The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
School of Chemistry and Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
Immunity. 2021 Aug 10;54(8):1758-1771.e7. doi: 10.1016/j.immuni.2021.06.009. Epub 2021 Jul 12.
Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.
细胞凋亡通过直接杀死微生物并消除其复制生态位，能够有效地抵御细胞内病原体。然而，据报道，结核分枝杆菌在体外能够限制巨噬细胞中的细胞凋亡途径，这导致凋亡被认为不是结核病中的宿主保护过程，尽管缺乏体内证据。在这里，我们定义了死亡受体介导的和 BCL-2 调节的凋亡途径的关键体内功能，这些途径通过消除不同群体的感染巨噬细胞和中性粒细胞并启动 T 细胞反应，介导对结核病的保护。我们进一步表明，凋亡途径可以通过具有临床阶段的化合物进行治疗性靶向，这些化合物拮抗凋亡抑制蛋白 (IAP) 以促进小鼠体内结核分枝杆菌的清除。这些发现表明，结核分枝杆菌对凋亡的任何抑制在体内都是不完全的，这提高了我们对结核病宿主保护反应的理解，并揭示了可能可用于治疗疾病的宿主途径。
