Academic Journal
Modulation of NF-κB in tuberculosis - understanding host-pathogen interactions and therapeutic opportunities.
| Title: | Modulation of NF-κB in tuberculosis - understanding host-pathogen interactions and therapeutic opportunities. |
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| Authors: | Mehraj S; Clinical Microbiology and PK/PD Division, CSIR- Indian Institute of Integrative Medicine, Srinagar, 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Ahmad Z; Clinical Microbiology and PK/PD Division, CSIR- Indian Institute of Integrative Medicine, Srinagar, 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: zahoorap@iiim.res.in. |
| Source: | Microbial pathogenesis [Microb Pathog] 2026 Oct; Vol. 219, pp. 108766. Date of Electronic Publication: 2026 Aug 11. |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: Academic Press Country of Publication: England NLM ID: 8606191 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-1208 (Electronic) Linking ISSN: 08824010 NLM ISO Abbreviation: Microb Pathog Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London ; Orlando : Academic Press, c1986- |
| MeSH Terms: | Host-Pathogen Interactions*/immunology , Mycobacterium tuberculosis*/pathogenicity , Mycobacterium tuberculosis*/immunology , NF-kappa B*/metabolism , Tuberculosis*/immunology , Tuberculosis*/microbiology , Tuberculosis*/drug therapy, Bacterial Proteins/metabolism ; Antigens, Bacterial/metabolism ; Humans ; Signal Transduction ; Animals ; Immunity, Innate ; Host-Directed Therapy |
| Abstract: | Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), remains a major global health challenge and a leading cause of infectious mortality. Central to TB pathogenesis is the nuclear factor-kappa B (NF-κB) signaling network, a master regulator of inflammation, immune activation, and host defense. This review highlights the complex molecular interplay between M. tb virulence determinants and host NF-κB pathways, emphasizing how the pathogen strategically manipulates transcriptional responses to promote survival, persistence, and transmission. Early during infection, cell wall-derived muramyl dipeptide (MDP) activates the NOD2-RIP2 signaling axis, triggering canonical NF-κB activation and p50/RelA-dependent transcription of pro-inflammatory mediators essential for innate immune containment. However, persistent infection is characterized by extensive immune reprogramming. Antigen 85-derived trehalose dimycolate (TDM), biofilm-associated structures, phenolic glycolipids (PGLs), sulfatides, and the catalase-peroxidase enzyme KatG selectively suppress protective NF-κB responses through mechanisms involving p50/p50 homodimer accumulation, RelA repression, disruption of TLR2-MyD88 signaling, and inhibition of redox-dependent IKK activation. In parallel, the ESX-1-secreted ESAT-6/CFP-10 complex and stress-induced heat shock proteins drive persistent NF-κB hyperactivation, resulting in excessive cytokine production, matrix metalloproteinase release, tissue destruction, and bacterial dissemination. Furthermore, antigenic variation mediated by PE/PPE protein families continuously rewires receptor-dependent signaling pathways, preventing effective adaptive immune memory formation. Collectively, these findings reveal that M. tb does not merely evade host immunity but actively remodels NF-κB signaling dynamics through coordinated activation, suppression, and pathological hyperactivation. Understanding these compartment-specific regulatory mechanisms provides a framework for developing precision host-directed therapies aimed at enhancing antimicrobial immunity while limiting immunopathology, offering promising avenues for improved management of drug-sensitive and drug-resistant tuberculosis. (Copyright © 2026 Elsevier Ltd. All rights reserved.) |
| Competing Interests: | Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript entitled "Modulation of NF-κB in Tuberculosis: Understanding Host–Pathogen Interactions and Therapeutic Opportunities" The authors have no conflicts of interest to disclose. |
| Contributed Indexing: | Keywords: Host-pathogen interactions; Mycobacterium tuberculosis; NF-κB; Pathogenesis; Therapeutics |
| Substance Nomenclature: | 0 (NF-kappa B) 0 (Bacterial Proteins) 0 (Antigens, Bacterial) |
| Entry Date(s): | Date Created: 20260811 Date Completed: 20260821 Latest Revision: 20260821 |
| Update Code: | 20260822 |
| DOI: | 10.1016/j.micpath.2026.108766 |
| PMID: | 42580427 |
| Database: | MEDLINE |
| ISSN: | 1096-1208 |
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| DOI: | 10.1016/j.micpath.2026.108766 |