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首页 » 细胞凋亡 » PLoS Pathog:树突状细胞诱导凋亡而抑制嗜肺军团菌生长

PLoS Pathog:树突状细胞诱导凋亡而抑制嗜肺军团菌生长

来源:生物通 2009-09-15 09:25

耶鲁大学的研究人员发现了树突状细胞如何通过迅速实现细胞凋亡从而抑制嗜肺军团菌的生长。之前的研究表明,通过感应包括模式识别受体NAIP5(一种细胞凋亡抑制蛋白质,能够对细胞质中的细菌鞭毛蛋白作出响应)和1型半胱氨酸蛋白酶在内的炎症调节细胞的死亡,巨噬细胞限制了嗜肺军团菌的复制。然而,树突状细胞却能够忍受细胞凋亡,同时在被嗜肺军团菌感染而缺乏NAIP5或1型半胱氨酸蛋白酶的情况下控制细菌的生长,并且比在巨噬细胞中观察到的具有更快的动力学特征。

为了进一步研究这一问题,研究人员调查了NAIP5信号有缺陷的小鼠体内树突状细胞中的3型半胱氨酸蛋白酶——细胞凋亡的一种下游调节因子——受损后造成的影响。尽管在被传染两小时后,缺乏3型半胱氨酸蛋白酶的树突状细胞与NAIP5信号有缺陷但树突状细胞中3型半胱氨酸蛋白酶充足的小鼠表现出了类似的响应,但前者在被传染后10小时则表现出了更高的传染速度,以及较低的细胞凋亡水平。这一观测结果意味着由3型半胱氨酸蛋白酶决定的细胞凋亡路径对于诱导树突状细胞的死亡是重要的,并从而在传染后及早限制了病原体的复制。

3型半胱氨酸蛋白酶能够被细胞凋亡的内部(或线粒体)路径所激活,其中包括促进细胞凋亡蛋白质BAK和BAX。在被传染后,缺乏树突状细胞的BAK和BAX与野生型树突状细胞表现出了类似的细胞凋亡水平,这意味着由NAIP5决定的路径依然具有功能,并且补偿了BAK与BAX的损失。然而,缺乏BAX和缺乏BAK的树突状细胞却表现出了明显更低的细胞凋亡水平,并且在被一种鞭毛蛋白编码基因flaA产生突变(并因此无法诱发NAIP5的活化)的嗜肺军团菌感染后,支持了增加的细菌复制。因此,由NAIP5决定的路径和细胞内部路径是细胞凋亡的两个独立路径,它们都能够抑制嗜肺军团菌的复制。有趣的是,由flaA突变的嗜肺军团菌感染的树突状细胞导致的B细胞淋巴瘤2(BCL-2)——能够抵消BAX和BAK功效的一种促生存蛋白质——的过度生产限制了细胞凋亡,并因此导致了细胞内细菌复制的增加,从而确定了内部的细胞凋亡路径在这一过程中的重要性。

研究表明,两种细胞死亡路径能够防止细菌的复制,但与炎症调节路径相比,细胞凋亡的内部路径能够在传染的较早期开始运作。研究人员提出,对细胞凋亡的感应就像是一种天生的免疫机制,从而防止细菌在树突状细胞转移到淋巴组织期间发生传播。(生物谷Bioon.com)

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PLoS Pathog 5(6): e1000478. doi:10.1371/journal.ppat.1000478

Rapid Pathogen-Induced Apoptosis: A Mechanism Used by Dendritic Cells to Limit Intracellular Replication of Legionella pneumophila

Catarina V. Nogueira1,2, Tullia Lindsten3, Amanda M. Jamieson4, Christopher L. Case1, Sunny Shin1, Craig B. Thompson3, Craig R. Roy1*

1 Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America, 2 Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomedicas Dr. Abel Salazar, Universidade do Porto, Porto, Portugal, 3 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 4 Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America

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 na?ve 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.

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