Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins
Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins
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DOI：
10.1128/jvi.00912-16
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发表时间：
2016-11-01
影响因子：
5.4
通讯作者：
Mohana-Borges，Ronaldo
中科院分区：
文献类型：
--
作者：
Conde，Jonas Nascimento;da Silva，Emiliana Mandarano;Mohana-Borges，Ronaldo
登革病毒（DENV）感染全世界数百万人，是一个主要的公共卫生问题。登革病毒非结构蛋白1（NS 1）是一种保守的糖蛋白，与膜相关，也分泌到登革病毒感染患者的血浆中。本研究描述了一种新的机制，其中NS 1抑制末端补体途径。我们首先通过使用酵母双杂交系统鉴定了末端补体调节因子玻连蛋白（VN）作为新的DENV 2 NS 1结合伴侣。通过酶联免疫吸附测定（ELISA）和表面等离子体共振（SPR）测定进一步评估这种相互作用。NS 1-VN复合物也在DENV感染患者的血浆中检测到，表明这种相互作用发生在DENV感染期间。我们还证明了DENV 2 NS 1蛋白，无论是通过自身还是通过与VN相互作用，都阻碍了膜攻击复合物（MAC）和C9聚合的形成。最后，我们发现，在哺乳动物细胞中产生的DENV 2，西尼罗河病毒（WNV）和寨卡病毒（ZIKV）NS 1蛋白抑制C9聚合。综上所述，我们的研究结果表明NS 1作为补体系统的末端通路抑制剂的作用。重要提示登革热是当今最重要的节肢动物传播的病毒性疾病，由登革病毒（DENV）引起。黄病毒NS 1糖蛋白在功能上被表征为补体逃避蛋白，其可以减弱经典途径、凝集素途径和旁路途径的激活。本研究描述了DENV NS 1抑制末端补体途径的新机制。我们确定了末端补体调节因子玻连蛋白（VN）作为一种新的DENV NS 1结合伴侣，并在DENV感染患者的血浆中检测到NS 1-VN复合物，表明这种相互作用发生在DENV感染期间。我们还证明了NS 1-VN复合物抑制膜攻击复合物（MAC）的形成，从而干扰补体末端途径。有趣的是，NS 1本身也抑制MAC活性，表明该蛋白在抑制过程中的直接作用。我们的研究结果暗示了NS 1作为补体系统的末端通路抑制剂的作用。
Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system.IMPORTANCEDengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV). The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system.