Host-pathogen crosstalk in tuberculosis: intracellular survival strategies, immune evasion, and host directed therapies

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains among the top 10 leading causes of death worldwide, infecting more than 10 million people annually. Upon inhalation into the host lungs, Mtb is internalized by alveolar macrophages, where it deploys complex strategies to evade the host immune response and enhance its intracellular survival. This review synthesizes the current understanding of the major molecular pathways driving Mtb ’s intracellular persistence, focusing on its ability to disrupt phagolysosomal maturation and autophagic pathways, while also manipulating host apoptotic pathways. Furthermore, we detail how these mechanisms are aided by genetic and epigenetic manipulations within the host macrophages, such as the silencing of antimicrobial peptides, downregulation of transcriptional regulators, and the use of non-coding RNAs. Understanding these host-pathogen interfaces provides targets for the development of host directed therapies (HDTs) which can overcome the survival mechanisms that make Mtb so resilient to classical antibiotics.