tetano
Editor, Senior Moderator
PLoS Biol
. 2023 Feb 9;21(2):e3001967.
doi: 10.1371/journal.pbio.3001967. eCollection 2023 Feb.
Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs
Lipin Loo[SUP] 1 [/SUP], Matthew A Waller[SUP] 1 [/SUP], Cesar L Moreno[SUP] 1 [/SUP], Alexander J Cole[SUP] 2 [/SUP], Alberto Ospina Stella[SUP] 3 [/SUP], Oltin-Tiberiu Pop[SUP] 4 [/SUP], Ann-Kristin Jochum[SUP] 4 5 [/SUP], Omar Hasan Ali[SUP] 4 6 7 [/SUP], Christopher E Denes[SUP] 1 [/SUP], Zina Hamoudi[SUP] 1 [/SUP], Felicity Chung[SUP] 1 [/SUP], Anupriya Aggarwal[SUP] 3 [/SUP], Jason K K Low[SUP] 8 [/SUP], Karishma Patel[SUP] 8 [/SUP], Rezwan Siddiquee[SUP] 8 [/SUP], Taeyoung Kang[SUP] 9 [/SUP], Suresh Mathivanan[SUP] 9 [/SUP], Joel P Mackay[SUP] 8 [/SUP], Wolfram Jochum[SUP] 5 [/SUP], Lukas Flatz[SUP] 4 10 [/SUP], Daniel Hesselson[SUP] 2 [/SUP], Stuart Turville[SUP] 3 [/SUP], G Gregory Neely[SUP] 1 [/SUP]
Affiliations
Abstract
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.
. 2023 Feb 9;21(2):e3001967.
doi: 10.1371/journal.pbio.3001967. eCollection 2023 Feb.
Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs
Lipin Loo[SUP] 1 [/SUP], Matthew A Waller[SUP] 1 [/SUP], Cesar L Moreno[SUP] 1 [/SUP], Alexander J Cole[SUP] 2 [/SUP], Alberto Ospina Stella[SUP] 3 [/SUP], Oltin-Tiberiu Pop[SUP] 4 [/SUP], Ann-Kristin Jochum[SUP] 4 5 [/SUP], Omar Hasan Ali[SUP] 4 6 7 [/SUP], Christopher E Denes[SUP] 1 [/SUP], Zina Hamoudi[SUP] 1 [/SUP], Felicity Chung[SUP] 1 [/SUP], Anupriya Aggarwal[SUP] 3 [/SUP], Jason K K Low[SUP] 8 [/SUP], Karishma Patel[SUP] 8 [/SUP], Rezwan Siddiquee[SUP] 8 [/SUP], Taeyoung Kang[SUP] 9 [/SUP], Suresh Mathivanan[SUP] 9 [/SUP], Joel P Mackay[SUP] 8 [/SUP], Wolfram Jochum[SUP] 5 [/SUP], Lukas Flatz[SUP] 4 10 [/SUP], Daniel Hesselson[SUP] 2 [/SUP], Stuart Turville[SUP] 3 [/SUP], G Gregory Neely[SUP] 1 [/SUP]
Affiliations
- PMID: 36757924
- DOI: 10.1371/journal.pbio.3001967
Abstract
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.