结核分枝杆菌免疫逃逸机制研究进展

Advances in immune escape mechanisms of Mycobacterium tuberculosis

结核病(tuberculosis,TB)是由结核分枝杆菌(Mycobacterium tuberculosis,Mtb)感染引起的一种对全球人类健康和经济社会发展具有重大影响的人兽共患病.结核分枝杆菌感染人类已有数千年的历史,在其与人类宿主共同进化的过程中,Mtb已发展出多种巧妙的策略以逃避宿主的免疫防御,从而建立持续性感染.然而,我们对其免疫逃逸的分子机制以及细菌的毒力因子在Mtb不同感染阶段下发挥的作用了解有限.研究表明,在Mtb感染的早期阶段,肺泡巨噬细胞无法控制Mtb的感染,在进入肺间质后,Mtb可通过调控细胞内感染、损害抗原提呈、破坏巨噬细胞和T细胞功能等手段达到免疫逃逸的目的.本文详细回顾并综述了近年来结核分枝杆菌调控巨噬细胞自噬、凋亡以及适应性免疫应答等过程的分子机制,这些分子机制对于开发新的宿主导向疗法以及保护性疫苗至关重要.

Tuberculosis (TB) is a zoonotic disease caused by infection with Mycobacterium tuberculosis (Mtb);it exerts a majorimpact on human health and socio-economic development globally. Mtb, which has been infecting humans for severalmillennia, is responsible for more deaths than any other microorganism. One-quarter of the world’s population is estimatedto carry Mtb. During infection, Mtb can undergo immune escape and lie dormant within a lesion, maintaining hostpathogen 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 willdevelop active TB, while in the majority of immunocompetent individuals, the infection is either cleared or contained. Asan extremely successful intracellular pathogen, Mtb hijacks the host immune response to establish an environmentfavorable for survival and remains latent in the host for prolonged time periods. However, our understanding of the immuneescape mechanisms adopted by Mtb and the roles of bacterial virulence factors in different stages of Mtb infection remainlimited.Studies using mouse infection models have shown that Mtb enters the alveoli through the airway and mainly infectsalveolar macrophages (AMs) during the first two weeks of infection;subsequently, the infected AMs migrate from thealveolar space to the lung interstitium via a mechanism dependent on host IL-1β signaling and the Type VII secretionsystem 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 formantigen-specific T helper type 1 (Th1) cells. Activated T cells are recruited to the infected lung and form granulomasaround the infected lesions. An initial infection with Mtb would stimulate AMs to generate inflammation and activate anadaptive immune response, leading to a rapid response to lung infection. However, AMs cannot robustly detect Mtbinfection. Mtb achieves immune escape by modulating intracellular infection, impairing antigen presentation, anddestroying 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 andvaccine strategies must consider the infection process and immune-escape mechanisms. The promotion of phagosomelysosome fusion, enhancement of LC3-associated phagocytosis and autophagy, induction of reactive oxygen speciesproduction, enhancement of NADPH oxidase activity, overcoming T-cell initiation delays, and the judicious use ofantibiotics, may be necessary to achieve substantial host protection. Here, we summarize the recent advances of researchregarding the molecular mechanisms whereby Mtb regulates macrophage autophagy, apoptosis, and adaptive immuneresponses, which are important for the development of novel host-directed therapies and protective vaccines.