Abstract The long-term goal of our research is to develop effective therapies against SARS-CoV-2-elicited disease Covid-19. SARS-CoV-2 spike (S) protein binds to its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine proteases (TMPRSSs), promotes cellular entry. Co-expressions of these viral entry factors are found in the epithelial cells of many organs, including oral mucosa. Recently, oral mucosa has been found to be a potentially high-risk route of SARS-CoV-2 infection. GRHL2, as a transcriptional factor, modulates epithelial gene expression and plasticity through multiple signaling pathways. ACE2 and TMPRSS2 are strongly expressed in epithelial cells, coinciding with the pattern of GRHL2 expression in oral mucosa. GRHL2 regulates ACE2 and TMPRSS2 expression in normal human oral keratinocytes (NHOK). Ectopic expression of GRHL2 induces ACE2 and TMPRSSs expression, while knockdown of GRHL2 leads to decreased levels of these entry factors. ACE2 is an interferon-stimulated gene. IFN-α activates ACE2 expression in part through regulating GRHL2. Small-molecule inhibitors of GRHL2 suppress viral entry factor expression in NHOK. ACE2 and TMPRSS2 are widely expressed in oral mucosal epithelium, knockout of GRHL2 leads to suppression of ACE2 and TMPRSS2 expression in vivo. These findings indicate that GRHL2 is required for ACE2 and TMPRSS expression in NHOK cultured in vitro and oral mucosal epithelium in vivo. Based on these data, we hypothesize that targeting GRHL2 inhibits SARS-CoV-2 transmission into oral mucosal epithelium through regulating viral entry factor expression. This novel hypothesis will be tested by examining the molecular mechanism underlying GRHL2 regulates expression of SARS-CoV-2 entry factors (ACE2 and TMPRSSs) in oral mucosal epithelial cells. Analysis of variance methods will be used to compare means of these gene expression levels. We will also generate a pseudotyped virus in which vesicular stomatitis virus (VSV) green fluorescent protein (GFP) reporter virus expressing SARS- CoV-2 S in replacement of native glycoprotein. Utilizing this chimeric virus, a high throughput assay will be developed to screen GRHL2 inhibitors, which possess the potentials to abrogate SARS-CoV-2 virus infection into oral mucosal epithelium.