LRRC15 inhibits SARS-CoV-2 cellular entry in trans

Abstract

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.

Fibroblast-expressed LRRC15 suppresses SARS-CoV-2 infection and controls antiviral and antifibrotic transcriptional programs

“…These studies corroborate our findings, despite their use of different Spike formulations, overexpression strategies, and cell lines. Moreover, since our initial submission 34 , Song et al have replicated our finding that LRRC15 can act in trans to suppress SARS-CoV-2 infections and this has now been published 33 . Together, our studies highlight a fundamental new role for LRRC15 in SARS-CoV-2 biology and likely beyond.…”

“…Of the TLR family, LRRC15 is most related to TLR5, which also recognises a major extracellular virulence factor, the bacterial extracellular protein flagellin 31 . Remarkably, while our manuscript was in preparation and then review, two other groups independently released preprints describing similar ORF/CRISPR activation screening strategies to identify new host factors that can regulate Spike binding; both screens also pulled out LRRC15 as a top factor driving Spike/host cell interactions 32, 33 . These studies corroborate our findings, despite their use of different Spike formulations, overexpression strategies, and cell lines.…”

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

“…These studies corroborate our findings, despite their use of different spike formulations, overexpression strategies, and cell lines. Moreover, since our initial submission [ 34 ], Song and colleagues have replicated our finding that LRRC15 can act in trans to suppress SARS-CoV-2 infections and this has now been published [ 33 ]. Together, our studies highlight a fundamental new role for LRRC15 in SARS-CoV-2 biology and likely beyond.…”

“…Of the TLR family, LRRC15 is most related to TLR5, which also recognizes a major extracellular virulence factor, the bacterial extracellular protein flagellin [ 31 ]. Remarkably, while our manuscript was in preparation and then review, 2 other groups independently released preprints describing similar ORF/CRISPR activation screening strategies to identify new host factors that can regulate spike binding; both screens also pulled out LRRC15 as a top factor driving spike/host cell interactions [ 32 , 33 ]. These studies corroborate our findings, despite their use of different spike formulations, overexpression strategies, and cell lines.…”

Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?

“…LRRC15 expression was associated with inflamed conditions such as cancer, autoimmunity and inflammatory diseases [ 123 ]. Through a whole-genome CRISPR activation screening approach, LRRC15 was found to bind to SARS-CoV-2 spike [ 124 , 125 , 126 ]. This interaction was confirmed in vitro.…”