通过芳基烃受体信号抑制SARS-CoV-2受体的血管紧张素转化酶2，从而在体外抑制SARS-CoV-2的感染,bioRxiv - Molecular Biology

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通过芳基烃受体信号抑制SARS-CoV-2受体的血管紧张素转化酶2，从而在体外抑制SARS-CoV-2的感染
bioRxiv - Molecular Biology Pub Date : 2021-03-04 , DOI: 10.1101/2021.03.04.433658
Keiji Tanimoto , Kiichi Hirota , Takahiro Fukazawa , Yoshiyuki Matsuo , Toshihito Nomura , Nazmul Tanuza , Nobuyuki Hirohashi , Hidemasa Bono , Takemasa Sakaguchi

由于了解SARS-CoV-2感染的分子机制对于开发针对COVID-19的有效疗法极为重要，因此我们重点研究SAACE-CoV-2通过ACE2的内在化机制。尽管一般认为香烟烟雾对COVID-19的发病机理有害，但令人惊讶地发现香烟烟雾提取物（CSE）处理可抑制HepG2细胞中ACE2的表达。因此，我们试图阐明CSE对哺乳动物细胞中ACE2表达的作用机理。因为RNA序列分析表明对ACE2的抑制作用可能与诱导由芳烃受体（AHR）调控的基因呈负相关，所以AHR激动剂6-甲酰基吲哚（3,2-b）咔唑（FICZ）和奥美拉唑（OMP）进行了测试，以评估这些处理是否影响了ACE2的表达。FICZ和OMP均以剂量依赖性方式明显诱导CYP1A1抑制ACE2的表达。击倒实验表明通过FICZ处理以AHR依赖性方式减少ACE2。最后，通过检测SARS-CoV-2特异性核衣壳蛋白的免疫印迹分析确定，AHR激动剂的治疗抑制了SARS-CoV-2感染Vero E6细胞。我们在这里证明了用AHR激动剂（包括CSE，FICZ和OMP）进行的治疗通过AHR激活降低了ACE2的表达，从而抑制了哺乳动物细胞中SARS-CoV-2的感染。通过检测SARS-CoV-2特异性核衣壳蛋白的免疫印迹分析确定，AHR激动剂的治疗可抑制SARS-CoV-2感染Vero E6细胞。我们在这里证明了用AHR激动剂（包括CSE，FICZ和OMP）进行的治疗通过AHR激活降低了ACE2的表达，从而抑制了哺乳动物细胞中SARS-CoV-2的感染。通过检测SARS-CoV-2特异性核衣壳蛋白的免疫印迹分析确定，AHR激动剂的治疗可抑制SARS-CoV-2感染Vero E6细胞。我们在这里证明了用AHR激动剂（包括CSE，FICZ和OMP）进行的治疗通过AHR激活降低了ACE2的表达，从而抑制了哺乳动物细胞中SARS-CoV-2的感染。

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Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including CSE, FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

更新日期：2021-03-05

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