Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy-Shedding of ACE2 and TMPRSS2 via ADAM10.
Summary
In CaCo-2 epithelial cells, VIP downregulated ACE2 and TMPRSS2 at both mRNA and surface levels and induced ADAM10-dependent shedding, thereby reducing SARS-CoV-2 pseudovirus infection. These findings reveal a host-targeted mechanism by which VIP may impede viral entry, supporting further translational research on VIP/ADAM10 modulation.
Key Findings
- VIP reduced ACE2 and TMPRSS2 mRNA and surface expression in CaCo-2 cells stimulated with SARS-CoV-2 spike protein.
- VIP induced ADAM10 upregulation and mediated shedding of ACE2 and TMPRSS2 from the cell surface.
- These mechanisms decreased infection rates by a SARS-CoV-2 pseudovirus.
Clinical Implications
While preclinical, the data support evaluating inhaled or systemic VIP, or ADAM10 modulation, as host-directed therapies to reduce viral entry in severe viral pneumonias including COVID-19-associated ARDS.
Why It Matters
Identifying ADAM10-mediated shedding as a mechanism by which VIP reduces viral entry is a novel host-directed antiviral strategy with potential relevance beyond SARS-CoV-2.
Limitations
- In vitro findings in a single epithelial cell line may not translate directly to in vivo human disease.
- Use of pseudovirus rather than live virus limits assessment of complete viral life cycle effects.
Future Directions
Test VIP and ADAM10 modulation in primary airway models and animal ARDS/COVID-19 models; evaluate dosing, delivery routes, and safety; consider combination with antiviral agents.
Study Information
- Study Type
- Basic/Mechanistic research (in vitro)
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical in vitro mechanistic study without in vivo validation
- Study Design
- OTHER