title: Genomic diversity in autopsy samples reveals within-host dissemination of HIV-associated Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis remains a leading cause of death worldwide, especially among individuals infected with HIV. Whereas phylogenetic analysis has revealed M. tuberculosis spread throughout history and in local outbreaks, much less is understood about its dissemination within the body. Here we report genomic analysis of 2,693 samples collected post mortem from lung and extrapulmonary biopsies of 44 subjects in KwaZulu-Natal, South Africa, who received minimal antitubercular treatment and most of whom were HIV seropositive. We found that purifying selection occurred within individual patients, without the need for patient-to-patient transmission. Despite negative selection, mycobacteria diversified within individuals to form sublineages that co-existed for years. These sublineages, as well as distinct strains from mixed infections, were differentially distributed throughout the lung, suggesting temporary barriers to pathogen migration. As a consequence, samples taken from the upper airway often captured only a fraction of the population diversity, challenging current methods of outbreak tracing and resistance diagnostics. Phylogenetic analysis indicated that dissemination from the lungs to extrapulmonary sites was as frequent as between lung sites, supporting the idea of similar migration routes within and between organs, at least in subjects with HIV. Genomic diversity therefore provides a record of pathogen diversification and repeated dissemination across the body.
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Tami D
authors: TD
authors: Lieberman
authors: Department of Internal Medicine, Edendale Hospital, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
authors: Douglas
authors: D
authors: Wilson
authors: Department of Infection Prevention and Control, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors: Reshma
authors: 0000-0002-5512-9456
authors: R
authors: Misra
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Lealia L
authors: 0000-0001-7636-5936
authors: LL
authors: Xiong
authors: Department of Infection Prevention and Control, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors: Prashini
authors: P
authors: Moodley
authors: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.|Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Ted
authors: T
authors: Cohen
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.|Faculty of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Roy
authors: R
authors: Kishony
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D001431:Bacteriological Techniques; D060085:Coinfection / Q000382:microbiology; D004269:DNA, Bacterial / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008099:Liver / Q000382:microbiology*; D008168:Lung / Q000382:microbiology*; D008198:Lymph Nodes / Q000382:microbiology*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D013154:Spleen / Q000382:microbiology*; D014376:Tuberculosis / Q000150:complications / Q000382:microbiology*; D014386:Tuberculosis, Hepatic / Q000150:complications / Q000382:microbiology; D014388:Tuberculosis, Lymph Node / Q000150:complications / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000382:microbiology; D014400:Tuberculosis, Splenic / Q000150:complications / Q000382:microbiology
chemical_list: D004269:DNA, Bacterial