LRRC15 inhibits SARS-CoV-2 cellular entry in trans

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is mediated by the entry receptor angiotensin-converting enzyme 2 (ACE2). Although attachment factors and coreceptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown....

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Bibliographic Details
Published in:PLoS biology 2022-10, Vol.20 (10), p.e3001805
Main Authors: Song, Jaewon, Chow, Ryan D, Peña-Hernández, Mario A, Zhang, Li, Loeb, Skylar A, So, Eui-Young, Liang, Olin D, Ren, Ping, Chen, Sidi, Wilen, Craig B, Lee, Sanghyun
Format: Article
Language:English
Subjects:
ACE2
Angiotensin
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - genetics
Attachment
Biology and life sciences
Coronaviruses
COVID-19
COVID-19 - genetics
CRISPR
Enzymes
Fibroblasts
Flow cytometry
Gene expression
Gene sequencing
Genetic aspects
Health aspects
Heparan sulfate
Host-virus relationships
Humans
Immunoglobulins
Lungs
Medicine and health sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
Middle East respiratory syndrome
Peptidyl-dipeptidase A
Physiological effects
Plasma
Protein Binding
Proteins
Receptors
Research and Analysis Methods
Respiratory diseases
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - metabolism
Spike protein
Viral diseases
Virulence (Microbiology)
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Summary:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is mediated by the entry receptor angiotensin-converting enzyme 2 (ACE2). Although attachment factors and coreceptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown. Using a surfaceome CRISPR activation screen, we identified human LRRC15 as an inhibitory attachment factor for SARS-CoV-2 entry. LRRC15 directly binds to the receptor-binding domain (RBD) of spike protein with a moderate affinity and inhibits spike-mediated entry. Analysis of human lung single-cell RNA sequencing dataset reveals that expression of LRRC15 is primarily detected in fibroblasts and particularly enriched in pathological fibroblasts in COVID-19 patients. ACE2 and LRRC15 are not coexpressed in the same cell types in the lung. Strikingly, expression of LRRC15 in ACE2-negative cells blocks spike-mediated viral entry in ACE2+ cell in trans, suggesting a protective role of LRRC15 in a physiological context. Therefore, LRRC15 represents an inhibitory attachment factor for SARS-CoV-2 that regulates viral entry in trans.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001805