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

• DOI: 10.1371/journal.pbio.3001967
• Publication Date: 2023-02-09T18:28:21Z
• Authors: Lipin Loo; Matthew A. Waller; Cesar L. Moreno; Alexander J. Cole; Alberto Ospina St...; Oltin-Tiberiu Pop; Ann-Kristin Jochum; Omar Hasan Ali; Christopher E. Denes; Zina Hamoudi; Felicity Chung; Anupriya Aggarwal; Jason K. K. Low; Karishma Patel; Rezwan Siddiquee; Taeyoung Kang; Suresh Mathivanan; Joel P. Mackay; Wolfram Jochum; Lukas Flatz; Daniel Hesselson; Stuart Turville; G. Gregory Neely
• Keywords: 0301 basic medicine; QH301-705.5; SARS-CoV-2; COVID-19; Membrane Proteins; Fibroblasts; Antiviral Agents; 3. Good health; 03 medical and health sciences; Humans; Angiotensin-Converting Enzyme 2; Biology (General); Research Article; Protein Binding

Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was a TLR-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 spike binding where they form a cell surface complex. LRRC15 mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe Coronavirus Disease 2019 (COVID-19) infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection in trans. Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection.