Differential rates of Mycobacterium tuberculosis transmission associate with host–pathogen sympatry

Several human-adapted Mycobacterium tuberculosis complex (Mtbc) lineages exhibit a restricted geographical distribution globally. These lineages are hypothesized to transmit more effectively among sympatric hosts, that is, those that share the same geographical area, though this is yet to be confirmed while controlling for exposure, social networks and disease risk after exposure. Using pathogen genomic and contact tracing data from 2,279 tuberculosis cases linked to 12,749 contacts from three low-incidence cities, we show that geographically restricted Mtbc lineages were less transmissible than lineages that have a widespread global distribution. Allopatric host–pathogen exposure, in which the restricted pathogen and host are from non-overlapping areas, had a 38% decrease in the odds of infection among contacts compared with sympatric exposures. We measure tenfold lower uptake of geographically restricted lineage 6 strains compared with widespread lineage 4 strains in allopatric macrophage infections. We conclude that Mtbc strain–human long-term coexistence has resulted in differential transmissibility of Mtbc lineages and that this differs by human population. Epidemiological analysis of Mycobacterium tuberculosis genomes and public health data show that lineage-specific variation in transmission varies with the degree of host and pathogen geographical coincidence and reveals signals of a biological effect of host–pathogen coexistence.