期刊
PLOS BIOLOGY
卷 20, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3001805
关键词
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资金
- NIH [R00 AI141683, 2P20 GM109035-07, K08 AI128043, R01 AI148467, T32 GM007205, F30 CA250249, P20 GM119943]
- Smith Family Awards Program for Excellence in Biomedical Research
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Ludwig Family Foundation
- Mathers Charitable Foundation
- Emergent Ventures fast grant
- DoD PRMRP IIAR [W81XWH-21-1-0019]
LRRC15 is identified as an inhibitory attachment factor for SARS-CoV-2 entry, which directly binds to the receptor-binding domain of spike protein and inhibits viral entry. It is mainly expressed in fibroblasts, particularly in pathological fibroblasts in COVID-19 patients. Expression of LRRC15 in ACE2-negative cells blocks spike-mediated viral entry in ACE2+ cells, suggesting a protective role of LRRC15 in a physiological context.
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.
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