ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection
ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection
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DOI：
10.1111/j.1462-5822.2008.01177.x
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发表时间：
2008-09-01
影响因子：
3.4
通讯作者：
Brown, Eric J.
中科院分区：
文献类型：
--
作者：
Koo, Ingrid C.;Wang, Chen;Brown, Eric J.
巨噬细胞溶酶体的胞吐被描述为对微生物细胞毒素和溶血素的反应，以及在炎症小体激活过程中释放促炎细胞因子白细胞介素(IL)-1 β和IL-18。分枝杆菌ESX-1分泌系统部分由差异区-1编码，是海洋分枝杆菌中吞噬体逃逸和接触依赖性溶血素裂解宿主细胞所必需的毒力因子。本研究表明，来自海洋分枝杆菌和结核分枝杆菌的ESX-1是巨噬细胞依赖Ca（2+）诱导溶酶体分泌所必需的。分枝杆菌诱导的溶酶体分泌与IL-1 β和IL-18的释放同步，依赖于含有ESX-1的细菌的吞噬作用。缺乏ESX-1的死亡杆菌和细菌会合成IL-1 β和IL-18，但不会释放，这表明只有ESX-1调节细胞因子的释放。这些细胞因子的释放和溶酶体的胞外分泌独立于细胞内分枝杆菌的生长，但与分枝杆菌编码的溶血活性相关，表明这两种反应有平行的途径。我们进一步鉴定了炎性小体成分caspase-1、ASC和NALP3，但没有发现Ipaf，它们是IL-1 β和IL-18释放所必需的。总之，这些结果揭示了ESX-1在分枝杆菌感染期间触发溶酶体分泌以及IL-1 β和IL-18释放中的作用。
Exocytosis of lysosomes from macrophages has been described as a response to microbial cytotoxins and haemolysins, as well as for releasing pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18 during inflammasome activation. The mycobacterial ESX-1 secretion system, encoded in part by the Region of Difference-1, is a virulence factor necessary for phagosome escape and host cell lysis by a contact-dependent haemolysin in Mycobacterium marinum. Here we show that ESX-1 from M. marinum and M. tuberculosis is required for Ca(2+)-dependent induction of lysosome secretion from macrophages. Mycobacteria-induced lysosome secretion was concurrent to release of IL-1 beta and IL-18, dependent on phagocytosis of bacteria containing ESX-1. Synthesis but not release of IL-1 beta and IL-18 occurred in response to dead bacilli and bacteria lacking ESX-1, indicating that only cytokine release was regulated by ESX-1. Release of these cytokines and exocytosis of lysosomes were independent of intracellular mycobacterial growth, yet correlated with mycobacteria-encoded haemolytic activity, demonstrating a parallel pathway for the two responses. We further identified inflammasome components caspase-1, ASC and NALP3, but not Ipaf, required for release of IL-1 beta and IL-18. Collectively, these results reveal a role for ESX-1 in triggering secretion of lysosomes, as well as release of IL-1 beta and IL-18 during mycobacteria infection.