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

中文翻译：

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紧密连接蛋白 LSR 是小肠中抵御 SARS-CoV-2 感染的宿主防御因子。


鉴定具有抗病毒潜力的宿主因子对于制定针对 SARS-CoV-2 感染的有效预防和治疗策略非常重要。在这里，通过使用永生化细胞系、肠道类器官、离体肠道组织和人源化 ACE2 小鼠模型作为原理验证系统，我们已经确定脂肪分解刺激的脂蛋白受体 （LSR） 是小肠中对抗 SARS-CoV-2 感染的关键宿主防御因子。内源性 LSR 的缺失会增强 SARS-CoV-2 刺突 （S） 蛋白假型病毒和正宗 SARS-CoV-2 病毒的 ACE2 依赖性感染，而 LSR 的外源性给药可防止病毒感染。从机制上讲，LSR 在顺式和反式中都与 ACE2 相互作用，阻止其与 S 蛋白结合，从而抑制病毒进入和 S 蛋白介导的细胞间融合。最后，一个小的 LSR 衍生肽在体外阻断 S 蛋白与 ACE2 受体的结合。这些结果确定了 LSR 在抗病毒宿主防御 SARS-CoV-2 中以前未知的功能，以及对基于肽的泛变体治疗干预的潜在影响。