ABSTRACT
The severe acute respiratory syndrome (SARS)-CoV-2, a newly emerged coronavirus first identified in 2019, is the pathogenetic agent od Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE) 2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of ACE2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin, a natural flavonoid bind and activates the Aryl hydrocarbon Receptor (AhR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent DSS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of ACE2 mRNA expression. Colon levels of ACE2 mRNA were directly correlated with TNF mRNA levels. In contrast to ACE2 the angiotensin 1-7 receptor MAS was downregulated in the inflamed tissues. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV2 Spike protein to ACE2 and reduces the SARS-CoV2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.