Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila.
Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila.
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DOI：
10.1371/journal.ppat.1000220
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发表时间：
2008-11
期刊：
影响因子：
6.7
通讯作者：
Zamboni DS
中科院分区：
文献类型：
--
作者：
Shin S;Case CL;Archer KA;Nogueira CV;Kobayashi KS;Flavell RA;Roy CR;Zamboni DS
免疫系统必须区分致病微生物和非致病微生物，才能启动适当的反应。Toll样受体(TLRs)检测病原菌和非病原菌共有的微生物成分，而Nod样受体(NLRs)检测通过细菌病原体的特殊分泌系统或致孔毒素进入宿主细胞质的微生物成分。对细菌分泌系统作出反应的宿主信号通路仍然知之甚少。感染利用IV型分泌系统(T4SS)的病原体嗜肺军团菌，与T4SS失活的无毒细菌相比，诱导了更高的促炎细胞因子反应。这种增强的反应包括通过TLR信号激活NF-κB，以及检测到IV型分泌的Nod1和Nod2。此外，一条TLR和RIP2非依赖的途径导致p38和SAPK/JNK MAPK激活，在宿主对强毒肺炎杆菌的反应中发挥着同样重要的作用。该MAPK通路的激活是T4SS依赖的，并与TLR信号协调，以启动对强毒嗜肺性乳杆菌的强烈促炎细胞因子反应。这些发现定义了一种先前未知的宿主对细菌IV型分泌的反应，激活了MAPK信号，并证明了对多个细菌成分的一致检测能够在强毒细菌和无毒细菌之间进行免疫区分。宿主免疫系统通过识别保守的细菌成分来感知细菌感染。宿主可以通过检测将效应蛋白注入细胞的细菌分泌系统的活性来区分毒力细菌和无毒细菌。宿主对这种细菌分泌系统的反应还不完全清楚。利用致病细菌嗜肺军团菌和不同毒力特性的等基因突变体，鉴定了对嗜肺军团菌及其IV型分泌系统的强大免疫反应。利用缺乏天然免疫系统各个方面的巨噬细胞，发现这种宿主反应包括细胞外和细胞内免疫受体的信号，以及由IV型分泌系统触发的宿主信号。通过对感染肺炎链球菌的巨噬细胞进行基因组和生化分析，发现IV型分泌物激活了与已知免疫途径不同的额外宿主信号通路。我们的数据表明，对细菌感染的强大免疫反应需要对多个细菌成分的联合检测，并强调了由细菌IV型分泌物触发的促进这种免疫反应的关键宿主途径。
The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. This enhanced response involved NF-κB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria. The host immune system senses bacterial infection by recognizing conserved bacterial components. The host can differentiate between virulent and avirulent bacteria by detecting the activity of bacterial secretion systems that inject effector proteins into cells. How the host responds to such bacterial secretion systems is not fully understood. Using the bacterial pathogen Legionella pneumophila and isogenic mutants that differ in defined virulence properties, a robust immune response to L. pneumophila and its type IV secretion system was identified. Using macrophages lacking various aspects of the innate immune system, it was found that this host response is comprised of signaling by extracellular and intracellular immune receptors, as well as host signaling triggered by the type IV secretion system. Through genomic and biochemical analyses of L. pneumophila–infected macrophages, type IV secretion was found to activate additional host signaling pathways distinct from known immune pathways. Our data indicate that coincident detection of multiple bacterial components is required for a robust immune response to bacterial infection and highlights a key host pathway triggered by bacterial type IV secretion that contributes to this immune response.
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