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

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

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.