Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.
Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.
复制标题
阻断 C5a-C5aR 轴可减轻感染 MERS-CoV 的 hDPP4 转基因小鼠的肺损伤。
DOI：
10.1038/s41426-018-0063-8
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发表时间：
2018-04-24
影响因子：
13.2
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Jiang Y;Zhao G;Song N;Li P;Chen Y;Guo Y;Li J;Du L;Jiang S;Guo R;Sun S;Zhou Y
高致病性中东呼吸综合征冠状病毒（MERS - CoV）的发病机制仍知之甚少。在先前的一项研究中，我们建立了人二肽基肽酶4转基因（hDPP4 - Tg）小鼠模型，在该模型中，MERS - CoV感染会导致严重的急性呼吸衰竭和高死亡率，同时伴有细胞因子和趋化因子分泌增加。由于过度的补体激活是病毒感染后导致急性肺损伤的一个重要因素，在本研究中，我们探讨了补体在MERS - CoV诱导的肺损伤中的作用。我们的研究表明，通过观察到血清和肺组织中C5a和C5b - 9补体激活产物浓度分别升高，在MERS - CoV感染的hDPP4 - Tg小鼠中补体被过度激活。有趣的是，通过靶向其受体C5aR阻断C5a的产生，减轻了肺和脾组织损伤并减少了炎症反应。更重要的是，抗C5aR抗体治疗导致肺组织中病毒复制减少。此外，与假治疗对照组相比，治疗小鼠脾白髓中脾细胞的凋亡不太明显，并且观察到更多增殖的脾细胞，特别是在红髓中。这些数据表明：（1）宿主免疫反应失调导致MERS的严重后果；（2）MERS - CoV感染引发的过度补体激活促进了这种失调；（3）阻断C5a - C5aR轴可减少MERS - CoV感染诱导的组织损伤，表现为脾脏中细胞凋亡减少和T细胞再生。因此，本研究结果为MERS - CoV病例的临床干预和辅助治疗提出了一种新策略。
The pathogenesis of highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) remains poorly understood. In a previous study, we established an hDPP4-transgenic (hDPP4-Tg) mouse model in which MERS-CoV infection causes severe acute respiratory failure and high mortality accompanied by an elevated secretion of cytokines and chemokines. Since excessive complement activation is an important factor that contributes to acute lung injury after viral infection, in this study, we investigated the role of complement in MERS-CoV-induced lung damage. Our study showed that complement was excessively activated in MERS-CoV-infected hDPP4-Tg mice through observations of increased concentrations of the C5a and C5b-9 complement activation products in sera and lung tissues, respectively. Interestingly, blocking C5a production by targeting its receptor, C5aR, alleviated lung and spleen tissue damage and reduced inflammatory responses. More importantly, anti-C5aR antibody treatment led to decreased viral replication in lung tissues. Furthermore, compared with the sham treatment control, apoptosis of splenic cells was less pronounced in the splenic white pulp of treated mice, and greater number of proliferating splenic cells, particularly in the red pulp, was observed. These data indicate that (1) dysregulated host immune responses contribute to the severe outcome of MERS; (2) excessive complement activation, triggered by MERS-CoV infection, promote such dysregulation; and (3) blockade of the C5a–C5aR axis lead to the decreased tissue damage induced by MERS-CoV infection, as manifested by reduced apoptosis and T cell regeneration in the spleen. Therefore, the results of this study suggest a new strategy for clinical intervention and adjunctive treatment in MERS-CoV cases.
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影响因子：
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