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

Qiao Lu, Jia Liu, Shuai Zhao, Maria Florencia Gomez Castro, Maudry Laurent-Rolle, Jianbo Dong, Xiaojuan Ran, Payal Damani-Yokota, Hongzhen Tang, Triantafyllia Karakousi, 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. HsuMarianna 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. Stapleford, Peter Cresswell, Yue Liu, Siyuan Ding, Qi Xie, Jun Wang

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish
Pages (from-to)1304-1319.e9
JournalImmunity
Volume54
Issue number6
DOIs
StatePublished - Jun 8 2021

Keywords

  • ASGR1
  • CLEC10A
  • COVID-19
  • DC-SIGN
  • L-SIGN
  • LSECtin
  • SARS-CoV-2
  • TTYH2
  • myeloid cells
  • proinflammatory responses

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