RT Journal Article SR Electronic T1 LRRC15 suppresses SARS-CoV-2 infection and controls collagen production JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.11.09.467981 DO 10.1101/2021.11.09.467981 A1 Lipin Loo A1 Matthew A. Waller A1 Alexander J. Cole A1 Alberto Ospina Stella A1 Cesar L. Moreno A1 Christopher E. Denes A1 Zina Hamoudi A1 Felicity Chung A1 Anupriya Aggarwal A1 Jason K. K. Low A1 Karishma Patel A1 Rezwan Siddique A1 Joel Mackay A1 Stuart Turville A1 Daniel Hesselson A1 G. Gregory Neely YR 2021 UL http://biorxiv.org/content/early/2021/11/10/2021.11.09.467981.abstract AB Although ACE2 is the primary receptor for SARS-CoV-2 infection, a systematic assessment of factors controlling SARS-CoV-2 host interactions has not been described. Here we used whole genome CRISPR activation to identify host factors controlling SARS-CoV-2 Spike binding. The top hit was a Toll-like receptor-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 Spike binding where it forms a cell surface complex with LRRC15 but does not support infection. Instead, LRRC15 functioned as a negative receptor suppressing both pseudotyped and live SARS-CoV-2 infection. LRRC15 is expressed in collagen-producing lung myofibroblasts where it can sequester virus and reduce infection in trans. Mechanistically LRRC15 is regulated by TGF-β, where moderate LRRC15 expression drives collagen production but high levels suppress it, revealing a novel lung fibrosis feedback circuit. Overall, LRRC15 is a master regulator of SARS-CoV-2, suppressing infection and controlling collagen production associated with “long-haul” COVID-19.In Brief Using pooled whole genome CRISPR activation screening, we identify the TLR relative LRRC15 as a novel SARS-CoV-2 Spike interacting protein. LRRC15 is not a SARS-CoV-2 entry receptor, but instead can suppress SARS-CoV-2 infection. LRRC15 is expressed by lung fibroblasts and regulates both collagen production and infection of ACE2-expressing target cells. This may provide a direct link between SARS-CoV-2 particles and lung fibrosis seen in “long-haul” COVID-19 patients.HighlightsWhole genome CRISPR activation screening implicates the TLR relative LRRC15 in SARS-CoV-2 Spike bindingLRRC15 suppresses live SARS-CoV-2 virus infectionLRRC15 is expressed in lung fibroblasts and sequesters virus while controlling collagen productionLRRC15 can act as a master regulator of infection and fibrosis, potentially controlling SARS-CoV-2 infection outcomes and “long-haul” COVID-19Competing Interest StatementThe authors have declared no competing interest.