LRRC15 inhibits SARS-CoV-2 cellular entry in trans

PLoS Biol. 2022 Oct 13;20(10):e3001805. doi: 10.1371/journal.pbio.3001805. eCollection 2022 Oct.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2* / genetics
  • COVID-19* / genetics
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Protein Binding
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Angiotensin-Converting Enzyme 2
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • LRRC15 protein, human
  • Membrane Proteins