耶魯大學(xué)的研究人員發(fā)現(xiàn)了樹突狀細(xì)胞如何通過迅速實(shí)現(xiàn)細(xì)胞凋亡從而抑制嗜肺軍團(tuán)菌的生長(zhǎng),。之前的研究表明,，通過感應(yīng)包括模式識(shí)別受體NAIP5(一種細(xì)胞凋亡抑制蛋白質(zhì)，能夠?qū)?xì)胞質(zhì)中的細(xì)菌鞭毛蛋白作出響應(yīng))和1型半胱氨酸蛋白酶在內(nèi)的炎癥調(diào)節(jié)細(xì)胞的死亡,，巨噬細(xì)胞限制了嗜肺軍團(tuán)菌的復(fù)制,。然而，樹突狀細(xì)胞卻能夠忍受細(xì)胞凋亡,，同時(shí)在被嗜肺軍團(tuán)菌感染而缺乏NAIP5或1型半胱氨酸蛋白酶的情況下控制細(xì)菌的生長(zhǎng),，并且比在巨噬細(xì)胞中觀察到的具有更快的動(dòng)力學(xué)特征。
為了進(jìn)一步研究這一問題,，研究人員調(diào)查了NAIP5信號(hào)有缺陷的小鼠體內(nèi)樹突狀細(xì)胞中的3型半胱氨酸蛋白酶——細(xì)胞凋亡的一種下游調(diào)節(jié)因子——受損后造成的影響,。盡管在被傳染兩小時(shí)后，缺乏3型半胱氨酸蛋白酶的樹突狀細(xì)胞與NAIP5信號(hào)有缺陷但樹突狀細(xì)胞中3型半胱氨酸蛋白酶充足的小鼠表現(xiàn)出了類似的響應(yīng),，但前者在被傳染后10小時(shí)則表現(xiàn)出了更高的傳染速度,，以及較低的細(xì)胞凋亡水平。這一觀測(cè)結(jié)果意味著由3型半胱氨酸蛋白酶決定的細(xì)胞凋亡路徑對(duì)于誘導(dǎo)樹突狀細(xì)胞的死亡是重要的,，并從而在傳染后及早限制了病原體的復(fù)制,。
3型半胱氨酸蛋白酶能夠被細(xì)胞凋亡的內(nèi)部(或線粒體)路徑所激活，其中包括促進(jìn)細(xì)胞凋亡蛋白質(zhì)BAK和BAX,。在被傳染后,，缺乏樹突狀細(xì)胞的BAK和BAX與野生型樹突狀細(xì)胞表現(xiàn)出了類似的細(xì)胞凋亡水平，這意味著由NAIP5決定的路徑依然具有功能,，并且補(bǔ)償了BAK與BAX的損失,。然而，缺乏BAX和缺乏BAK的樹突狀細(xì)胞卻表現(xiàn)出了明顯更低的細(xì)胞凋亡水平,，并且在被一種鞭毛蛋白編碼基因flaA產(chǎn)生突變(并因此無(wú)法誘發(fā)NAIP5的活化)的嗜肺軍團(tuán)菌感染后,，支持了增加的細(xì)菌復(fù)制,。因此,，由NAIP5決定的路徑和細(xì)胞內(nèi)部路徑是細(xì)胞凋亡的兩個(gè)獨(dú)立路徑，它們都能夠抑制嗜肺軍團(tuán)菌的復(fù)制,。有趣的是,，由flaA突變的嗜肺軍團(tuán)菌感染的樹突狀細(xì)胞導(dǎo)致的B細(xì)胞淋巴瘤2(BCL-2)——能夠抵消BAX和BAK功效的一種促生存蛋白質(zhì)——的過度生產(chǎn)限制了細(xì)胞凋亡，并因此導(dǎo)致了細(xì)胞內(nèi)細(xì)菌復(fù)制的增加,，從而確定了內(nèi)部的細(xì)胞凋亡路徑在這一過程中的重要性,。
研究表明，兩種細(xì)胞死亡路徑能夠防止細(xì)菌的復(fù)制,，但與炎癥調(diào)節(jié)路徑相比,，細(xì)胞凋亡的內(nèi)部路徑能夠在傳染的較早期開始運(yùn)作,。研究人員提出，對(duì)細(xì)胞凋亡的感應(yīng)就像是一種天生的免疫機(jī)制,，從而防止細(xì)菌在樹突狀細(xì)胞轉(zhuǎn)移到淋巴組織期間發(fā)生傳播,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
