Potential role of skin in SARS-CoV-2 infection

尽管研发出了抗SARS-CoV-2疫苗，新冠肺炎仍是一场全球灾难。这是到期的 由于全球疫苗供应有限，疫苗接种犹豫不决，以及SARS新变种的出现-- CoV-2。此外，还缺乏关于SARS-CoV-2生物学的完整知识，包括潜在的 传播途径和不同的发病机制，特别是在种族群体，如非裔美国人(AA)和 与非西班牙裔白人(WNH)相比，受新冠肺炎影响的西班牙裔/拉美裔不成比例 人口。导致这些地区高感染率、住院率和死亡率的生物因素所起的作用 团体仍有待调查。SARS-CoV-2进入细胞依赖于病毒尖峰蛋白(S)的结合 对宿主细胞受体ACE2及其被宿主蛋白酶TMPRSS2的引发/切割。人们普遍认为， SARS CoV-2进入人体的主要途径是呼吸道上皮细胞。但是，其他区域中的单元格 包括心脏、肾脏、胰腺、眼睛和皮肤(主要是表皮)在内的组织/器官也表达ACE2和 TMPRSS2.最近的一些研究表明，皮肤可能直接成为SARS-CoV-2的靶标。事实上，病毒RNA 在皮肤活检中也能检测到衣壳蛋白。重要的是，一些炎症性皮肤病，如 牛皮癣和特应性皮炎，显著增加了患新冠肺炎的风险。这与研究结果相关联。 ACE2和TMPRSS2在银屑病患者皮损和创面皮肤中的表达增加 皮肤。此外，新冠肺炎与皮肤病的直接或有时持续表现有关 这可能是由于SARS-CoV-2直接(局部)或全身(通过循环病毒)感染而发生的。 然而，人类健康或发炎的皮肤在SARS-CoV-2进入和新冠肺炎中的潜在作用 发病机制尚未解决。已知肿瘤坏死因子-α、白介素6、白介素1β和干扰素-γ等细胞因子参与了 在细胞因子风暴期间，不同炎症性皮肤病的发生和水平增加 经常与病毒血症、多器官衰竭和严重致命新冠肺炎的发展相关 。 在我们的试点中 实验表明，肿瘤坏死因子-α+白介素6+白介素1β+干扰素-γ联合应用可显著诱导血管紧张素转换酶2的表达 和TMPRSS2在由原代人表皮角质形成细胞制成的3D人类皮肤等效物(3D-HSE)中 (Nhek)。根据这些新发现，我们推测发炎的皮肤可能会被野生型SARS感染。 CoV-2病毒及其新出现的突变变种，据报告特定种族的感染率较高 人群可能依赖于SARS-CoV-2进入细胞所涉及的蛋白质的较高表达水平。为了测试这些 假设，我们将使用伪型Spike(S)蛋白含慢病毒报告病毒，2D-和3D-HSE 由AA、西班牙裔和WNH角质形成细胞制成的培养物经与COVID相关的细胞因子鸡尾酒处理后- 19种细胞因子风暴(肿瘤坏死因子-α+白介素6+白介素1b+干扰素-γ)或细胞因子(白介素17+白介素22+肿瘤坏死因子α)或 特应性皮炎(IL4+IL13)在体外皮肤模型中的分子和形态变化。

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.