Major Mycobacterium tuberculosis Lineages Associate with Patient Country of Origin

Abstract

Over recent years, there has been an increasing acknowledgment of the diversity that exists among Mycobacterium tuberculosis clinical isolates. To facilitate comparative studies aimed at deciphering the relevance of this diversity to human disease, an unambiguous and easily interpretable method of strain classification is required. Presently, the most effective means of assigning isolates into a series of unambiguous lineages is the method of Gagneux et al. (S. Gagneux et al., Proc. Natl. Acad. Sci. USA 103:2869-2873, 2006) that involves the PCR-based detection of large sequence polymorphisms (LSPs). In this manner, isolates are classified into six major lineages, the majority of which display a high degree of geographic restriction. Here we describe an independent replicate of the Gagneux study carried out on 798 isolates collected over a 6-year period from mostly foreign-born patients resident on the island of Montreal, Canada. The original trends in terms of bacterial genotype and patient ethnicity are remarkably conserved within this Montreal cohort, even though the patient distributions between the two populations are quite distinct. In parallel with the LSP analysis, we also demonstrate that "clustered" tuberculosis (TB) cases defined through restriction fragment length polymorphism (RFLP) analysis (for isolates with >6 IS6110 copies) or RFLP in combination with spoligotyping (for isolates with <6 IS6110 copies) do not stray across the LSP-defined lineage boundaries. However, our data also demonstrate the poor discriminatory power of either RFLP or spoligotyping alone for these low-IS6110-copy-number isolates. We believe that this independent validation of the LSP method should encourage researchers to adopt this system in investigations aimed at elucidating the role of strain variation in TB.Infection with Mycobacterium tuberculosis, the bacillus responsible for tuberculosis (TB), still results in almost 2 million global deaths each year despite the availability of effective chemotherapy and a partially effective vaccine (bacillus Calmette-Guérin [Mycobacterium bovis BCG]) for well over half a century (43). Even though there have been real advances in our level of understanding of M. tuberculosis metabolic pathways and in the identification of potential virulenceassociated molecules since the advent of the "postgenomic era" (8), significant improvements with respect to treatment, diagnosis, and prevention of TB still remain elusive. Recent descriptions of variably expressed virulence factors and disease outcomes that are associated with particular lineages of M. tuberculosis further emphasize the layers of complexity that need to be overcome in our efforts to combat this devastating disease (6,25,31,32,38).While the fact that TB phenotypic diversity exists is no longer in dispute, there is heightened interest in epidemiological circles in establishing the relevance of this diversity to human disease. Of particular note are the recent publications suggesting that strains belonging to the M. tuberculosis W/...

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

“…Of these 5 subgroups, groups 2 to 5 represent the Beijing sublineage (27,47,48). Interestingly, the C507G SNP is restricted to the phylogenetically related East African/Indian (lineage 3) and East Asian lineages, while the C601T SNP is unique to the Beijing sublineage of the East Asian lineage ( Fig.…”

“…tuberculosis H37Rv was originally obtained from the American Type Culture Collection (ATCC 27294). The majority of clinical M. tuberculosis isolates used in this study were originally reported as part of an earlier molecular epidemiology investigation (48) in which isolates were classified according to the presence of large-sequence polymorphisms (LSPs) (47). Isolate 98_1663 was kindly provided by S. Gagneux (Swiss Tropical and Public Health Institute, Basel, Switzerland) and P. Small (Stony Brook University, Stony Brook, NY).…”

Bacterial Lung Disease and COPD

“…Today, we know that tuberculosis in humans is not caused by a single species, but instead by a complex of species including Mycobacterium tuberculosis, M. africanum, M. bovis, and M. canetti which originated from a common African ancestral strain 35,000-15,000 years ago [4]. To date, seven distinct phylogenetic lineages have been identified for the species M. tuberculosis and M. africanum, based on genomic polymorphisms [5,6], which differ with respect to global distribution, and in some causes infectivity and drug-resistance [7][8][9][10]. Compared to 1.2 million global deaths due to HIV/AIDS virus in 2014, TB has now emerged as the most common cause of human mortalities due to infectious disease with the toll reaching 1.5 million in same year [11].…”

Identification and Genotyping of Mycobacterium tuberculosis Complex Species by Use of a SNaPshot Minisequencing-Based Assay

“…The classification of MTBC strains into these distinct lineages is relevant for evolutionary purposes but also for TB control. Indeed, these discrete lineages are associated with particular human populations or geographical regions and show differences in virulence and disease outcomes (12,20,21,35,41,53).…”