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Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy-Shedding of ACE2 and TMPRSS2 via ADAM10

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...

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Main Authors: Gutzler, Charlotte (Author) , Höhne, Kerstin (Author) , Bani, Daniele (Author) , Kayser, Gian (Author) , Fähndrich, Sebastian Wolfgang (Author) , Ambros, Michael (Author) , Hug, Martin J. (Author) , Rieg, Siegbert (Author) , Falcone, Valeria (Author) , MüllerQuernheim, Joachim (Author) , Zissel, Gernot (Author) , Frye, Björn C. (Author)
Format: Article (Journal)
Language:English
Published: 16 March 2025
In: International journal of molecular sciences
Year: 2025, Volume: 26, Issue: 6, Pages: 114
ISSN:14220067
DOI:10.3390/ijms26062666
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms26062666
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Author Notes:Charlotte Gutzler, Kerstin Höhne, Daniele Bani, Gian Kayser, Sebastian Fähndrich, Michael Ambros, Martin J. Hug, Siegbert Rieg, Valeria Falcone, Joachim Müller-Quernheim, Gernot Zissel and Björn C. Frye
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Summary: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.
Item Description:Gesehen am 10.10.2025
Physical Description:Online Resource
ISSN:14220067
DOI:10.3390/ijms26062666

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