Host-directed insights into mycobacterial infections: Toward targeted immunomodulation

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a significant worldwide health threat, especially in resource-limited environments. This review emphasizes that manipulating host metabolic and epigenetic pathways can bolster immune defences and potentially shorten the duration of tuberculosis treatment. The growing prevalence of multidrug-resistant TB and the protracted nature of standard treatments underscore the urgent need for alternative therapeutic approaches. Host-directed treatment has arisen as a promising approach that aims to enhance or redirect the host's innate and adaptive responses rather than targeting the pathogen directly. This strategy focuses on counteracting M. tuberculosis-induced subversion of immune and cellular processes. Approaches under investigation include modulation of host metabolic pathways, stimulation of autophagy, epigenetic reprogramming, and strengthening of immune defense mechanisms to control or eliminate infection. These interventions hold potential for not only overcoming traditional drug resistance but also for accelerating recovery and reducing immunopathology. In this review, we explore recent advances in host-directed therapy research, with particular emphasis on mechanisms involving immunometabolic regulation, epigenetic remodeling, and enhancement of intercellular antimicrobial responses. The advancement of these methodologies may facilitate the creation of more accurate and efficacious tuberculosis treatments. We highlight recent work on three linked areas-immunometabolic regulation, epigenetic control, and autophagy driven antimicrobial activity drawing out the main advances and remaining debates that guide future host-directed approaches. Viewing host-directed therapy through this integrated lens outline a path toward more targeted, durable, and resistance-resilient interventions for tuberculosis.