SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.
SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.
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DOI：
10.1016/j.immuni.2021.05.006
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发表时间：
2021-06-08
期刊：
影响因子：
32.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Lu Q;Liu J;Zhao S;Gomez Castro MF;Laurent-Rolle M;Dong J;Ran X;Damani-Yokota P;Tang H;Karakousi T;Son J;Kaczmarek ME;Zhang Z;Yeung ST;McCune BT;Chen RE;Tang F;Ren X;Chen X;Hsu JCC;Teplova M;Huang B;Deng H;Long Z;Mudianto T;Jin S;Lin P;Du J;Zang R;Su TT;Herrera A;Zhou M;Yan R;Cui J;Zhu J;Zhou Q;Wang T;Ma J;Koralov SB;Zhang Z;Aifantis I;Segal LN;Diamond MS;Khanna KM;Stapleford KA;Cresswell P;Liu Y;Ding S;Xie Q;Wang J
尽管越来越多的证据表明严重急性呼吸综合征冠状病毒2(SARS-CoV-2)与免疫细胞结合，但大多数SARS-CoV-2的典型受体血管紧张素转换酶2(ACE2)几乎没有表达。在这里，使用髓系细胞受体聚焦的异位表达筛选，我们确定了几个C型凝集素(DC-SIGN、L-SIGN、LSECtin、ASGR1和CLEC10A)和Twety家族成员2(TTYH2)是SARS-CoV-2尖峰的糖依赖结合伙伴。除TTYH2外，这些分子主要通过受体结合域以外的区域与Spike相互作用。对2019年冠状病毒病患者肺细胞的单细胞核糖核酸测序分析(新冠肺炎)表明，这些分子主要表达在髓系细胞上。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系细胞中诱导了强大的促炎反应，这与新冠肺炎的严重程度相关。我们还制备了一个双功能的抗尖峰纳米抗体，它不仅可以阻断ACE2介导的感染，还可以阻断髓系受体介导的促炎反应。我们的研究结果表明，SARS-CoV-2-髓系受体相互作用促进免疫激活，这可能是新冠肺炎治疗的潜在靶点。大多数免疫细胞几乎不表达典型的SARS-CoV-2受体ACE2。Lu等人。报道称，C型凝集素和TTYH2作为SARS-CoV-2髓系细胞相互作用的伙伴，触发免疫过度激活，而不是感染。这些发现提出了这样一种可能性，即这些病毒-髓系细胞相互作用直接参与了新冠肺炎的免疫发病机制，并可能成为新冠肺炎治疗的靶点。
Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 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 individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the 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 receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy. Most immune cells express little, if any, of the canonical SARS-CoV-2 receptor, ACE2. Lu et al. report that C-type lectins and TTYH2 act as SARS-CoV-2 myeloid cell-interacting partners that trigger immune hyperactivation but not infection. These findings raise the possibility that these virus-myeloid cell interactions are directly involved in COVID-19 immunopathogenesis and could be targeted for COVID-19 therapy.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
影响因子：
64.5
作者：
Clausen, Thomas Mandel;Sandoval, Daniel R.;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.
影响因子：
3.7
作者：
Gong J;Dong H;Xia QS;Huang ZY;Wang DK;Zhao Y;Liu WH;Tu SH;Zhang MM;Wang Q;Lu FE
通讯作者：
Lu FE
影响因子：
3.7
作者：
Hillaire, Marine L. B.;Nieuwkoop, Nella J.;Rimmelzwaan, Guus F.
通讯作者：
Rimmelzwaan, Guus F.
影响因子：
158.5
作者：
Grein, J.;Ohmagari, N.;Flanigan, T.
通讯作者：
Flanigan, T.