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PreprintCited by 28SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesSARS-CoV-2 detection and testing

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

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Shilts, Jarrod, Crozier, Thomas W. M., Teixeira-Silva, Ana, Gabaev, Ildar, Greenwood, Edward J. D., Watson, Samuel James, Ortmann, Brian M., Gawden-Bone, Christian M., Pauzaite, Tekle, Hoffmann, Markus, Nathan, James A., Pöhlmann, Stefan, Lehner, Paul J., Wright, Gavin J.·2021·PLoS Biology
DOI 10.1101/2021.09.25.461776PMC PMC9897555

Preprint — published as 10.1371/journal.pbio.3001959

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Abstract

Summary: 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. In brief: We present evidence from genome-wide screening that the spike protein of SARS-CoV-2 interacts with human cells expressing LRRC15. The interaction is distinct from previously known classes of spike attachment factors, and appears to have emerged recently within the coronavirus family. Although not sufficient for cell invasion, this interaction can modulate viral infection. Our data point to an unappreciated host factor for SARS-CoV-2, with potential relevance to COVID-19. Highlights: - Two systematic cell-based screens for SARS-CoV-2 spike protein binding identify LRRC15 as a human host factor - Interaction with LRRC15 is reproducible in different human cell lines and independent of known glycan or ACE2 binding pathways - The C-terminal S1 domain of SARS-CoV-2 spike binds LRRC15 with sub-micromolar affinity, while related coronavirus spikes do not - LRRC15 is expressed in tissues with high ACE2 levels and may modulate infection

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Metadata

Authors
Shilts, J., Crozier, T. W. M., Teixeira-Silva, A., Gabaev, I., Greenwood, E. J. D., Watson, S. J., Ortmann, B. M., Gawden-Bone, C. M., Pauzaite, T., Hoffmann, M., Nathan, J. A., Pöhlmann, S., Lehner, P. J., & Wright, G. J.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • German Primate Center (DE)
Corresponding author
  • Lehner, Paul J.
  • Wright, Gavin J.
ORCID
Venue
PLoS Biology
Publisher
openRxiv
Published
2021-09-25
Volume
21
Issue
2
Pages
e3001959-e3001959
ISSN
1544-9173 (ISSN-L)
DOI
10.1101/2021.09.25.461776
PMC
PMC9897555
OpenAlex
W4319063252
Cited by
28
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 2
FWCI
4.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Apollo
  • Apollo (cc-by)
Funders
  • Pfizer
  • NHS Blood and Transplant (WPA15‐02)
  • Wellcome Trust (210688, 215477, 210688/Z/18/Z, 215477/Z/19/Z, 204845, 204845/Z/16/Z, Grant 206194, 206194)
  • National Institute for Health and Care Research (MR/V028448, 206194, MR/V028448/1)
  • University of Glasgow
  • Pfizer UK
  • Medical Research Council (204845/Z/16/Z, MR/T032413/1, MR/V011561/1, 215477/Z/19/Z, MR/X019705/1, MR/V028448/1)
  • Addenbrooke's Charitable Trust, Cambridge University Hospitals
  • NIHR Cambridge Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
Keywords
LRRC15, SARS-CoV-2 spike protein, host-virus interaction, ACE2 receptor, spike protein binding, viral entry, lung fibroblasts, lung inflammation, COVID-19 pandemic
MeSH terms
Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Humans, Membrane Proteins, Protein Binding, Spike Glycoprotein, Coronavirus

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