LRRC15, a newly identified, ACE-2-antagonizing SARS-CoV-2 viral receptor

A new SARS-CoV-2 viral receptor, "leucine-rich repeat containing protein 15" (LRRC15), has just been described by a team from the University of Sydney (Loo et al., 2023).
Published in Microbiology

The aforementioned molecule, sharing with the ACE-2 receptor a high binding affinity to SARS-CoV-2 viral spike (S) protein, is mainly expressed by pulmonary (myo)fibroblasts, alongside other host's cells and tissues, including the skin and the upper airways. However, following its binding to LRRC15, the SARS-CoV-2 betacoronavirus becomes "sequestered" by lung (myo)fibroblasts, thus being inhibited from gaining further access to ACE-2-expressing bronchiolar and alveolar epithelial cells, which will show in turn an increased LRRC15 production, with subsequent viral spread inhibition. The same investigators have also made us aware that, in parallel with LRRC15 expression, fibroblasts will suppress collagen biosynthesis, with this inhibiting the progression of COVID-19 pneumonia towards the chronic disease forms, which are characterized by an extensive lung fibrosis.

Besides, following SARS-CoV-2-LRRC15 interaction, an increased production of IFIT, OAS and MX family antiviral factors has been reported to occur (Loo et al., 2023).

In summary, the newly discovered LRRC15 receptor appears to be a key determinant of host's susceptibility/resistance to SARS-CoV-2 infection and, consequently, to COVID-19 disease magnitude and severity.

It could also contribute to modulate, together with the ACE-2 homology degree across different species and taxa, as well as with other non-ACE-2 viral receptors like neuropilin-1 (Di Guardo, 2022), the susceptibility/resistance of domestic animals and wildlife to natural and experimental SARS-CoV-2 infection, thereby taking into special account the One Health concept, reminding us that human, animal and environmental health are mutually and inextricably linked to each other!         


1) Di Guardo G. SARS-CoV-2 susceptibility of domestic and wild mammals: Is it all about the similarity of their ACE-2 receptor to the human one? Proc. Biol. Sci. 2022; 289(1968):20212560. doi: 10.1098/rspb.2021.2560. 

2) Loo L., et al. Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs. PLoS Biol. 2023; 21(2)e3001967. doi: 10.1371/journal.pbio.3001967.

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