School of Basic Medical Science, Chongqing Medical University, Chongqing, People's Republic of China.
Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing, People's Republic of China.
Viral Immunol. 2022 Dec;35(10):653-662. doi: 10.1089/vim.2022.0042. Epub 2022 Sep 29.
COVID-19 is a globally infectious viral epidemic of great public health concern caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) plays its role as the receptor for SARS-CoV-2 through binding with S protein and the binding results in ACE2 expression decrease. The change of ACE2 is supposed to elicit a series of cellular and molecular events. Other than as the receptor, ACE2's roles on infection by regulating other molecules need to be further studied during SARS-CoV-2 infection. In the present study, we established the ACE2 knockdown model using Vero E6 cells to study how ACE2 influenced the downstream signaling molecules. Analysis of transcriptome sequencing discovered that ACE2 alteration caused the alteration of immune factors, including some related to the viral infection-related signaling pathways. We found that ACE2 silencing induced the reduced interferon-induced transmembrane protein 3 (IFITM3) expression. Overexpression of IFITM3 promoted the SARS-CoV-2 pseudovirus infection of Vero E6 cells lacking the ACE2. It indicates that ACE2 can affect IFITM3 expression and function to affect the SARS-CoV-2 infection. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and contribute to explaining the rapid spread and pathogenesis especially in the case of ACE2 low expression.
新型冠状病毒肺炎（COVID-19）是一种具有高度公共卫生意义的全球传染性病毒性疾病，由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起。血管紧张素转化酶 2（ACE2）通过与 S 蛋白结合作为 SARS-CoV-2 的受体发挥作用，结合导致 ACE2 表达减少。ACE2 的变化预计会引发一系列细胞和分子事件。除了作为受体之外，在 SARS-CoV-2 感染期间，需要进一步研究 ACE2 通过调节其他分子在感染中的作用。在本研究中，我们使用 Vero E6 细胞建立了 ACE2 敲低模型，以研究 ACE2 如何影响下游信号分子。转录组测序分析发现，ACE2 的改变导致免疫因子的改变，包括一些与病毒感染相关信号通路相关的因子。我们发现 ACE2 沉默诱导干扰素诱导跨膜蛋白 3（IFITM3）表达减少。IFITM3 的过表达促进了缺乏 ACE2 的 Vero E6 细胞中 SARS-CoV-2 假病毒的感染。这表明 ACE2 可以影响 IFITM3 的表达和功能，从而影响 SARS-CoV-2 的感染。我们的结果揭示了影响 SARS-CoV-2 感染性的可能机制，并有助于解释其快速传播和发病机制，特别是在 ACE2 低表达的情况下。
