Gutzler Charlotte, Höhne Kerstin, Bani Daniele, Kayser Gian, Fähndrich Sebastian, Ambros Michael, Hug Martin J, Rieg Siegbert, Falcone Valeria, Müller-Quernheim Joachim, Zissel Gernot, Frye Björn C
Department for Pneumology, University Medical Center, Faculty of Medicine-University of Freiburg, 79106 Freiburg, Germany.
Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Int J Mol Sci. 2025 Mar 16;26(6):2666. doi: 10.3390/ijms26062666.
Patients infected with SARS-CoV-2 may develop mild respiratory symptoms but also Acute Respiratory Distress Syndrome (ARDS). Additionally, severe systemic inflammation contributes to morbidity and mortality. The SARS-CoV-2 virus enters the cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, followed by cleavage by transmembrane serine protease 2 (TMPRSS2). Vasoactive intestinal peptide (VIP) is known for its immune-modulating effects by suppressing the release of pro-inflammatory cytokines and enhancing regulatory T-cells. Furthermore, it has been tested in SARS-CoV-2-related clinical trials. We set out to investigate its role in the setting of SARS-CoV-2 infection in vitro. Epithelial cells (CaCo-2) were stimulated with SARS-CoV-2 spike protein, treated with native VIP and analyzed to investigate the mRNA and surface expression of ACE2 and TMPRSS2, the enzyme activity of TMPRSS2 and the infection rate by a SARS-CoV-2 pseudovirus. VIP downregulated ACE2 and TMPRSS2 mRNA and surface expression. Beyond these direct effects, VIP mediates the shedding of surface-expressed ACE2 and TMPRSS2 via upregulation of a sheddase protease (ADAM10). Functionally, these dual mechanisms of VIP-mediated downregulation of proteins involved in SARS-CoV-2 cell entry resulted in a reduced infection rate by the SARS-CoV-2 pseudovirus. These data imply that VIP hampers viral entry mechanisms based on SARS-CoV-2 and the linkage to ADAM10 may stimulate research in other indications beyond SARS-CoV-2.
感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的患者可能会出现轻微的呼吸道症状，也可能发展为急性呼吸窘迫综合征（ARDS）。此外，严重的全身炎症会导致发病和死亡。SARS-CoV-2病毒通过与血管紧张素转换酶2（ACE2）受体结合进入细胞，随后被跨膜丝氨酸蛋白酶2（TMPRSS2）切割。血管活性肠肽（VIP）因其免疫调节作用而闻名，它可以抑制促炎细胞因子的释放并增强调节性T细胞。此外，它已在与SARS-CoV-2相关的临床试验中进行了测试。我们着手研究其在体外SARS-CoV-2感染情况下的作用。用SARS-CoV-2刺突蛋白刺激上皮细胞（CaCo-2），用天然VIP处理，并进行分析以研究ACE2和TMPRSS2的mRNA和表面表达、TMPRSS2的酶活性以及SARS-CoV-2假病毒的感染率。VIP下调了ACE2和TMPRSS2的mRNA和表面表达。除了这些直接作用外，VIP还通过上调一种脱落酶蛋白酶（ADAM10）介导表面表达的ACE2和TMPRSS2的脱落。在功能上，VIP介导的下调参与SARS-CoV-2细胞进入的蛋白质的这两种机制导致SARS-CoV-2假病毒的感染率降低。这些数据表明，VIP阻碍了基于SARS-CoV-2的病毒进入机制，并且与ADAM10的联系可能会刺激SARS-CoV-2以外其他适应症的研究。
