Rapid pathogen-induced apoptosis: a mechanism used by dendritic cells to limit intracellular replication of Legionella pneumophila.
Rapid pathogen-induced apoptosis: a mechanism used by dendritic cells to limit intracellular replication of Legionella pneumophila.
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快速病原体诱导的凋亡：树突状细胞用来限制肺炎军团菌的细胞内复制的一种机制。
DOI：
10.1371/journal.ppat.1000478
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Roy CR
中科院分区：
文献类型：
--
作者：
Nogueira CV;Lindsten T;Jamieson AM;Case CL;Shin S;Thompson CB;Roy CR
树突状细胞（Dendritic cells，DC）是一种特殊的吞噬细胞，能将外源性抗原和微生物在外周部位内化，然后迁移到淋巴器官向幼稚T细胞展示外源性多肽。有几个例子表明，与巨噬细胞相比，DC在限制病原体的细胞内复制方面更有效，这是一种可以防止DC增强病原体传播的特性。为了了解DC对病原体的反应，我们研究了小鼠DC能够限制细胞内病原体嗜肺军团菌复制的机制。我们发现DC和巨噬细胞都有干扰L.嗜肺菌通过caspase-1和Naip 5介导的细胞死亡途径复制。L.然而，避免Naip 5依赖性应答的嗜肺细胞在巨噬细胞中显示出稳健的复制，但仍然不能在DC中复制。Caspase-3介导的细胞凋亡在感染L.与类似感染的巨噬细胞相比。清除促凋亡蛋白Bax和巴克或过量产生抗凋亡蛋白Bcl-2均能恢复L.嗜肺菌在DC中复制。因此，DC具有快速激活细胞凋亡以限制病原体复制的微生物应答途径。免疫系统被设计为识别进入体内的微生物，并引发阻止这些生物体复制和传播的反应。树突状细胞在调节宿主对病原体的免疫中起重要作用。它们的吞噬能力使DC能够内化和破坏大多数微生物，并且DC迁移到专门的淋巴器官的能力对于诱导抗原特异性免疫是重要的。在这里，我们分析了树突状细胞和嗜肺军团菌之间的相互作用，嗜肺军团菌是一种细菌病原体，可以破坏吞噬宿主细胞的功能，产生一个空泡，允许细胞内复制。我们发现L. pneumophila感染迅速诱导DCs通过凋亡进行细胞死亡。感染巨噬细胞后没有观察到快速凋亡，巨噬细胞是支持L。嗜肺菌在受感染动物的肺中复制。使用来自基因敲除小鼠的细胞，我们发现缺乏Bax和巴克蛋白的DC不能限制L.嗜肺菌同样，Bcl-2的过度表达，这是一种凋亡的负调节因子，导致DC对L。嗜肺复制这些数据表明，当被能够在细胞内复制的微生物感染时，DC具有快速经历凋亡的能力，并且这种应答有效地防止病原体复制。我们推测，这种反应可能是为了干扰受感染的DC通过淋巴系统的迁移，这将防止DC作为“特洛伊木马”，将病原微生物从外周部位运输到中央器官。
Dendritic cells (DCs) are specialized phagocytes that internalize exogenous antigens and microbes at peripheral sites, and then migrate to lymphatic organs to display foreign peptides to naïve T cells. There are several examples where DCs have been shown to be more efficient at restricting the intracellular replication of pathogens compared to macrophages, a property that could prevent DCs from enhancing pathogen dissemination. To understand DC responses to pathogens, we investigated the mechanisms by which mouse DCs are able to restrict replication of the intracellular pathogen Legionella pneumophila. We show that both DCs and macrophages have the ability to interfere with L. pneumophila replication through a cell death pathway mediated by caspase-1 and Naip5. L. pneumophila that avoided Naip5-dependent responses, however, showed robust replication in macrophages but remained unable to replicate in DCs. Apoptotic cell death mediated by caspase-3 was found to occur much earlier in DCs following infection by L. pneumophila compared to macrophages infected similarly. Eliminating the pro-apoptotic proteins Bax and Bak or overproducing the anti-apoptotic protein Bcl-2 were both found to restore L. pneumophila replication in DCs. Thus, DCs have a microbial response pathway that rapidly activates apoptosis to limit pathogen replication. The immune system is designed to identify microbes that enter the body and elicit responses that prevent the replication and dissemination of these organisms. Dendritic cells play an important role in regulating host immunity to pathogens. Their phagocytic capacity enables DCs to internalize and destroy most microbes, and the ability of DCs to migrate to specialized lymphoid organs is important for inducing antigen-specific immunity. Here, we analyzed interactions between DCs and Legionella pneumophila, a bacterial pathogen that can subvert phagocytic host cell functions to create a vacuole that permits intracellular replication. We found that L. pneumophila infection rapidly induced DCs to commit cell death through apoptosis. Rapid apoptosis was not observed after infection of macrophages, which are the phagocytic cells that support L. pneumophila replication in the lungs of infected animals. Using cells derived from knockout mice, we found that DCs deficient in the proteins Bax and Bak, which are essential for induction of the apoptosis pathway, were unable to restrict the intracellular replication of L. pneumophila. Likewise, overproduction of Bcl-2, which is a negative regulator of apoptosis, resulted in DCs that were permissive for L. pneumophila replication. These data indicate DCs have the ability to rapidly undergo apoptosis when infected with a microbe capable of replicating intracellularly, and this response effectively prevents pathogen replication. We hypothesize that this response may be designed to interfere with the migration of infected DCs through the lymphatic system, which would prevent DCs from serving as a “Trojan Horse” that transports pathogenic microbes from peripheral sites to central organs.
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