Advances in immune escape mechanisms of Mycobacterium tuberculosis

Tuberculosis (TB) is a zoonotic disease caused by infection with Mycobacterium tuberculosis (Mtb); it exerts a major impact on human health and socio-economic development globally. Mtb, which has been infecting humans for several millennia, is responsible for more deaths than any other microorganism. One-quarter of the world's population is estimated to carry Mtb. During infection, Mtb can undergo immune escape and lie dormant within a lesion, maintaining host-pathogen homeostasis through granuloma formation. Most infected individuals have latent tuberculosis infection (LTBI), which may cause the reactivation of Mtb when host immunity declines. Approximately 5%-15% of LTBI patients will develop active TB, while in the majority of immunocompetent individuals, the infection is either cleared or contained. As an extremely successful intracellular pathogen, Mtb hijacks the host immune response to establish an environment favorable for survival and remains latent in the host for prolonged time periods. However, our understanding of the immune escape mechanisms adopted by Mtb and the roles of bacterial virulence factors in different stages of Mtb infection remain limited. Studies using mouse infection models have shown that Mtb enters the alveoli through the airway and mainly infects alveolar macrophages (AMs) during the first two weeks of infection; subsequently, the infected AMs migrate from the alveolar space to the lung interstitium via a mechanism dependent on host IL-1 beta signaling and the Type VII secretion system ESX-1. Mtb infects mononuclear macrophages, polymorphonuclear neutrophils (PMNs), and dendritic cells (DCs). The infected DCs migrate to the draining lymph nodes, causing the proliferation and differentiation of naive T cells to form antigen-specific T helper type 1 (Th1) cells. Activated T cells are recruited to the infected lung and form granulomas around the infected lesions. An initial infection with Mtb would stimulate AMs to generate inflammation and activate an adaptive immune response, leading to a rapid response to lung infection. However, AMs cannot robustly detect Mtb infection. Mtb achieves immune escape by modulating intracellular infection, impairing antigen presentation, and destroying macrophage and T cell functions, allowing it to survive and proliferate in host cells. With increasing antibiotic resistance, Mtb infection remains a global public health issue, therefore; novel therapeutic and vaccine strategies must consider the infection process and immune-escape mechanisms. The promotion of phagosome-lysosome fusion, enhancement of LC3-associated phagocytosis and autophagy, induction of reactive oxygen species production, enhancement of NADPH oxidase activity, overcoming T-cell initiation delays, and the judicious use of antibiotics, may be necessary to achieve substantial host protection. Here, we summarize the recent advances of research regarding the molecular mechanisms whereby Mtb regulates macrophage autophagy, apoptosis, and adaptive immune responses, which are important for the development of novel host-directed therapies and protective vaccines.