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

Abstract

The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (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 functionally restricted to SARS-CoV-2 by accessibility. 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. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that 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.

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.…”

“…This interaction was confirmed in vitro. The interaction involved RBD domain [ 125 , 126 ]. Interestingly, LRRC15 did not facilitate entry of the virus but it was found to inhibit infection of permissive cells.…”

“…The authors postulated that LRRC15 could participate in the innate immune protection of tissues, besides other related molecules such as TLR. The binding to spike could sequesters SARS-CoV-2 virions and thus limit infection [ 124 , 125 , 126 ].…”

Dissecting the Molecular Basis of Host Leucine-Rich Repeat Containing 15 Mediated Interaction with Receptor Binding Domain of SARS-CoV-2 Spike Protein: A Computational Approach

“…3 It is noteworthy to mention that the binding of SARS-CoV-2 differs from any other previously studied spikebinding viruses. 4 However, due to the similarity between SARS-CoV-1 and SARS CoV-2 sequences, Angiotensinconverting enzyme 2 (ACE2) has been identified as one of the primary S protein binding receptors, possessing higher affinity for the later, thereby considered a contributing factor for its increased pathogenicity. 3,5,6 The S1 subunit, among the two S protein subunits, has been studied in depth and shown to possess strong binding affinities toward various host cell receptors, when the S2 subunit enables the viral membrane to fuse into the host cell membrane, admitting the virus inside.…”

“…11 Recent studies have advocated that the Leucine-rich repeat containing protein 15 (LRRC15) receptor, a member of the horseshoe shaped Leucine-rich repeats (LRR) family of receptors may also contribute greatly toward the SARS-CoV-2 infectivity by inducing spike binding. 4 Earlier this year, a study of public expression data sets by Shilts et al remarkably revealed the unique binding pattern of LRRC15 specific to only SARS-CoV-2 among all the coronaviruses; LRRC15 is also able to bind to SARS-CoV-1 spike upon deglycosylation, but with less accessibility than SARS-CoV-2. 4 LRRC15 shows significant binding affinity with the RBD of the S protein to facilitate viral entry within the host.…”