Journal Article

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

Ali, Omar Hasan, Low, Jason K. K., Patel, Karishma, Mathivanan, Suresh, Cole, Alexander J., Aggarwal, Anupriya, Neely, G. Gregory, Loo, Lipin, Hesselson, Daniel, Waller, Matthew A., Turville, Stuart, Denes, Christopher E., Kang, Taeyoung, Mackay, Joel P., Flatz, Lukas, Pop, Oltin-Tiberiu, Moreno, Cesar L., Stella, Alberto Ospina, Hamoudi, Zina, Jochum, Ann-Kristin, Chung, Felicity, Jochum, Wolfram, Siddiquee, Rezwan

2023

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ACE2 / Analysis / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - metabolism / Antiviral Agents - pharmacology / Antiviral drugs / Binding / Binding proteins / Biology and life sciences / Cell surface / Collagen / Coronaviruses / COVID-19 / COVID-19 - genetics / CRISPR / Engineering and Technology / Enzymes / Fibroblasts / Fibroblasts - metabolism / Flow cytometry / Gene expression / Genes / Genetic aspects / Genomes / Genomics / Humans / Identification and classification / Leucine / Medicine and health sciences / Membrane Proteins - genetics / Membrane Proteins - metabolism / Properties / Protein Binding / Proteins / Receptors / Research and Analysis Methods / Respiratory diseases / SARS-CoV-2 - metabolism / Severe acute respiratory syndrome coronavirus 2 / Spike protein / Viral diseases