Host-pathogen co-adaptation shapes susceptibility to infection with Mycobacterium tuberculosis

The obligate human pathogen Mycobacterium tuberculosis complex (Mtbc) separates genetically into nine lineages several of which demonstrate sympatry with their human host i.e. have distinct and restricted patterns of geographical distribution globally.1-3 Geographically restricted Mtbc lineages have been hypothesized to be adapted to infect and/or transmit among sympatric human hosts, i.e. to be niche specialists, but this is yet to be confirmed while controlling for exposure, social networks and risk of disease after exposure.1,4 Here we show that strains of geographically restricted (Mtbc lineages L1,L2restricted, L3,L4restricted, L5,L6 are intrinsically less transmissible than widespread Mtbc lineages (L2widespread, L4widespread) across Western European and North American cosmopolitan populations. Comparing transmissibility between sympatric and allopatric contact-pathogen pairs, we find the first controlled evidence for a biological impact of sympatry between Mtbc strains and their human hosts; allopatric host-pathogen exposures has a 38% decrease in the odds of infection among contacts compared with sympatric exposures. We measure 10- fold lower phagocytosis and growth rates of L6 geographically restricted strains compared to L4widespread in in vitro allopatric macrophage infections. Long-term co-existence of Mtbc strains and humans has resulted in differential transmissibility between allopatric and sympatric hosts for strains of geographically restricted lineages. Understanding the specific genetic and immunological underpinnings of sympatry in TB may inform rational vaccine design and TB control.