Publikation
Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs.
Wissenschaftlicher Artikel/Review - 09.02.2023
Loo Lipin, Waller Matthew A, Moreno Cesar L, Cole Alexander J, Stella Alberto Ospina, Pop Oltin-Tiberiu, Jochum Ann-Kristin, Ali Omar Hasan, Denes Christopher E, Hamoudi Zina, Chung Felicity, Aggarwal Anupriya, Low Jason K K, Patel Karishma, Siddiquee Rezwan, Kang Taeyoung, Mathivanan Suresh, Mackay Joel P, Jochum Wolfram, Flatz Lukas, Hesselson Daniel, Turville Stuart G, Neely G Gregory
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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.