The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the IκB kinase subunit IKKα
The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the IκB kinase subunit IKKα
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DOI：
10.1073/pnas.1007765107
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发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Cossart, Pascale
中科院分区：
文献类型：
--
作者：
Gouin, Edith;Adib-Conquy, Minou;Cossart, Pascale
单核细胞增生李斯特菌是导致严重食源性感染的细胞内病原体。它可以在吞噬性和非吞噬性哺乳动物细胞中复制。细胞水平的感染过程已被广泛研究，但细菌如何克服早期宿主先天免疫反应仍然很大程度上是未知的。在这里，我们发现InlC是internalin家族的一员，在细胞内分泌，并直接与IKK α相互作用，IKK α是ikappa B激酶复合物的一个亚基，对ikappa B的磷酸化和NF-kappa B的激活至关重要，后者是先天免疫反应的主要调节因子。对WT李斯特菌或InlC缺失突变体的感染实验以及转染InlC的细胞表明，InlC表达损害了磷酸化，从而延迟了通常由tnf - α（一种经典的nf - κ B刺激剂）诱导的I κ B降解。此外，与WT相比，inlC突变体感染RAW 264.7巨噬细胞导致促炎细胞因子的产生增加。最后，在腹膜炎小鼠模型中，我们发现与WT感染相比，inlC突变体感染可诱导趋化因子的产生增加，并增加腹腔中性粒细胞的募集。总之，这些结果表明，inlC通过与IKK α相互作用，在感染过程中抑制李斯特菌诱导的宿主先天反应。
Listeria monocytogenes is an intracellular pathogen responsible for severe foodborne infections. It can replicate in both phagocytic and nonphagocytic mammalian cells. The infectious process at the cellular level has been studied extensively, but how the bacterium overcomes early host innate immune responses remains largely unknown. Here we show that InlC, a member of the internalin family, is secreted intracellularly and directly interacts with IKK alpha, a subunit of the I kappa B kinase complex critical for the phosphorylation of I kappa B and activation of NF-kappa B, the major regulator of innate immune responses. Infection experiments with WT Listeria or the inlC-deletion mutant and transfection of cells with InlC reveal that InlC expression impairs phosphorylation and consequently delays I kappa B degradation normally induced by TNF-alpha, a classical NF-kappa B stimulator. Moreover, infection of RAW 264.7 macrophages by the inlC mutant leads to increased production of proinflammatory cytokines compared with that obtained with the WT. Finally, in a peritonitis mouse model, we show that infection with the inlC mutant induces increased production of chemokines and increased recruitment of neutrophils in the peritoneal cavity compared with infection with WT. Together, these results demonstrate that InlC, by interacting with IKK alpha, dampens the host innate response induced by Listeria during the infection process.