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

Loo, L.; Waller, M. A.; Cole, A. J.; Stella, A. O.; Moreno, C. L.; Denes, C. E.; Hamoudi, Z.; Chung, F.; Aggarwal, A.; Low, J. K. K.; Patel, K.; Siddique, R.; Mackay, J.; Turville, S.; Hesselson, D.; Neely, G. G.

doi:10.1101/2021.11.09.467981

bioRxiv · 10.1101/2021.11.09.467981

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

Loo, L.·Waller, M. A.·Cole, A. J.·Stella, A. O.·Moreno, C. L.·Denes, C. E.·Hamoudi, Z.·Chung, F.·Aggarwal, A.·Low, J. K. K.·Patel, K.·Siddique, R.·Mackay, J.·Turville, S.·Hesselson, D.·Neely, G. G.

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Abstract

Although ACE2 is the primary receptor for 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 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.

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Loo, L., Waller, M. A., Cole, A. J., Stella, A. O., Moreno, C. L., Denes, C. E., Hamoudi, Z., Chung, F., Aggarwal, A., Low, J. K. K., Patel, K., Siddique, R., Mackay, J., Turville, S., Hesselson, D., Neely, G. G.. 2021-11-10. LRRC15 suppresses SARS-CoV-2 infection and controls collagen production. https://doi.org/10.1101/2021.11.09.467981

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