CLEC5A is critical for dengue-virus-induced lethal disease
CLEC5A is critical for dengue-virus-induced lethal disease
复制标题
DOI：
10.1038/nature07013
复制
发表时间：
2008-05-29
期刊：
影响因子：
64.8
通讯作者：
Hsieh, Shie-Liang
中科院分区：
文献类型：
--
作者：
Chen, Szu-Ting;Lin, Yi-Ling;Hsieh, Shie-Liang
登革出血热和登革休克综合征是对登革病毒（DV）感染最严重的反应，其特征是血浆渗漏（由于血管通透性增加）和血小板计数低（1，2）。CLEC 5A（C型凝集素结构域家族5，成员A;也称为髓样DAP 12相关凝集素（MDL-1））（3）含有类似于自然杀伤T细胞C型凝集素结构域的C型凝集素样折叠，并与髓样细胞上的12- kDa DNAX激活蛋白（DAP 12）（4）相关.在这里，我们表明CLEC 5A直接与登革病毒体相互作用，从而导致DAP 12磷酸化。CLEC 5A DV相互作用不导致病毒进入，但刺激促炎细胞因子的释放。CLEC 5A-DV相互作用的阻断抑制促炎细胞因子的分泌而不影响干扰素-α的释放，支持CLEC 5A充当促炎细胞因子释放的信号传导受体的观点。此外，抗CLEC 5A单克隆抗体抑制DV诱导的血浆渗漏，以及皮下和重要器官出血，并使STAT 1缺陷型小鼠中DV感染的死亡率降低约50%。我们观察到CLEC 5A介导的信号传导的阻断减弱了由DV感染的巨噬细胞（单独或与增强抗体复合）产生的促炎细胞因子，这为减轻组织损伤和增加患有登革出血热和登革休克综合征，甚至可能是其他病毒诱导的炎性疾病的患者的存活提供了有希望的策略.
Dengue haemorrhagic fever and dengue shock syndrome, the most severe responses to dengue virus ( DV) infection, are characterized by plasma leakage ( due to increased vascular permeability) and low platelet counts(1,2). CLEC5A ( C- type lectin domain family 5, member A; also known as myeloid DAP12- associating lectin ( MDL-1))(3) contains a C- type lectin- like fold similar to the natural- killer T- cell C- type lectin domains and associates with a 12- kDa DNAX- activating protein ( DAP12)(4) on myeloid cells. Here we show that CLEC5A interacts with the dengue virion directly and thereby brings about DAP12 phosphorylation. The CLEC5A DV interaction does not result in viral entry but stimulates the release of proinflammatory cytokines. Blockade of CLEC5A - DV interaction suppresses the secretion of proinflammatory cytokines without affecting the release of interferon-alpha, supporting the notion that CLEC5A acts as a signalling receptor for proinflammatory cytokine release. Moreover, anti- CLEC5A monoclonal antibodies inhibit DV- induced plasma leakage, as well as subcutaneous and vital- organ haemorrhaging, and reduce the mortality of DV infection by about 50% in STAT1- deficient mice. Our observation that blockade of CLEC5A- mediated signalling attenuates the production of proinflammatory cytokines by macrophages infected with DV ( either alone or complexed with an enhancing antibody) offers a promising strategy for alleviating tissue damage and increasing the survival of patients suffering from dengue haemorrhagic fever and dengue shock syndrome, and possibly even other virus- induced inflammatory diseases.