Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection.
Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection.
复制标题
DOI：
10.1371/journal.ppat.1000361
复制
发表时间：
2009-04
期刊：
影响因子：
6.7
通讯作者：
Amer AO
中科院分区：
文献类型：
--
作者：
Akhter A;Gavrilin MA;Frantz L;Washington S;Ditty C;Limoli D;Day C;Sarkar A;Newland C;Butchar J;Marsh CB;Wewers MD;Tridandapani S;Kanneganti TD;Amer AO
嗜肺军团菌（L. pneumophila）是一种叫做军团病的严重肺炎的病原体，在人类单核细胞和巨噬细胞中复制。除了A/J、Nlrc4−/−(Ipaf−/−)和caspase-1−/−衍生的巨噬细胞外，大多数近交小鼠菌株对嗜肺乳杆菌感染具有限制性。特别是在嗜肺乳杆菌感染小鼠巨噬细胞时检测到caspase-1激活，而在人细胞中则没有。最近的体外实验表明，caspase-7可以被caspase-1切割。然而，caspase-7在caspase-1下游活化的生物学作用尚不清楚。此外，这种反应是否与细胞凋亡或炎症途径有关，或者是否介导了一种尚未确定的作用，目前尚不清楚。利用细胞内病原体嗜肺乳杆菌，我们发现，在小鼠巨噬细胞感染后，caspase-7在Nlrc4炎性体下游被激活，并且需要caspase-1激活。这种caspase-7的激活是由鞭毛蛋白介导的，需要一个功能性的Naip5。值得注意的是，缺乏caspase-7及其巨噬细胞的小鼠允许大量嗜肺乳杆菌复制。caspase-7 - / -巨噬细胞对细胞内病原体的容许性是由于生物体向溶酶体的递送有缺陷以及在感染的早期阶段延迟细胞死亡。这些结果揭示了Nlrc4炎性体下游caspase-7激活的新机制，并提出了caspase-7在宿主防御细胞内细菌中的新的生物学作用。嗜肺军团菌引起一种叫做军团病的严重肺炎。在人巨噬细胞中，嗜肺乳杆菌形成特殊的液泡，不与溶酶体融合，在细胞内生长。然而，在小鼠巨噬细胞中，细菌被有效地递送到溶酶体中进行降解。重要的是，caspase-1在嗜肺乳杆菌感染小鼠巨噬细胞时被激活，而在感染人类细胞时则不会被激活。Caspase-1的激活促进嗜肺乳杆菌液泡与溶酶体的融合和巨噬细胞的死亡。然而，介导这种作用的caspase-1底物尚不清楚。体外实验表明，caspase-7是caspase-1的底物。然而，目前尚不清楚这种反应是否发生在巨噬细胞内，也不清楚它是否有任何生物学效应。在本研究中，我们发现在小鼠巨噬细胞中，caspase-7被caspase-1下游的嗜肺乳杆菌激活，并需要宿主受体Nlrc4和Naip5。值得注意的是，在嗜肺乳杆菌感染过程中，caspase-7的激活通过促进巨噬细胞早期死亡和生物体向溶酶体的有效递送来限制生长。因此，嗜肺乳杆菌在caspase-7 - / -小鼠的巨噬细胞和肺中生长。因此，我们证明了一种新的caspase-7激活途径有助于限制嗜肺乳杆菌感染。
Legionella pneumophila (L. pneumophila), the causative agent of a severe form of pneumonia called Legionnaires' disease, replicates in human monocytes and macrophages. Most inbred mouse strains are restrictive to L. pneumophila infection except for the A/J, Nlrc4−/− (Ipaf−/−), and caspase-1−/− derived macrophages. Particularly, caspase-1 activation is detected during L. pneumophila infection of murine macrophages while absent in human cells. Recent in vitro experiments demonstrate that caspase-7 is cleaved by caspase-1. However, the biological role for caspase-7 activation downstream of caspase-1 is not known. Furthermore, whether this reaction is pertinent to the apoptosis or to the inflammation pathway or whether it mediates a yet unidentified effect is unclear. Using the intracellular pathogen L. pneumophila, we show that, upon infection of murine macrophages, caspase-7 was activated downstream of the Nlrc4 inflammasome and required caspase-1 activation. Such activation of caspase-7 was mediated by flagellin and required a functional Naip5. Remarkably, mice lacking caspase-7 and its macrophages allowed substantial L. pneumophila replication. Permissiveness of caspase-7−/− macrophages to the intracellular pathogen was due to defective delivery of the organism to the lysosome and to delayed cell death during early stages of infection. These results reveal a new mechanism for caspase-7 activation downstream of the Nlrc4 inflammasome and present a novel biological role for caspase-7 in host defense against an intracellular bacterium. Legionella pneumophila causes a severe form of pneumonia called Legionnaires' disease. In human macrophages, L. pneumophila establishes special vacuoles that do not fuse with the lysosome and grows intracellularly. However, in mouse macrophages, the bacteria are efficiently delivered to the lysosome for degradation. Importantly, caspase-1 is activated when L. pneumophila infects mouse macrophages, but not when it infects human cells. Caspase-1 activation promotes the fusion of the L. pneumophila vacuole with the lysosome and macrophage death. However, the caspase-1 substrate mediating such effects is unknown. Experiments performed in vitro demonstrate that caspase-7 is a substrate of caspase-1. Yet, it is not known if the reaction takes place within the macrophage, and it is unclear if it has any biological effect. In this study we show that, in mouse macrophages, caspase-7 is activated by L. pneumophila downstream of caspase-1 and requires the host receptors Nlrc4 and Naip5. Remarkably, caspase-7 activation during L. pneumophila infection restricts growth by promoting early macrophage death and efficient delivery of the organism to the lysosome. Consequently, L. pneumophila grows in the macrophages and the lungs of caspase-7−/− mice. Therefore, we demonstrate a novel caspase-7 activation pathway that contributes to the restriction of L. pneumophila infection.
登录
查看更多内容
DOI：
10.1084/jem.158.6.2108
发表时间：
1983-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Horwitz MA
通讯作者：
Horwitz MA
影响因子：
3.4
作者：
Amer, AO;Swanson, MS
通讯作者：
Swanson, MS
DOI：
10.1073/pnas.0504271103
发表时间：
2006-01-03
影响因子：
11.1
作者：
Gavrilin, MA;Bouakl, IJ;Wewers, MD
通讯作者：
Wewers, MD
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
3.1
作者：
Derré, I;Isberg, RR
通讯作者：
Isberg, RR