LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein

Abstract

The interactions between severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to COVID-19. The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary ACE2 receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was restricted to SARS-CoV-2, suggesting LRRC15 represents a novel class of spike binding interaction. We localized the interaction to the C-terminus of the S1 domain, and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

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

“…The robust and specific inhibitory effect of LRRC15 on multiple variants of SARS-CoV-2 and SARS-CoV-1 (but not MERS-CoV) suggests an arms race between humans and coronaviruses. While this manuscript was in preparation, LRRC15 was also identified as a SARS-CoV-2 spike binding factor in two preprints [43, 44]. This demonstrates the LRRC15-spike interaction is robust and detectable in multiple cell line models.…”

LRRC15 inhibits SARS-CoV-2 cellular entry in trans

“…The robust and specific inhibitory effect of LRRC15 on multiple variants of SARS-CoV-2 and SARS-CoV-1 (but not MERS-CoV) suggests an arms race between humans and coronaviruses. While this manuscript was in preparation, LRRC15 was also identified as a SARS-CoV-2 spike-binding factor in 2 preprints [ 50 , 51 ]. This demonstrates the LRRC15-spike interaction is robust and detectable in multiple cell line models.…”

Multi-omics identify LRRC15 as a COVID-19 severity predictor and persistent pro-thrombotic signals in convalescence

“…Importantly, both lasso and random forests identified plasma LRRC15 protein levels as the most important predictor of COVID-19 severity. Interestingly, this protein was recently identified by two pre-prints as a receptor for SARS-COV-2 [33, 34]. We next examined LRRC15’s longitudinal trajectory over the course of COVID-19 infection, finding that it displayed a different temporal profile dependent on the disease course (p<0.0001, TxCC interaction, LMM).…”

“…Our findings are particularly intriguing as two recent pre-prints have identified LRRC15 as an accessory factor for SARS-CoV-2 entry to cells. Using arrayed transmembrane protein and pooled genome-wide CRISPR activation screens, Shilts and colleagues demonstrated that the SARS-CoV-2 spike protein interacts with LRRC15 [33]. Both screens identified the interaction and the CRISPRa screen identified LRRC15 and the established SARS-CoV-2 binding partner, ACE2, as the two most prominent interactors.…”