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

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.树突状细胞（Dendritic cells, DCs）是一类特化的吞噬细胞，可在外周组织摄取外源性抗原与微生物，随后迁移至淋巴器官，将外源肽段呈递给初始T细胞。已有多项研究表明，相较于巨噬细胞，DCs在限制病原体胞内复制方面效率更高，这一特性可阻止DCs促进病原体播散。为探究DCs应对病原体的应答机制，本研究针对小鼠DCs限制胞内病原体嗜肺军团菌（Legionella pneumophila）复制的具体机制展开了研究。结果显示，DCs与巨噬细胞均可通过半胱天冬酶-1 (caspase-1) 与Naip5介导的细胞死亡通路，干扰嗜肺军团菌的复制。然而，能够规避Naip5依赖性应答的嗜肺军团菌，虽可在巨噬细胞中实现高效复制，却仍无法在DCs中完成增殖。研究还发现，相较于同等条件下感染的巨噬细胞，嗜肺军团菌感染后的DCs中，由半胱天冬酶-3 (caspase-3) 介导的细胞凋亡发生时间显著更早。进一步实验证实，敲除促凋亡蛋白Bax与Bak，或是过表达抗凋亡蛋白B细胞淋巴瘤/白血病-2 (Bcl-2)，均可恢复嗜肺军团菌在DCs中的复制能力。综上，DCs拥有一套微生物应答通路，可快速激活细胞凋亡以限制病原体的复制。