title: Whole-Genome Sequencing of Mycobacterium tuberculosis Provides Insight into the Evolution and Genetic Composition of Drug-Resistant Tuberculosis in Belarus.
abstract: The emergence and spread of drug-resistant Mycobacterium tuberculosis (DR-TB) are critical global health issues. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. To better understand the genetic composition and evolution of MDR- and XDR-TB in the region, we sequenced and analyzed the genomes of 138 M. tuberculosis isolates from 97 patients sampled between 2010 and 2013 in Minsk, Belarus. MDR and XDR-TB isolates were significantly more likely to belong to the Beijing lineage than to the Euro-American lineage, and known resistance-conferring loci accounted for the majority of phenotypic resistance to first- and second-line drugs in MDR and XDR-TB. Using a phylogenomic approach, we estimated that the majority of MDR-TB was due to the recent transmission of already-resistant M. tuberculosis strains rather than repeated de novo evolution of resistance within patients, while XDR-TB was acquired through both routes. Longitudinal sampling of M. tuberculosis from 34 patients with treatment failure showed that most strains persisted genetically unchanged during treatment or acquired resistance to fluoroquinolones. HIV+ patients were significantly more likely to have multiple infections over time than HIV- patients, highlighting a specific need for careful infection control in these patients. These data provide a better understanding of the genomic composition, transmission, and evolution of MDR- and XDR-TB in Belarus and will enable improved diagnostics, treatment protocols, and prognostic decision-making.
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Wollenberg
authors.affiliation: The Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Desjardins
authors.affiliation: Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
authors.forename: Aksana
authors.initials: A
authors.lastname: Zalutskaya
authors.affiliation: Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
authors.forename: Vervara
authors.initials: V
authors.lastname: Slodovnikova
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Quiñones
authors.affiliation: The Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Abeel
authors.affiliation: The Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.
authors.forename: Sinead B
authors.initials: SB
authors.lastname: Chapman
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tartakovsky
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Gabrielian
authors.affiliation: Department of Microbiology, The Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.affiliation: Belarusian State Medical University, Minsk, Belarus.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Skrahin
authors.affiliation: The Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.affiliation: Office of Cyber Infrastructure & Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus alena.skrahina@gmail.com aearl@broadinstitute.org.
authors.forename: Alena
authors.initials: A
authors.lastname: Skrahina
authors.affiliation: The Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA alena.skrahina@gmail.com aearl@broadinstitute.org.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Earl
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology; D018562:Disease Transmission, Infectious; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D002094:Republic of Belarus / Q000453:epidemiology; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000382:microbiology* / Q000635:transmission
chemical_list: D000995:Antitubercular Agents
keywords: Belarus; Mycobacterium tuberculosis; extensively drug resistant; multidrug resistant