Poster Presentation 43rd Lorne Genome Conference 2022

LRRC15 suppresses SARS-CoV-2 infection and controls collagen production (#220)

Lipin Loo 1 , Matthew A. Waller 1 , Alexander J. Cole 2 , Alberto O. Stella 3 , Cesar L. Moreno 1 , Christopher E. Denes 1 , Zina Hamoudi 1 , Felicity Chung 1 , Anupriya Aggarwal 3 , Jason K.K. Low 4 , Redzwan Siddiquee 4 , Joel P. Mackay 4 , Stuart Turville 3 , Daniel Hesselson 2 , Greg Neely 1
  1. Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, Centenary Institute, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW, Australia
  2. Centenary Institute and Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  3. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia
  4. School of Life and Environmental Sciences, The University of Sydney, , Sydney, NSW, Australia

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.