LRRC15 suppresses SARS-CoV-2 infection and controls collagen production

Abstract

SummaryAlthough 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 BriefUsing 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-19