Possible involvement of metformin in SARS-CoV-2 infection via salivary ACE2 and TMPRSS2

Abstract

The severe acute respiratory syndrome coronavirus 2 （SARS-CoV-2）-related proteins, angiotensin-converting enzyme 2 （ACE2） and transmembrane protease serine 2 （TMPRSS2）, which promote the entry of the virus into host cells, are determinants of SARS-CoV-2 infection. Although these proteins are expressed in oral-related tissues, their expression patterns and modulatory mechanisms in the salivary glands remain unknown. We herein showed that full-length ACE2, which has both a fully functional enzyme catalytic site and high affinity SARS-CoV-2 spike S1-binding sites, was more highly expressed in salivary glands than in oral mucosal epithelial cells and the lungs. Regarding TMPRSS2, zymogen and the cleaved form were both expressed in the salivary glands, whereas only zymogen was expressed in murine lacrimal glands and the lungs. Metformin, an adenosine monophosphate-activated protein kinase activator, increased stimulated saliva secretion and full-length ACE2 expression and decreased cleaved TMPRSS2 expression in the salivary glands, and exerted the same effects on soluble ACE2 （sACE2） and sTMPRSS2 in saliva. Collectively, these results suggest that the protein expression patterns of ACE2 and TMPRSS2 in the salivary glands differ from those in other oral-related cells and tissues, and also that metformin affect the salivary expression of ACE2 and TMPRSS2, which have potential as targets for preventing the transmission of SARS-CoV-2.