The impact of macrophage phenotype during Mycobacterium tuberculosis infection and in host-directed therapeutic interventions

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading global health concern, with millions of new cases and deaths annually. Macrophages, a key subset of immune cells, are essential to the body’s defense against infections. These cells exhibit phenotypic diversity influenced by factors such as epigenetics, external signals like microbial products, and the surrounding microenvironment. Of particular interest are the M1 (classically activated/pro-inflammatory) and M2 (alternatively activated/anti-inflammatory) macrophage phenotypes, each playing distinct roles in infection response. This review explores how macrophage phenotypes impact M. tuberculosis infection, highlighting the therapeutic potential of promoting M1 polarization to enhance mycobacterial clearance. Research has shown that shifting macrophages towards the pro-inflammatory M1 state can significantly improve control over intracellular mycobacteria, reducing bacterial persistence and facilitating infection clearance. This, however, also increases the body’s regulatory responses and risk of immunopathology. Immunomodulatory strategies, termed host-directed therapy (HDT), aim to boost the protective immune response, minimizing prolonged antibiotic use and addressing antimicrobial resistance (AMR). Designing effective HDTs requires in-depth knowledge of the target host response. Transcriptional profiling of macrophages provides valuable insights into the signaling pathways that govern cell behavior during infection, offering new avenues for targeted interventions. This review discusses the latest information on macrophage biology and the use of novel approaches to enhance the host’s immune cells response in TB.