Variable host–pathogen compatibility in <em>Mycobacterium tuberculosis</em>

Sebastien Gagneux

Kathryn DeRiemer

Tran Van

Midori Kato-Maeda

Kristin Kremer+4 authors

^{Institute for Systems Biology, Seattle, WA 98103;}

^{Division of Infectious Diseases and Geographic Medicine, Stanford University Medical Center, Stanford, CA 94305;}

^{School of Medicine, University of California, Davis, CA 95616;}

^{Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital and University of California, San Francisco, CA 94110;}

^{MRC Laboratories, Fajara, P.O. Box 273, The Gambia;}

^{Department of Immunology, Tuberculosis Research Center, Chennai 600031, India;}

^{Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa;}

^{Forschungszentrum Borstel, National Reference Center for Mycobacteria, 23848 Borstel, Germany;}

^{Mycobacteria Reference Unit, National Institute of Public Health and the Environment, Bilthoven, 3720 BA, The Netherlands;}

^{Mycobacteria Reference Laboratory, Institut Pasteur, 75724 Paris, France;}

^{Swiss Tropical Institute, 4002 Basel, Switzerland; and}

^{Bill and Melinda Gates Foundation, Seattle, WA 98102}

^{To whom correspondence should be addressed at: Institute for Systems Biology, 1441 North 34th Street, Seattle WA 98103., E-mail:}gro.ygoloibsmetsys@xuengags

Communicated by Leroy E. Hood, Institute for Systems Biology, Seattle, WA, December 28, 2005.

Author contributions: S.G., K.D., and P.M.S. designed research; S.G., T.V., M.K.-M., B.C.d.J., and S. Narayanan performed research; B.C.d.J., S. Narayanan, M.N., S. Niemann, K.K., M.C.G., and M.H. contributed new reagents/analytic tools; S.G. and K.D. analyzed data; and S.G., K.D., P.C.H., and P.M.S. wrote the paper.

Received 2005 Sep 22

Freely available online through the PNAS open access option.

Abstract

Mycobacterium tuberculosis remains a major cause of morbidity and mortality worldwide. Studies have reported human pathogens to have geographically structured population genetics, some of which have been linked to ancient human migrations. However, no study has addressed the potential evolutionary consequences of such longstanding human–pathogen associations. Here, we demonstrate that the global population structure of M. tuberculosis is defined by six phylogeographical lineages, each associated with specific, sympatric human populations. In an urban cosmopolitan environment, mycobacterial lineages were much more likely to spread in sympatric than in allopatric patient populations. Tuberculosis cases that did occur in allopatric hosts disproportionately involved high-risk individuals with impaired host resistance. These observations suggest that mycobacterial lineages are adapted to particular human populations. If confirmed, our findings have important implications for tuberculosis control and vaccine development.

Keywords: coevolution, deletions, lineage, polymorphism, population

Abstract

Several studies have reported geographically structured populations in human pathogens (1 –4). Recently, the genetic population structure of Helicobacter pylori and Mycobacterium leprae have been linked to ancient human migrations (1, 4, 5). Such long-standing host–pathogen associations could lead to adaptive genetic changes between interacting host and pathogen populations. Studies in invertebrate model systems have shown that pathogens can adapt to specific host species (6). However, no example of host-specific pathogen adaptation has yet been documented in pathogens affecting different human populations. The observation of geographically structured populations of human pathogens implies that particular strains and their corresponding patient populations can be classified as sympatric or allopatric (6). Compatibility, defined as the ability of a given pathogen to infect a particular host, often differs in sympatric versus allopatric host–pathogen combinations, with sympatric combinations usually displaying a greater compatibility (6).

Mycobacterium tuberculosis occurs world-wide and is still killing 2–3 million people each year (7). New tools for tuberculosis control are urgently needed, including a more effective vaccine (8). A series of genotyping tools for M. tuberculosis have been developed (9). Most of these make use of mobile genetic elements or repetitive DNA. Even though these tools have been invaluable for detecting ongoing tuberculosis transmission, the markers upon which they are based change relatively rapidly, making it difficult to define deep phylogenetic relationships (4). In contrast, large sequence polymorphisms (LSPs) represent unique event polymorphisms that can be used to construct robust phylogenies for M. tuberculosis (10). An additional advantage is that, once LSPs have been identified (e.g., by comparative whole-genome hybridization), simple PCR can be used to screen large numbers of strains in a high-throughput fashion.

In this study, we used comparative genomic and molecular epidemiological tools to define the global population structure of M. tuberculosis and to investigate its influence on the transmission dynamics of M. tuberculosis in San Francisco during an 11-year period.

CI, confidence interval.

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Acknowledgments

We thank Bruce Levin and James H. Jones for their valuable comments on the manuscript, and Colette Diguimbaye (Laboratoire de Recherches Vétérinaires et Zootechniques de Farcha, N’Djamena, Chad) and Erik Post (German Leprosy and TB Relief Association, Würzburg, Germany) for providing strains. This research was supported by the Swiss National Science Foundation and the Novartis Foundation (S.G.), the National Institutes of Health (K.D., B.C.d.J., and P.C.H.), and the Wellcome Trust (P.M.S.).

Acknowledgments

Abbreviations

RFLP	restriction fragment length polymorphism
LSP	large sequence polymorphism.

Abbreviations

Footnotes

Conflict of interest statement: No conflicts declared.

Footnotes

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