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MTBC strains exhibit genetic diversity that influences host\u2013pathogen interactions, immune evasion, and disease outcomes. The complement system, a crucial component of innate immunity, plays a dual role in pathogen detection and potential immune evasion, yet its interactions with MTBC strains remain underexplored. We investigated the roles of C1q and mannose-binding lectin (MBL), key pattern recognition molecules (PRMs) of the classical and lectin pathways, respectively, in complement activation against diverse clinical MTBC strains. We observed that both C1q and MBL recognize mycobacteria directly as PRMs but that the degree of binding was strain dependent. Both molecules facilitated complement cascade activation, leading to the deposition of C4b and C3b and the formation of the membrane attack complex (MAC) on bacterial surfaces. However, inhibition experiments revealed that C1q is the primary driver of complement activation in nonimmune serum, while MBL plays a supportive but nonredundant role. Despite robust complement activation, MAC formation did not significantly impact the viability of MTBC strains. Nevertheless, these findings highlight a nuanced interplay between the complement system and MTBC lineage diversity. Our results provide novel insights into early host\u2013pathogen dynamics in TB, emphasizing the importance of considering MTBC lineage diversity in understanding the immune response against mycobacteria.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf294","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T16:13:26Z","timestamp":1763655206000},"source":"Crossref","is-referenced-by-count":0,"title":["C1q and mannose-binding lectin binding and complement activation across genetically diverse\n                    <i>Mycobacterium tuberculosis<\/i>\n                    complex strains"],"prefix":"10.1093","volume":"215","author":[{"given":"Mario Alejandro","family":"Duque-Villegas","sequence":"first","affiliation":[{"name":"Infection Immunology, Research Center Borstel , Borstel,","place":["Germany"]},{"name":"Molecular and Experimental Mycobacteriology, Research Center Borstel , Borstel,","place":["Germany"]},{"name":"Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Rigshospitalet, Copenhagen University Hospital , Copenhagen,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian Peter","family":"G\u00f6tz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Rigshospitalet, Copenhagen University Hospital , Copenhagen,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie","family":"Rousseau","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Mycobacteriology, Research Center Borstel , Borstel,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Homolka","sequence":"additional","affiliation":[{"name":"Diagnostic Mycobacteriology, National Reference Center for Mycobacteria, Research Center Borstel , Borstel,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Niemann","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Mycobacteriology, Research Center Borstel , Borstel,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), partner site Hamburg-L\u00fcbeck-Borstel-Riems , Borstel,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2876-8586","authenticated-orcid":false,"given":"Peter","family":"Garred","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Rigshospitalet, Copenhagen University Hospital , Copenhagen,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"H\u00f6lscher","sequence":"additional","affiliation":[{"name":"Infection Immunology, Research Center Borstel , Borstel,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), partner site Hamburg-L\u00fcbeck-Borstel-Riems , Borstel,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7883-4433","authenticated-orcid":false,"given":"Kerstin","family":"Walter","sequence":"additional","affiliation":[{"name":"Infection Immunology, Research Center Borstel , Borstel,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), partner site Hamburg-L\u00fcbeck-Borstel-Riems , Borstel,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6736-3138","authenticated-orcid":false,"given":"Anne","family":"Rosbjerg","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Rigshospitalet, Copenhagen University Hospital , 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