The frustrated host response to Legionella pneumophila is bypassed by MyD88-dependent translation of pro-inflammatory cytokines.
The frustrated host response to Legionella pneumophila is bypassed by MyD88-dependent translation of pro-inflammatory cytokines.
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DOI：
10.1371/journal.ppat.1004229
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发表时间：
2014-07
期刊：
影响因子：
6.7
通讯作者：
Isberg RR
中科院分区：
文献类型：
--
作者：
Asrat S;Dugan AS;Isberg RR
许多病原体，特别是那些需要宿主生存的病原体，已经设计了颠覆宿主免疫反应的机制，以便在细胞内生存和复制。嗜肺军团菌是军团病的病原体，通过其IV型蛋白分泌机制将蛋白质转移到宿主细胞质中，从而促进细胞内的生长。至少有5个细菌易位效应子干扰宿主细胞延长因子的功能，阻止翻译并导致诱导独特的宿主细胞转录图谱。此外，嗜肺乳杆菌还通过阻止宿主细胞中依赖帽子的翻译来干扰翻译的启动。在这里，我们证明了嗜肺乳杆菌的蛋白质翻译抑制会导致宿主MAPK反应受挫，其中参与该途径的基因被转录，但由于细菌诱导的蛋白质合成抑制而无法翻译。令人惊讶的是，很少有促炎细胞因子，如IL-1α和IL-1β，绕过这种抑制，在军团菌效应器存在的情况下合成。我们发现，这些基因的选择性合成需要MyD88信号，并且发生在携带细菌的感染细胞和邻近的旁观者细胞中。我们的发现为宿主细胞如何能够应对病原体编码的活动提供了一个视角，这些活动扰乱了正常的细胞过程，并启动了成功的炎症反应。翻译抑制是许多病原体(如白喉毒素、志贺毒素和假单胞菌外毒素A)共同使用的毒力机制。在病原体阻止蛋白质合成的条件下，宿主细胞如何启动病原体特异的反应和明确的感染一直是一个谜。以嗜肺军团菌为模型，这是一种有效阻止宿主蛋白质翻译机制的细菌，我们在这里表明，先天性免疫系统已经设计出一种机制，通过选择性地合成炎症所需的蛋白质来应对翻译抑制。
Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its host cytosol through its type IV protein secretion machinery. At least 5 of the bacterial translocated effectors interfere with the function of host cell elongation factors, blocking translation and causing the induction of a unique host cell transcriptional profile. In addition, L. pneumophila also interferes with translation initiation, by preventing cap-dependent translation in host cells. We demonstrate here that protein translation inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes involved in the pathway are transcribed but fail to be translated due to the bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory cytokines, such as IL-1α and IL-1β, bypass this inhibition and get synthesized in the presence of Legionella effectors. We show that the selective synthesis of these genes requires MyD88 signaling and takes place in both infected cells that harbor bacteria and neighboring bystander cells. Our findings offer a perspective of how host cells are able to cope with pathogen-encoded activities that disrupt normal cellular process and initiate a successful inflammatory response. Translation inhibition is a common virulence mechanism used by a number of pathogens (e.g. Diphtheria Toxin, Shiga Toxin and Pseudomonas Exotoxin A). It has been a mystery how host cells mount a pathogen-specific response and clear infection under conditions where protein synthesis is blocked by pathogens. Using Legionella pneumophila as a model, a bacterium that efficiently blocks the host protein translation machinery, we show here that the innate immune system has devised a mechanism to cope with translation inhibition by selectively synthesizing proteins that are required for inflammation.
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影响因子：
3.4
作者：
Heidtman M;Chen EJ;Moy MY;Isberg RR
通讯作者：
Isberg RR
影响因子：
30.5
作者：
Ausubel, FM
通讯作者：
Ausubel, FM
影响因子：
3.4
作者：
Archer KA;Alexopoulou L;Flavell RA;Roy CR
通讯作者：
Roy CR
影响因子：
4.4
作者：
Akira, S;Hemmi, H
通讯作者：
Hemmi, H
DOI：
10.4049/jimmunol.1300100
发表时间：
2013-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Barry KC;Fontana MF;Portman JL;Dugan AS;Vance RE
通讯作者：
Vance RE