Human keratinocytes exhibit limited potential for SARS-CoV-2 infection despite ACE2 and mature cathepsin L expression

The distribution of receptors and cellular factors across tissues determines differential susceptibility of cells to viral infection. For severe acute respiratory syndrome coronavirus 2, viral spike and nucleocapsid proteins have been detected in the skin of infected patients. Whether the virus can directly infect skin cells has yet to be fully evaluated. Severe acute respiratory syndrome coronavirus 2 enters cells through 2 routes: ACE2-driven endocytosis and TMPRSS2-mediated plasma membrane fusion or ACE2/alternative receptors-driven endocytosis and cathepsin L-dependent fusion. This study assessed the gene and protein expression of these entry receptors and coreceptors in primary keratinocytes and fibroblasts. We found that the main severe acute respiratory syndrome coronavirus 2 receptor ACE2 is present in human keratinocytes and is upregulated during their differentiation and toll-like receptor 3-mediated activation, whereas the coreceptor TMPRSS2 for fusion is absent, but mature cathepsin L is expressed. In vitro infection assays using the severe acute respiratory syndrome coronavirus 2 Delta variant showed that the virus can bind to the cell surface but cannot replicate within the cells. These findings suggest that although active viral replication in keratinocytes is unlikely, the presence and inducible upregulation of ACE2 in response to inflammatory stimuli may confer a limited potential for cutaneous viral entry, warranting further investigation into the consequences in terms of local inflammation and viral transmission.