REVIEW article
Front. Tuberc.
Sec. Pathogen and Host Biology of Tuberculosis
Mycobacteria as evolutionary drivers of host innate immunity: insights from comparing experimental host models
Provisionally accepted
- 1Experimental Tuberculosis Unit (UTE), Institut de Recerca Germans Trias i Pujol, Badalona, Spain
- 2Microbiology and Genetics Department, Universitat Autonoma de Barcelona, Barcelona, Spain
- 3Laboratori Clínic de la Metropolitana Nord (LCMN), Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- 4Centre de Medicina Momparativa i Bioimatge de Catalunya (CMCiB), Badalona, Spain
- 5Centro de Investigacion Biomedica en Red Enfermedades Respiratorias, Madrid, Spain
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The genus Mycobacterium exerts a strong selective force, shaping the evolution and structure of innate immune systems across various hosts and revealing overarching, conserved principles of host defense. Despite their phylogenetic distance, amoebae, nematodes, insects, wax moth larvae, and zebrafish share fundamental innate immune strategies while also exhibiting key differences in tissue organization, immune complexity, and the presence or absence of adaptive immunity. This comparative review synthesizes insights from these systems to highlight both the conserved mechanisms that mycobacteria repeatedly exploit and the lineage-specific features that shape host susceptibility. Amoebae demonstrate ancient, cell-autonomous defenses, including nutritional immunity through metal trafficking (Nramp1/zinc intoxication) and membrane repair pathways (ESCRT/autophagy) against the ESX-1 system. Moving to metazoans, the importance of conserved signaling, such as the p38 MAPK (PMK-1) pathway in C. elegans, becomes evident, which M. marinum actively suppresses via VHP-1. In other invertebrates, such as Drosophila, integrated immunometabolism is present, in which disruption of the Akt–FOXO axis causes a conserved wasting syndrome, and Galleria mimics chronic TB pathology by forming granuloma-like structures with lipid-accumulating hemocytes and demonstrating innate immune priming. Larval zebrafish, which depend solely on innate immunity, show pathogen-driven granuloma formation and spread, with ESX-1 mediating pro-necrotic cell death and the Asc-dependent inflammasome contributing to restriction. Overall, these cross-species comparisons demonstrate how mycobacteria exploit foundational host mechanisms while revealing the evolutionary breadth and limits of innate immune strategies across the animal kingdom.
Keywords: mycobacteria, evolution, Virulence, Tuberculosis, innate immunity, Non-mammalian models
Received: 30 Oct 2025; Accepted: 25 Nov 2025.
Copyright: © 2025 Cortacans and Cardona. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pere Joan Cardona
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