Cell invasion and strain dependent induction of suppressor of cytokine signaling-1 by Toxoplasma gondii.
Cell invasion and strain dependent induction of suppressor of cytokine signaling-1 by Toxoplasma gondii.
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DOI：
10.1016/j.imbio.2011.08.008
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发表时间：
2012-01
期刊：
影响因子：
2.8
通讯作者：
Dalpke AH
中科院分区：
文献类型：
--
作者：
Stutz A;Kessler H;Kaschel ME;Meissner M;Dalpke AH
弓形虫是一种细胞内寄生虫，必须科普IFNγ的杀微生物作用。我们之前报道过寄生虫介导的细胞因子信号蛋白抑制因子1（SOCS 1）的诱导有助于抑制IFNγ信号传导。然而，信号要求仍然难以捉摸。我们发现IFNγ诱导SOCS 1和抑制一氧化氮的产生不依赖于Toll样受体的刺激。而T.弓形虫导致了已报道的调节SOCS表达的转录因子的诱导。事实上，egr 2和SOCS 1的诱导依赖于p38 MAP激酶，阻断p38 MAP激酶可抑制SOCS 1的表达。此外，我们还发现，以前鉴定的T. SOCS 1对IFNγ介导的巨噬细胞NO分泌的调节和逃逸是必需的。令人惊讶的是，当进一步分析Mic 8缺陷型寄生虫时，我们注意到IFNγ介导的MHC-II类和ICAM 1分子上调的抑制与细胞侵袭无关。此外，这些抑制作用在T.弓形虫，并依赖于排泄和分泌的抗原。相反，只有强毒RH I型菌株额外诱导SOCS 1，并通过IFNγ有效抑制一氧化氮分泌。结果表明，T.弓形虫利用两种不同的机制逃避IFNγ活性，一种模式是菌株依赖性的，依赖于活跃的细胞侵袭和SOCS 1诱导。
Toxoplasma gondii is an intracellular parasite that has to cope with the microbicidal actions of IFNγ. Previously we reported that parasite-mediated induction of suppressor of cytokine signaling protein 1 (SOCS1) contributes to inhibition of IFNγ signaling. However, the signaling requirements remained elusive. We now show that induction of SOCS1 and inhibition of nitric oxide production by IFNγ was independent of stimulation of Toll-like receptors. Instead, infection by T. gondii resulted in induction of egr transcription factors which have been reported to regulate SOCS expression. Indeed, induction of egr2 as well as SOCS1 was dependent on p38 MAP kinase and blockade of egr inhibited SOCS1 expression. Moreover, we found that Mic8, a previously identified invasion factor of T. gondii, was necessary for SOCS1 regulation and escape of IFNγ mediated nitric oxide secretion within macrophages. Surprisingly, when further analyzing Mic8 deficient parasites we noted that inhibition of IFNγ mediated up-regulation of MHC-class II and ICAM1 molecules was independent of cell invasion. Furthermore, these inhibitory effects were equally observed in type I and II strains of T. gondii and were dependent on excreted and secreted antigens. In contrast, only the virulent RH type I strain additionally induced SOCS1 and efficiently inhibited nitric oxide secretion by IFNγ. The results show that T. gondii makes use of two different mechanisms to escape from IFNγ activity with one mode being strain dependent and relying on active cell invasion and SOCS1 induction.