Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2...

SARS-CoV-2, the causative virus of COVID-19, increases the risk of pregnancy complications including hypertensive disorders and placental inflammation. The spike glycoprotein mediates viral cell entry by interacting with the angiotensin-converting enzyme (ACE)2 in conjunction with the transmembrane serine protease 2 (TMPRSS2). ACE1, ACE2 and renin are components of the renin-angiotensin system (RAS), which regulates blood pressure. As the placenta expresses all these proteins, it is a target for SARS-CoV-2 and a source of blood pressure modulators. Noteworthy, an ACE1/ACE2 ratio imbalance can lead to RAS dysregulation and a bad prognosis in COVID-19 patients. Calcitriol, the most active vitamin D metabolite, negatively regulates RAS, reduces inflammation, and enhances antiviral immunity, thereby protecting against COVID-19 severity. However, contrasting information exists on the regulatory role of calcitriol upon RAS components and SARS-CoV-2 receptors; while the impact of calcitriol on spike-induced inflammation in placental cells has not been explored. Thus, we studied the effects of calcitriol on these parameters using the trophoblast cell line HTR-8/SVneo and primary syncytiotrophoblasts. By RT-qPCR, ELISA, and immunocytochemistry, we found that the spike enhanced proinflammatory cytokines expression and secretion, while calcitriol significantly downregulated this effect. Calcitriol also diminished ACE1, ACE2, TMPRSS2, and renin gene expression, as well as ACE1/ACE2 mRNA ratio. CONCLUSIONS: In the human placenta, calcitriol reduced the gene expression of main RAS components and TMPRSS2, resulting in the inhibition of spike-induced inflammation. This outcome suggest that vitamin D participates in restricting SARS-CoV-2 placental infection by rendering trophoblasts less permissive to infection while helping to regulate maternal blood pressure and decreasing inflammation.