{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:26Z","timestamp":1787005766091,"version":"build-2736575974"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Government | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN148362"],"award-info":[{"award-number":["FDN148362"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Government | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-186143"],"award-info":[{"award-number":["PJT-186143"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                    complex (MTBC) includes\n                    <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">M. tb<\/jats:italic>\n                    ), the primary cause of human tuberculosis,\n                    <jats:italic toggle=\"yes\">M. bovis,<\/jats:italic>\n                    the classical zoonotic pathogen and cause of bovine tuberculosis, and\n                    <jats:italic toggle=\"yes\">M. orygis,<\/jats:italic>\n                    a recently recognized multihost pathogen. Given that\n                    <jats:italic toggle=\"yes\">M. tb, M. bovis,<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">M. orygis<\/jats:italic>\n                    pose significant threats to the health of humans and animals, we sought to understand fundamental differences in pathogenicity among these closely related organisms. Building upon historical observations, we conducted a comparative virulence assessment of these pathogens using both bovine and murine infection models. Holstein calves were infected via aerosol with\n                    <jats:italic toggle=\"yes\">M. tb, M. bovis,<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">M. orygis<\/jats:italic>\n                    , and pathology was analyzed through macroscopic and microscopic assessments of lungs and lymph nodes, along with quantitative tissue bacterial burden measurements. In C57BL\/6 mice, we compared virulence using three readouts, namely survival, lethal dose determination, and detailed pathological assessments. Despite genomic similarity, animal-adapted MTBCs consistently showed dramatically enhanced virulence compared to\n                    <jats:italic toggle=\"yes\">M. tb<\/jats:italic>\n                    with distinct immunopathology and, in the murine model, mortality within 24 days. Using gene disruption studies guided by proteomic comparisons, we determined that these infection outcomes were dependent on shared (ESAT-6) and lineage-associated (MPT70) virulence factors, the route of infection, and prior infection or immunization. Our findings reveal unexpected virulence hierarchies within the MTBC, with fundamental and translational implications for tuberculosis research.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2507104122","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T18:14:11Z","timestamp":1760638451000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Virulence hierarchies within the\n                    <i>Mycobacterium tuberculosis<\/i>\n                    complex"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1792-7717","authenticated-orcid":false,"given":"Sarah N.","family":"Danchuk","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, McGill University","place":["Montreal, Canada"]},{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]},{"name":"McGill International Tuberculosis Centre","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2296-9907","authenticated-orcid":false,"given":"Shannon C.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaryd","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Centre for Computational and Integrative Biology, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed","family":"Beenish Rufai","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Lethbridge","place":["Lethbridge, Canada"]},{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona A.","family":"McIntosh","sequence":"additional","affiliation":[{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]},{"name":"McGill International Tuberculosis Centre","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9anne","family":"Lupien","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, McGill University","place":["Montreal, Canada"]},{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]},{"name":"McGill International Tuberculosis Centre","place":["Montreal, Canada"]},{"name":"Department of Medicine, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke B.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]},{"name":"Department of Medicine, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4857-2920","authenticated-orcid":false,"given":"Hojjat","family":"Ghasemi Goojani","sequence":"additional","affiliation":[{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]},{"name":"McGill International Tuberculosis Centre","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne","family":"Taylor","sequence":"additional","affiliation":[{"name":"Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Goodman Cancer Institute, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7784-6387","authenticated-orcid":false,"given":"Philippe","family":"Joubert","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cytology, Institut Universitaire de Cardiologie et de Pneumologie de Qu\u00e9bec-Laval University","place":["Quebec City, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0177-3032","authenticated-orcid":false,"given":"Rasmus","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, Department of Infectious Disease Immunology, Statens Serum Institut","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-3802","authenticated-orcid":false,"given":"Jeffrey M.","family":"Chen","sequence":"additional","affiliation":[{"name":"Mycobacterial Pathogenesis and Tuberculosis Research Laboratory, Vaccine and Infectious Disease Organization, University of Saskatchewan","place":["Saskatoon, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirajan","family":"Niroula","sequence":"additional","affiliation":[{"name":"Mycobacterial Pathogenesis and Tuberculosis Research Laboratory, Vaccine and Infectious Disease Organization, University of Saskatchewan","place":["Saskatoon, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Stevens","sequence":"additional","affiliation":[{"name":"Mycobacterial Pathogenesis and Tuberculosis Research Laboratory, Vaccine and Infectious Disease Organization, 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