@article{f733077db93e43979db7f1a2289709c7,
title = "SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2",
abstract = "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.",
keywords = "ASGR1, CLEC10A, COVID-19, DC-SIGN, L-SIGN, LSECtin, SARS-CoV-2, TTYH2, myeloid cells, proinflammatory responses",
author = "Qiao Lu and Jia Liu and Shuai Zhao and {Gomez Castro}, {Maria Florencia} and Maudry Laurent-Rolle and Jianbo Dong and Xiaojuan Ran and Payal Damani-Yokota and Hongzhen Tang and Triantafyllia Karakousi and Juhee Son and Kaczmarek, {Maria E.} and Ze Zhang and Yeung, {Stephen T.} and McCune, {Broc T.} and Chen, {Rita E.} and Fei Tang and Xianwen Ren and Xufeng Chen and Hsu, {Jack C.C.} and Marianna Teplova and Betty Huang and Haijing Deng and Zhilin Long and Tenny Mudianto and Shumin Jin and Peng Lin and Jasper Du and Ruochen Zang and Su, {Tina Tianjiao} and Alberto Herrera and Ming Zhou and Renhong Yan and Jia Cui and James Zhu and Qiang Zhou and Tao Wang and Jianzhu Ma and Koralov, {Sergei B.} and Zemin Zhang and Iannis Aifantis and Segal, {Leopoldo N.} and Diamond, {Michael S.} and Khanna, {Kamal M.} and Stapleford, {Kenneth A.} and Peter Cresswell and Yue Liu and Siyuan Ding and Qi Xie and Jun Wang",
note = "Funding Information: We thank Dr. Pratip Chattopadhyay and Dr. Nathaniel Landau from New York University Grossman School of Medicine for providing human PBMCs from healthy donors and help with the anti-ACE2 blocking antibody, respectively; Dr. Peihui Wang from Shandong University for providing the pcDNA6B-FLAG-ACE2 plasmid; Dr. Lu Lu from Fudan University for providing the SARS-CoV-2 pseudovirus plasmids; and members of the laboratories of New York University Grossman School of Medicine and Ab Studio for helpful discussions and technical assistance. This work is supported by internal funds provided by the Office of Science & Research (OSR) and the Department of Pathology of New York University Grossman School of Medicine (to J.W.); the Westlake Education Foundation , the Tencent Foundation ( XHTX202001008 ), and the Hangzhou Science and Technology Development Foundation ( 20202013A05 ) (to Q.X.); National Institutes of Health (NIH) DDRCC grant P30 DK052574 , NIH grants R00 AI135031 and R01 AI150796 , and COVID-19 Fast Grants funding (to S.D.); NIH grants R01 AI157155 (to M.S.D.); NIH grants R01 AI143861 and AI143861S1 (to K.M.K.); NIH grants R01-AI059167 (to P.C.); and a Cancer Research Institute Irvington postdoctoral fellowship (to J.H.). Funding Information: We thank Dr. Pratip Chattopadhyay and Dr. Nathaniel Landau from New York University Grossman School of Medicine for providing human PBMCs from healthy donors and help with the anti-ACE2 blocking antibody, respectively; Dr. Peihui Wang from Shandong University for providing the pcDNA6B-FLAG-ACE2 plasmid; Dr. Lu Lu from Fudan University for providing the SARS-CoV-2 pseudovirus plasmids; and members of the laboratories of New York University Grossman School of Medicine and Ab Studio for helpful discussions and technical assistance. This work is supported by internal funds provided by the Office of Science & Research (OSR) and the Department of Pathology of New York University Grossman School of Medicine (to J.W.); the Westlake Education Foundation, the Tencent Foundation (XHTX202001008), and the Hangzhou Science and Technology Development Foundation (20202013A05) (to Q.X.); National Institutes of Health (NIH) DDRCC grant P30 DK052574, NIH grants R00 AI135031 and R01 AI150796, and COVID-19 Fast Grants funding (to S.D.); NIH grants R01 AI157155 (to M.S.D.); NIH grants R01 AI143861 and AI143861S1 (to K.M.K.); NIH grants R01-AI059167 (to P.C.); and a Cancer Research Institute Irvington postdoctoral fellowship (to J.H.). Conceptualization, J.W.; interaction discovery and mutation studies, J.W. Q.L. and J.L.; interaction analysis, J.W. Q.L. Q.X. J.L. and S.Z.; pseudovirus studies, J.L. S.Z. Q.L. J.W. and Q.X.; authentic virus studies, M.F.G.C. M.L.-R. J.S. M.E.K. K.A.S. P.D.-Y. J.L. Q.L. J.C.C.H. S.D. P.C. B.T.M. R.E.C. M.S.D. and K.M.K.; BAL samples, L.N.S.; structural analysis, M.T.; bioinformatics, H.T. X. Ran, X. Ren, F.T. Q.L. J.M. Q.X. A.H. S.B.K. J.W. J.Z. T.W. and Zemin Zhang; nanobodies, Q.L. J.D. J.W. J.L. B.H. and Y.L.; data analysis, Q.L. J.L. Ze Zhang, T.K. X.C. H.D. Z.L. T.M. S.J. S.T.Y. K.M.K. P.L. J.D. and R.Z.; resources, X.C. J.C. I.A. R.Y. and Q.Z.; writing – review & editing, J.W. Q.L. S.D. T.T.S. and Q.X.; visualization, J.W. Q.L. J.L. Q.X. and S.D.; supervision, J.W. Q.X. and S.D.; project administration, J.W. Q.L. Q.X. and S.D.; funding acquisition, J.W. Q.X. and S.D. J.W. Q.L. J.L. B.H. J.D. and Y.L. are named inventors on a patent application that describes the anti-SARS-CoV-2 blocking nanobodies. J.W. is a consultant for Lilly Asia Ventures and is on the Scientific Advisory Board of Rootpath Genomics, which is not relevant to this work. M.S.D. is a consultant for Inbios, Vir Biotechnology, and NGM Biopharmaceuticals and is on the Scientific Advisory Board of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "8",
doi = "10.1016/j.immuni.2021.05.006",
language = "English (US)",
volume = "54",
pages = "1304--1319.e9",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}