{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:18:41Z","timestamp":1793312321254,"version":"4.5.0"},"reference-count":136,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Tuberculosis (TB) caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    ) and respiratory viral infections remain major, intersecting global health challenges, and their co-occurrence imposes a disproportionate burden in high-HIV\/high-TB regions such as sub-Saharan Africa. Coinfection biology is heterogeneous and dynamic, driven by viral diversity including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A\/B, Respiratory Syncytial Virus (RSV), parainfluenza, metapneumovirus, rhinovirus, adenovirus, and bocavirus, and by the underlying TB stage, from latent and subclinical to active and reactivation disease. Innate sensing pathways, such as Toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I), and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS\u2013STING), converge during coinfection, reshaping type I interferon (IFN-I), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB), and AP-1\u2013driven responses and triggering a network of autocrine and paracrine signaling that reprograms macrophages, dendritic cells, and T-cell subsets. This immune rewiring alters granuloma equilibrium through suppressed Th1\/IFN-\u03b3 coordination, exaggerated Th17\/IL-17-driven neutrophilia, and regulatory T-cell or IL-10-mediated dampening, which together destabilize macrophage activation and tissue architecture. Oxidative stress, mitochondrial dysfunction, and Matrix Metalloproteinases (MMP)-driven matrix remodeling further integrate with these pathways, converting inflammatory signals into epithelial damage, cavitation, and fibrosis. Consequently, disease outcomes depend critically on timing, viral burden, pathogen order, host immune endotype, and TB stage, such that the same virus can either preserve containment or drive progression depending on the local immunological context. Importantly, the effects of respiratory viral coinfection vary across the TB disease continuum, influencing early granuloma formation, latent infection, reactivation risk, and established disease through distinct immunological mechanisms. Host-directed therapies (HDT) targeting interferon, IL-1, TNF, inflammasome, or metabolic checkpoints hold mechanistic promise but exhibit variable clinical translation, underscoring the need for precision approaches that integrate stage- and endotype-specific biomarkers. This narrative review proposes an integrated systems framework that links viral sensing, immune rewiring, granuloma biology, and tissue-remodeling to TB\u2013respiratory virus coinfection, and emphasizes how timing-aware, biomarker-guided strategies can refine diagnosis, clinical management, prognosis, and vaccine design in vulnerable populations.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1863302","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:25:39Z","timestamp":1782966339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular signaling in coinfection: how M. tuberculosis and respiratory viruses rewire host immunity and alter TB outcomes"],"prefix":"10.3389","volume":"17","author":[{"given":"Qaqamba","family":"Feya","sequence":"first","affiliation":[{"name":"School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal","place":["Durban, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilungile Lynette","family":"Mkhize-Kwitshana","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal","place":["Durban, South Africa"]},{"name":"Biomedical Sciences, Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa (UNISA), Florida Science Campus","place":["Johannesburg, South Africa"]},{"name":"Research Capacity Development Division, South African Medical Research Council","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ridwaan Nazeer","family":"Milase","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, North-West University, Mahikeng Campus","place":["Mmabatho, South 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