Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA.
Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA.
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DOI：
10.1038/ncomms10205
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发表时间：
2015-12-21
影响因子：
16.6
通讯作者：
Zamboni DS
中科院分区：
文献类型：
--
作者：
Cunha LD;Ribeiro JM;Fernandes TD;Massis LM;Khoo CA;Moffatt JH;Newton HJ;Roy CR;Zamboni DS
伯纳蒂克希菌是一种传染性很强的细菌，它通过抑制几种宿主细胞的反应来促进自身在巨噬细胞中的复制。在这里，我们发现伯氏梭菌抑制原代小鼠巨噬细胞中caspase-1的激活。通过联合感染实验，我们确定巨噬细胞感染伯氏杆菌可抑制caspase-11介导的NLRP3炎性体的非典型激活，这种激活是由随后感染大肠杆菌或嗜肺军团菌引起的。利用嗜肺乳杆菌的鞭毛蛋白突变体作为替代宿主进行遗传筛选，揭示了一种新的伯纳氏菌基因（IcaA）参与抑制半胱天冬酶的激活。嗜肺乳杆菌表达IcaA抑制巨噬细胞caspase-11的激活。此外，burnetii的icaA-突变体无法抑制嗜肺乳杆菌诱导的caspase-11介导的炎性体激活。我们的数据显示IcaA是一种新的伯氏c效应蛋白，由Dot/Icm IV型分泌系统分泌，并干扰caspase-11诱导的炎症小体的非规范激活。伯纳蒂克希菌主要感染肺泡巨噬细胞，引起急性肺炎，称为Q热。Cunha等人描述了一种被称为IcaA的IV型分泌效应物，由伯纳氏杆菌表达，可抑制炎性体的激活，因此可能有助于细菌的先天免疫逃避。
Coxiella burnetii is a highly infectious bacterium that promotes its own replication in macrophages by inhibiting several host cell responses. Here, we show that C. burnetii inhibits caspase-1 activation in primary mouse macrophages. By using co-infection experiments, we determine that the infection of macrophages with C. burnetii inhibits the caspase-11-mediated non-canonical activation of the NLRP3 inflammasome induced by subsequent infection with Escherichia coli or Legionella pneumophila. Genetic screening using flagellin mutants of L. pneumophila as a surrogate host, reveals a novel C. burnetii gene (IcaA) involved in the inhibition of caspase activation. Expression of IcaA in L. pneumophila inhibited the caspase-11 activation in macrophages. Moreover, icaA- mutants of C. burnetii failed to suppress the caspase-11-mediated inflammasome activation induced by L. pneumophila. Our data reveal IcaA as a novel C. burnetii effector protein that is secreted by the Dot/Icm type IV secretion system and interferes with the caspase-11-induced, non-canonical activation of the inflammasome. Coxiella burnetti primarily infects alveolar macrophages and causes an acute form of pneumonia called Q fever. Cunha et al. describe a type IV secretion effector, termed IcaA, expressed by Coxiella burnetii that inhibits inflammasome activation and therefore may contribute to innate immune evasion by bacteria.