Modulation of NF-κB in Tuberculosis - Understanding Host-Pathogen Interactions and Therapeutic Opportunities.

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.