LSR is a cell-intrinsic defence factor against SARS-CoV-2 infection in small intestine

Abstract The identification of host factors with antiviral potential is important for developing effective prevention as well as therapeutic strategies against SARS-CoV-2. Here, we have identified the lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host-defense factor against SARS-CoV-2 infection in small intestine using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues, and humanized ACE2 mouse model as proof-of-principle systems. Loss of endogenous LSR enhances ACE2-dependent infection by pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protect against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to Spike protein, and thus blocking viral entry and restricting Spike-mediated cell-cell fusion. These results identify both a previously unknown function for LSR and an associated antiviral host defense mechanism against SARS-CoV-2. The capacity of a small LSR-derived peptide to block Spike binding to the ACE2 receptor holds promise for pan-variant therapeutic interventions.