Host-pathogen sympatry and differential transmissibility of Mycobacterium tuberculosis complex

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][1]–[3][2] 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][1],[4][3] 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. ### 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) http://evolung.fz-471borstel.de/, 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: #ref-1 [2]: #ref-3 [3]: #ref-4