London School of Hygiene & Tropical Medicine, Infectious and Tropical Diseases-Immunology, London, UK.
Eur J Immunol. 2010 Feb;40(2):396-405. doi: 10.1002/eji.200939583.
Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MPhi. IFN-gamma secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MPhi to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MPhi. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophil-driven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.
结核病仍然是全球最危险的细菌性感染。病原体结核分枝杆菌是静止 MPhi 的兼性细胞内病原体。自然杀伤细胞、CD4 Th1 和 CD8 T 细胞在 IL-12 和 -18 的指令下分泌的 IFN-γ激活 MPhi 以限制分枝杆菌的生长。两种细胞因子的产生都是由 DC 和 MPhi 中的 TLR 信号诱导的。缺乏 TLR 衔接子 MyD88 的小鼠对结核分枝杆菌感染高度敏感。MyD88 被 TLR 和 IL-1 和 IL-18 受体的信号级联共用促使我们重新审视 IL-18 在结核分枝杆菌实验感染期间的作用。我们表明，缺乏 IL-18 和 MyD88 但不缺乏 IL-18 受体的小鼠与 WT 或 TLR-2/-4 双 KO 小鼠相比，迅速死于结核分枝杆菌感染，表明缺乏 IL-18 导致 MyD88 KO 小鼠对结核分枝杆菌的高易感性。没有 IL-18，保护性 Th1 反应减少，因此有利于分枝杆菌的繁殖。中性粒细胞驱动的肺免疫病理学与分枝杆菌的不受控制生长很可能是 IL-18 KO 小鼠过早死亡的原因。因此，IL-18 在针对结核病的保护性免疫中起着决定性的作用。
