title: Within Host Evolution Selects for a Dominant Genotype of Mycobacterium tuberculosis while T Cells Increase Pathogen Genetic Diversity.
abstract: Molecular epidemiological assessments, drug treatment optimization, and development of immunological interventions all depend on understanding pathogen adaptation and genetic variation, which differ for specific pathogens. Mycobacterium tuberculosis is an exceptionally successful human pathogen, yet beyond knowledge that this bacterium has low overall genomic variation but acquires drug resistance mutations, little is known of the factors that drive its population genomic characteristics. Here, we compared the genetic diversity of the bacteria that established infection to the bacterial populations obtained from infected tissues during murine M. tuberculosis pulmonary infection and human disseminated M. bovis BCG infection. We found that new mutations accumulate during in vitro culture, but that in vivo, purifying selection against new mutations dominates, indicating that M. tuberculosis follows a dominant lineage model of evolution. Comparing bacterial populations passaged in T cell-deficient and immunocompetent mice, we found that the presence of T cells is associated with an increase in the diversity of the M. tuberculosis genome. Together, our findings put M. tuberculosis genetic evolution in a new perspective and clarify the impact of T cells on sequence diversity of M. tuberculosis.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Copin
authors.affiliation: Department of Mathematics and Statistics, Washington State University, Pullman, WA, United States of America.
authors.forename: Xueying
authors.identifier: http://orcid.org/0000-0001-6445-8887
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY, United States of America.
authors.forename: Eddie
authors.initials: E
authors.lastname: Louie
authors.affiliation: Microbiology laboratory, Wadsworth Center, New York State Department of Health, Albany, NY, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Escuyer
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Mireia
authors.identifier: http://orcid.org/0000-0003-0752-0538
authors.initials: M
authors.lastname: Coscolla
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA, United States of America.
authors.forename: Guy H
authors.initials: GH
authors.lastname: Palmer
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY, United States of America.|Department of Microbiology, New York University School of Medicine, New York, NY, United States of America.|Department of Pathology, New York University School of Medicine, New York, NY, United States of America.
authors.forename: Joel D
authors.identifier: http://orcid.org/0000-0001-9951-6207
authors.initials: JD
authors.lastname: Ernst
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology*