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SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.
- Source :
-
Immunity [Immunity] 2021 Jun 08; Vol. 54 (6), pp. 1304-1319.e9. Date of Electronic Publication: 2021 May 09. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests 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.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Angiotensin-Converting Enzyme 2 metabolism
Binding Sites
COVID-19 genetics
Cell Line
Cytokines
Gene Expression Regulation
Humans
Inflammation Mediators metabolism
Lectins, C-Type chemistry
Membrane Proteins chemistry
Models, Molecular
Neoplasm Proteins chemistry
Protein Binding
Protein Conformation
Single-Domain Antibodies immunology
Spike Glycoprotein, Coronavirus chemistry
Spike Glycoprotein, Coronavirus immunology
Spike Glycoprotein, Coronavirus metabolism
Structure-Activity Relationship
COVID-19 metabolism
COVID-19 virology
Host-Pathogen Interactions genetics
Host-Pathogen Interactions immunology
Lectins, C-Type metabolism
Membrane Proteins metabolism
Myeloid Cells immunology
Myeloid Cells metabolism
Neoplasm Proteins metabolism
SARS-CoV-2 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 54
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 34048708
- Full Text :
- https://doi.org/10.1016/j.immuni.2021.05.006