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