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

• DOI: 10.1016/j.immuni.2021.05.006
• Publication Date: 2021-05-09T16:33:52Z
• Authors: Qiao Lu; Jia Liu; Shuai Zhao; Maria Florencia G...; Maudry Laurent-Rolle; Jianbo Dong; Xiaojuan Ran; Payal Damani-Yokota; Hongzhen Tang; Triantafyllia Kar...; 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. Staple...; Peter Cresswell; Yue Liu; Siyuan Ding; Qi Xie; Jun Wang
• Keywords: Models, Molecular; 0301 basic medicine; Binding Sites; Protein Conformation; SARS-CoV-2; COVID-19; Membrane Proteins; Single-Domain Antibodies; Article; Cell Line; Neoplasm Proteins; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; Gene Expression Regulation; Host-Pathogen Interactions; Spike Glycoprotein, Coronavirus; Cytokines; Humans; Lectins, C-Type; Myeloid Cells; Angiotensin-Converting Enzyme 2; Inflammation Mediators; Protein Binding

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.