious Diseases.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: 9 Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts; and.|10 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Megan
authors.initials: M
authors.lastname: Murray
authors.affiliation: 4 Department of Internal Medicine and Radboud Center for Infectious Diseases.
authors.forename: Reinout
authors.identifier: 0000-0001-7445-0854
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: 1 National Institute for Public Health and the Environment, Bilthoven, the Netherlands.|11 Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
mesh_terms: D005819:Genetic Markers / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics* / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology*; D010641:Phenotype
chemical_list: D005819:Genetic Markers
keywords: bacterial genomes; immunology; transmission; tuberculosis