Deletion of ripA Alleviates Suppression of the Inflammasome and MAPK by Francisella tularensis
Deletion of ripA Alleviates Suppression of the Inflammasome and MAPK by Francisella tularensis
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DOI：
10.4049/jimmunol.1002154
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发表时间：
2010-11-01
影响因子：
4.4
通讯作者：
Ting, Jenny Pan-Yun
中科院分区：
文献类型：
--
作者：
Huang, Max Tze-Han;Mortensen, Brittany L.;Ting, Jenny Pan-Yun
土拉热弗朗西丝菌是一种兼性胞内病原菌和潜在的生物威胁因子。免疫反应的逃避有助于这种生物体的非凡毒力，尽管其机制尚不清楚。而野生型菌株诱导低水平的细胞因子，F。土拉热菌ripA缺失突变体（LVS Delta ripA）引起静息巨噬细胞显著释放IL-1 β、IL-18和TNF-α。IL-1 β和IL-18的分泌依赖于炎性体组分pyrin-caspase募集结构域/含有caspase募集结构域和caspase-1的凋亡斑点蛋白，并且TLR/IL-1 R信号分子MyD 88是炎性细胞因子合成所需的。用编码ripA的质粒互补LVS Delta ripA恢复了免疫逃避。在人单核细胞系中观察到类似的发现。ripA的存在几乎消除了包括ERK 1/2、JNK和p38的MAPK的活化，并且这三种MAPK的药理学抑制剂减少了LVS Delta ripA的细胞因子诱导。感染LVS Delta ripA的动物比感染野生型活疫苗株的小鼠产生更强的IL-1 β和TNF-α应答。该分析揭示了F.土拉热。免疫学杂志，2010，185：5476-5485。
Francisella tularensis is a facultative intracellular pathogen and potential biothreat agent. Evasion of the immune response contributes to the extraordinary virulence of this organism although the mechanism is unclear. Whereas wild-type strains induced low levels of cytokines, an F. tularensis ripA deletion mutant (LVS Delta ripA) provoked significant release of IL-1 beta, IL-18, and TNF-alpha by resting macrophages. IL-1 beta and IL-18 secretion was dependent on inflammasome components pyrin-caspase recruitment domain/apoptotic speck-containing protein with a caspase recruitment domain and caspase-1, and the TLR/IL-1R signaling molecule MyD88 was required for inflammatory cytokine synthesis. Complementation of LVS Delta ripA with a plasmid encoding ripA restored immune evasion. Similar findings were observed in a human monocytic line. The presence of ripA nearly eliminated activation of MAPKs including ERK1/2, JNK, and p38, and pharmacologic inhibitors of these three MAPKs reduced cytokine induction by LVS Delta ripA. Animals infected with LVS Delta ripA mounted a stronger IL-1 beta and TNF-alpha response than that of mice infected with wild-type live vaccine strain. This analysis revealed novel immune evasive mechanisms of F. tularensis. The Journal of Immunology, 2010, 185: 5476-5485.