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bioRxiv · 10.1101/2021.11.23.469714

LRRC15 is an inhibitory receptor blocking SARS-CoV-2 spike-mediated entry in trans

Song, J.·Chow, R. D.·Pena-Hernandez, M.·Zhang, L.·Loeb, S. A.·So, E.-Y.·Liang, O. D.·Wilen, C. B.·Lee, S.
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Abstract

SARS-CoV-2 infection is mediated by the entry receptor ACE2. Although attachment factors and co-receptors 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 receptor 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 co-expressed 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 receptor for SARS-CoV-2 regulating viral entry in trans.

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Song, J., Chow, R. D., Pena-Hernandez, M., Zhang, L., Loeb, S. A., So, E.-Y., Liang, O. D., Wilen, C. B., Lee, S.. 2021-11-24. LRRC15 is an inhibitory receptor blocking SARS-CoV-2 spike-mediated entry in trans. https://doi.org/10.1101/2021.11.23.469714

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