1. Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs.
- Author
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Lipin Loo, Matthew A Waller, Cesar L Moreno, Alexander J Cole, Alberto Ospina Stella, 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, and G Gregory Neely
- Subjects
Biology (General) ,QH301-705.5 - Abstract
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.
- Published
- 2023
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