Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15
Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15
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DOI：
10.1128/iai.01185-12
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发表时间：
2013-06-01
影响因子：
3.1
通讯作者：
Saeij, Jeroen P. J.
中科院分区：
文献类型：
--
作者：
Jensen, Kirk D. C.;Hu, Kenneth;Saeij, Jeroen P. J.
刚地弓形虫在中间宿主之间的传播依赖于摄入感染慢性期形成的囊壁。在食用后，寄生虫必须立即通过防止不良炎症反应和/或限制自身复制来确保宿主的生存。由于弓形虫分泌的效应物rhoptry 16激酶（ROP16）和致密颗粒15 （GRA15）分别激活JAK-STAT3/6和NF-kappa B信号通路，我们探索了这些效应物的特定组合是否影响肠道炎症和体内寄生虫的生存。本文报道，仅在内源性GRA15表达的情况下，II型菌株（菌株II+ROP16(I)）中表达stat激活版本的ROP16才能促进宿主对口腔感染的抗性。保护的特点是肠道寄生虫负担较低，炎症减轻。宿主对II+ROP16(I)菌株的抗性独立于STAT6和T细胞共抑制受体B7-DC和B7-H1，这两个受体被ROP16上调。此外，在肿瘤坏死因子α / γ干扰素刺激的巨噬细胞内，ROP16和GRA15的共表达以stat3 /6独立的方式增强了寄生虫的易感性。感染了STAT3-和stat6缺陷的巨噬细胞以及被II+ROP16菌株口服攻击的小鼠的Peyer's斑块的转录谱分析(I)表明，ROP16激活STAT5来调节宿主基因表达。与这一假设一致，ROP16激酶诱导弓形虫感染细胞中STAT5的持续磷酸化和核定位。综上所述，只有gr15和ROP16的联合表达才能促进宿主对急性口腔感染的抗性，弓形虫可能靶向STAT5信号通路在肠道中产生保护性免疫。
Toxoplasma gondii transmission between intermediate hosts is dependent on the ingestion of walled cysts formed during the chronic phase of infection. Immediately following consumption, the parasite must ensure survival of the host by preventing adverse inflammatory responses and/or by limiting its own replication. Since the Toxoplasma secreted effectors rhoptry 16 kinase (ROP16) and dense granule 15 (GRA15) activate the JAK-STAT3/6 and NF-kappa B signaling pathways, respectively, we explored whether a particular combination of these effectors impacted intestinal inflammation and parasite survival in vivo. Here we report that expression of the STAT-activating version of ROP16 in the type II strain (strain II+ROP16(I)) promotes host resistance to oral infection only in the context of endogenous GRA15 expression. Protection was characterized by a lower intestinal parasite burden and dampened inflammation. Host resistance to the II+ROP16(I) strain occurred independently of STAT6 and the T cell coinhibitory receptors B7-DC and B7-H1, two receptors that are upregulated by ROP16. In addition, coexpression of ROP16 and GRA15 enhanced parasite susceptibility within tumor necrosis factor alpha/gamma interferon-stimulated macrophages in a STAT3/6-independent manner. Transcriptional profiling of infected STAT3- and STAT6-deficient macrophages and parasitized Peyer's patches from mice orally challenged with strain II+ROP16(I) suggested that ROP16 activated STAT5 to modulate host gene expression. Consistent with this supposition, the ROP16 kinase induced the sustained phosphorylation and nuclear localization of STAT5 in Toxoplasma-infected cells. In summary, only the combined expression of both GRA15 and ROP16 promoted host resistance to acute oral infection, and Toxoplasma may possibly target the STAT5 signaling pathway to generate protective immunity in the gut.