Potential role of skin in SARS-CoV-2 infection

COVID-19 continues to be a global catastrophe despite development of anti-SARS-CoV-2 vaccines. This is due to the worldwide limited vaccine availability, vaccination hesitancy, and the emergence of new variants of SARS- CoV-2. Moreover, there is a lack of complete knowledge about SARS-CoV-2 biology, including potential transmission routes and variable pathogenesis, especially in ethnic groups, such as African American (AA) and Hispanic/Latino that were disproportionally affected by COVID-19 compared to White Non-Hispanic (WNH) population. The role of biological factors contributing to high infection, hospitalization, and death rates in these groups remains to be investigated. Cell entry of SARS-CoV-2 depends on binding of the viral spike (S) protein to the host cell receptor ACE2 and its priming/cleavage by host protease TMPRSS2. It is well accepted that the main route of the SARS CoV-2 entry into the body is via respiratory epithelial cells. However, cells in other tissues/organs including the heart, kidney, pancreas, eye and skin (mostly epidermis) also express ACE2 and TMPRSS2. Some recent studies indicate that skin could be directly targeted by SARS-CoV-2. Indeed, viral RNA and capsid proteins were detectable in skin biopsies. Importantly, some inflammatory skin diseases, such as psoriasis and atopic dermatitis, significantly increased the risk of COVID-19. This correlates with the findings that ACE2 and TMPRSS2 expression was increased in lesional skin of psoriasis patients as well as in wounded skin. In addition, COVID-19 is associated with dermatological immediate or sometimes persistent manifestations which could occur because of direct (topical) or systemic (via circulating virus) infection by SARS-CoV-2. Nevertheless, the potential role of human healthy or inflamed skin in SARS-CoV-2 entry and COVID-19 pathogenesis has not been addressed. It is known that TNF-α, IL-6, IL-1β, and IFN-γ cytokines are involved in the development of different inflammatory skin diseases and their level is increased during cytokine storm frequently associated with viremia, multi-organ failure, and development of severe deadly COVID-19 . In our pilot experiments, we showed that combination of TNF-α + IL-6 + IL-1β + INF-γ strongly induced expression of ACE2 and TMPRSS2 in 3D human skin equivalents (3D-HSE) made from primary human epidermal keratinocytes (NHEK). Based on these novel findings, we hypothesize that inflamed skin could be infected by wild type SARS- CoV-2 virus and its emerging mutated variants, and that higher infection rates reported for specific ethnic populations may depend on higher expression levels of proteins involved in SARS-CoV-2 cell entry. To test these hypotheses, we will use pseudotyped Spike (S) protein-containing reporter lentiviruses, 2D- and 3D-HSE cultures made from AA, Hispanic and WNH keratinocytes pretreated with cytokine cocktails related to COVID- 19 cytokine storm (TNF-α+IL-6+IL-1b+INF-γ) or cytokines proven to induce pro-psoriasis (IL17+IL22+TNFa) or pro-atopic dermatitis (IL4+IL13) molecular and morphological changes in in vitro skin models.