2021-05-12

美国纽约大学Jun Wang等研究人员合作发现，SARS-CoV-2通过C型凝集素受体和Tweety家族成员2加剧髓样细胞的促炎反应 。相关论文于2021年5月9日在线发表在《免疫》杂志上。

通过使用针对髓样细胞受体的异位表达筛选，研究人员确定了几种C型凝集素（DC-SIGN、L-SIGN、LSECtin、ASGR1和CLEC10A）和Tweety家族成员2（TTYH2）可作为聚糖依赖性结合SARS-CoV-2突刺的结合伙伴蛋白。除了TTYH2，这些分子主要通过受体结合结构域之外的区域与刺突相互作用。对来自COVID-19患者的肺细胞进行单细胞RNA测序分析表明，这些分子主要在髓样细胞上表达。尽管这些受体不支持SARS-CoV-2的主动复制，但它们与病毒的结合在髓细胞中诱导了强烈的促炎反应，这与COVID-19的严重程度有关。

研究人员还获得了一种双特异性的突刺纳米抗体，它不仅可以阻断ACE2介导的感染，而且还可以阻止髓样受体介导的促炎反应。这些发现表明，SARS-CoV-2-髓样受体相互作用可促进免疫超活化，这代表了COVID-19治疗的潜在靶标。

据介绍，尽管有越来越多的证据表明SARS-CoV-2与免疫细胞结合，但大多数细胞表达的SARS-CoV-2经典受体（ACE2）很少。

附：英文原文

Title: SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2

Author: Qiao Lu, Jia Liu, Shuai Zhao, Maria Florencia Gomez Castro, Maudry Laurent-Rolle, Jianbo Dong, Xiaojuan Ran, Payal Damani-Yokota, Hongzhen Tang, Triantafyllia Karakousi, Juhee Son, Maria E. Kaczmarek, Ze Zhang, Stephen T. Yeung, Broc T. McCune, Rita E. Chen, Fei Tang, Xianwen Ren, Xufeng Chen, Jack C.C. Hsu, Marianna Teplova, Betty Huang, Haijing Deng, Zhilin Long, Tenny Mudianto, Shumin Jin, Peng Lin, Jasper Du, Ruochen Zang, Tina Tianjiao Su, Alberto Herrera, Ming Zhou, Renhong Yan, Jia Cui, James Zhu, Qiang Zhou, Tao Wang, Jianzhu Ma, Sergei B. Koralov, Zemin Zhang, Iannis Aifantis, Leopoldo N. Segal, Michael S. Diamond, Kamal M. Khanna, Kenneth A. Stapleford, Peter Cresswell, Yue Liu, Siyuan Ding, Qi Xie, Jun Wang

Issue&Volume: 2021-05-09

Abstract: Despite mounting evidence for SARS-CoV-2 engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, ACE2. Here, using a myeloid-cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA-sequencing analysis of pulmonary cells from COVID-19 patients indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptors-mediated proinflammatory responses. Our findings suggest SARS-CoV-2-myeloid receptor interactions promote immune hyper-activation, which represents potential targets for COVID-19 therapy.

DOI: 10.1016/j.immuni.2021.05.006