Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses
Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses
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DOI：
10.1038/ncomms1522
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发表时间：
2011-11-01
影响因子：
16.6
通讯作者：
Sharma, Amit
中科院分区：
文献类型：
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作者：
Bhatt, Tarun Kumar;Khan, Sameena;Sharma, Amit
疟疾感染引发人类的促炎反应，对宿主健康有害。寄生虫诱导的细胞因子水平的增强与疟疾相关的病理学相关。在这里，我们表明，寄生虫酪氨酰-tRNA合成酶（PfTyrRS），管家蛋白翻译酶，诱导宿主免疫细胞的促炎反应。PfTyrRS从寄生虫细胞质退出进入感染的红细胞（iRBC）细胞质，在iRBC裂解时从那里释放到细胞外培养基中。使用其ELR肽基序，PfTyrRS特异性结合并内化到宿主巨噬细胞中，导致促炎细胞因子TNF-α和IL-6的分泌增强。PfTyrRS-巨噬细胞相互作用还增强粘附连接的宿主内皮受体ICAM-1和VCAM-1的表达。我们将PfTyrRS描述为触发促炎宿主反应的寄生虫分泌蛋白，沿着其与酪氨酰-腺苷酸复合的原子分辨率晶体结构，为在抗寄生虫策略中靶向PfTyrRS提供了新的平台。
Malaria infection triggers pro-inflammatory responses in humans that are detrimental to host health. Parasite-induced enhancement in cytokine levels correlate with malaria-associated pathologies. Here we show that parasite tyrosyl-tRNA synthetase (PfTyrRS), a housekeeping protein translation enzyme, induces pro-inflammatory responses from host immune cells. PfTyrRS exits from the parasite cytoplasm into the infected red blood cell (iRBC) cytoplasm, from where it is released into the extracellular medium on iRBC lysis. Using its ELR peptide motif, PfTyrRS specifically binds to and internalizes into host macrophages, leading to enhanced secretion of the pro-inflammatory cytokines TNF-alpha and IL-6. PfTyrRS-macrophage interaction also augments expression of adherence-linked host endothelial receptors ICAM-1 and VCAM-1. Our description of PfTyrRS as a parasite-secreted protein that triggers proinflammatory host responses, along with its atomic resolution crystal structure in complex with tyrosyl-adenylate, provides a novel platform for targeting PfTyrRS in anti-parasitic strategies.