Stable association between strains of Mycobacterium tuberculosis and their human host populations

Abstract

Mycobacterium tuberculosis is an important human pathogen in virtually every part of the world. Here we investigate whether distinct strains of M. tuberculosis infect different human populations and whether associations between host and pathogen populations are stable despite global traffic and the convergence of diverse strains of the pathogen in cosmopolitan urban centers. The recent global movement and transmission history of 100 M. tuberculosis isolates was inferred from a molecular epidemiologic study of tuberculosis that spans 12 years. Genetic relationships among these isolates were deduced from the distribution of large genomic deletions, which were identified by DNA microarray and confirmed by PCR and sequence analysis. Phylogenetic analysis of these deletions indicates that they are unique event polymorphisms and that horizontal gene transfer is extremely rare in M. tuberculosis. In conjunction with the epidemiological data, phylogenies reveal three large phylogeographic regions. A host's region of origin is predictive of the strain of tuberculosis he or she carries, and this association remains strong even when transmission takes place in a cosmopolitan urban center outside of the region of origin. Approximate dating of the time since divergence of East Asian and Philippine clades of M. tuberculosis suggests that these lineages diverged centuries ago. Thus, associations between host and pathogen populations appear to be highly stable.M ycobacterium tuberculosis is a global pathogen, killing 1.9 million people each year and infecting Ϸ2 billion people worldwide (1, 2). Although it is primarily a scourge of the developing world, tuberculosis affects virtually every nation and every ethnicity (2). In view of this ubiquity, an important question in understanding the epidemiology and basic disease biology of the current pandemic is whether there are geographically or ethnically defined human populations within which transmission of M. tuberculosis is relatively common but between which transmission is far more limited. Do global traffic and ''small world'' effects result in a single, panmictic population of M. tuberculosis, or is the pathogen population somehow subdivided, with genetically distinct varieties carried in distinct populations of human hosts?The answer to this basic question may have direct implications for the development and administration of tuberculosis vaccines. Genetic variability in the pathogen population, as in Plasmodium and Streptococcus pneumoniae, can render vaccines ineffective against certain strains or in certain geographic regions. There is substantial geographic variability in the efficacy of the world's current tuberculosis vaccine (3, 4), and the reasons for this variation are not yet well understood. Although it is possible that genetic differences among strains of M. tuberculosis play a role in the variable efficacy of bacillus Calmette-Guérin, actual associations between distinct strains of M. tuberculosis and their human host populations have not been demonstrated, and ...

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