The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors may also play major roles in viral infection. Here we report that the stress-inducible molecular chaperone GRP78 can form a complex with the SARS-CoV-2 Spike protein and ACE2 intracellularly and on the cell surface, and that the substrate binding domain of GRP78 is critical for this function. Knock-down of GRP78 by siRNA dramatically reduced cell surface ACE2 expression. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159), selected for its ability to cause GRP78 endocytosis and its safe clinical profile in preclinical models, reduces cell surface ACE2 expression, SARS-CoV-2 Spike-driven viral entry, and significantly inhibits SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78.

中文翻译：

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GRP78结合SARS-CoV-2 Spike蛋白和ACE2，消耗GRP78的抗体在体外阻断病毒进入和感染

严重急性呼吸综合症冠状病毒2（SARS-CoV-2）是当前COVID-19全球大流行的病原体，它利用宿主受体血管紧张素转化酶2（ACE2）进入病毒。但是，其他宿主因素也可能在病毒感染中起主要作用。在这里我们报告应力诱导分子伴侣GRP78可以与SARS-CoV-2 Spike蛋白和ACE2在细胞内和细胞表面形成复合物，并且GRP78的底物结合域对该功能至关重要。siRNA抑制GRP78可以大大降低细胞表面ACE2的表达。选择人源化单克隆抗体（hMAb159）来治疗肺上皮细胞，原因是它具有引起GRP78内吞作用的能力以及在临床前模型中的安全临床特征，因此可降低细胞表面ACE2的表达，SARS-CoV-2 Spike驱动的病毒进入，并在体外显着抑制SARS-CoV-2感染。我们的数据表明，GRP78是SARS-CoV-2进入和感染的重要宿主辅助因子，也是对抗这种新型病原体和其他利用GRP78的病毒的潜在目标。