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


The study of host-pathogen co-evolution is fundamental to understanding the emergence and spread of infectious diseases. The obligate human pathogen of the Mycobacterium tuberculosis complex (Mtbc) separates genetically into nine lineages with distinct patterns of geographical distribution that in some cases parallel that of human subpopulations. Based on these observations, geographically restricted Mtbc lineages have been hypothesized to be niche specialists that preferentially infect particular human subpopulations, but this is yet to be confirmed while controlling for social networks and risk of disease among exposed hosts. To address this question, we used a multi-site cohort of tuberculosis index cases with pathogen sequence data and linked contacts. Our data show that strains of specialist (spec) Mtbc lineages L1,L2spec,L3,L4spec,L5,L6 are intrinsically less transmissible than generalist Mtbc lineages (L2gen,L4gen) across Western European and North American cosmopolitan populations. Comparing transmissibility between sympatric and allopatric host-pathogen pairs, we found the first controlled evidence for co-adaptation between Mtbc strains and their human hosts; allopatric host-pathogen exposures had a 32% decrease in the odds of infection among contacts compared with sympatric exposures. We measured 10-fold decreased phagocytosis and growth rates of L6 specialist strains compared to L4gen in in vitro allopatric macrophage infections. In conclusion, long term co-adaptation between Mtbc strains and humans has resulted in differential transmissibility between allopatric and sympatric hosts for the specialist lineages. Understanding the specific genetic and immunological underpinnings of this co-adaptation may inform rational vaccine design and TB control.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was funded by National Institutes of Health / National Institute of Allergy and Infectious Diseases R21 AI154089 to MRF. MIG is supported by the German Research Foundation (GR5643/1-1). FJPL, SN, and SH were funded by the Leibniz Science Campus EvoLUNG (Evolutionary Medicine of the Lung), grant number W47/2019. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.


The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study is approved by the Institutional Review Boards at Harvard Medical School (IRB19-1910), the University of Lübeck (AZ-19-071), the New York City Department of Hygiene and Mental Health (20-078), and the Registration Committee of the Netherlands Tuberculosis Register NTR (11-2019).

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Data Availability

All data produced in the present study are available upon reasonable request to the authors

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