key: cord-0975724-0imhdrup authors: Xu, Qiannan; Zhang, Li; Chen, Lihong; Zhao, Xiaoqing; Wang, Xiaopan; Hu, Mengyan; Le, Yunchen; Xue, Feng; Li, Xia; Zheng, Jie title: SARS-CoV-2 might transmit through the skin while the skin barrier function could be the mediator date: 2022-01-03 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110752 sha: 92ae667a7f25e8486b5f63a1d6ef79c415aa2493 doc_id: 975724 cord_uid: 0imhdrup During the coronavirus disease 2019 (COVID-19) pandemic, it were reported that COVID-19 patients could have cutaneous symptoms, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was observed on the skin of COVID-19 patients, which indicated that the skin is one target of SARS-CoV-2. Meanwhile, reports about SARS-CoV-2 transmission through food cold-chain overpacks emerged. With the fact that SARS-CoV-2 could survive on the skin for more than 9 hours, the skin could be implicated in SARS CoV-2 transmission. Angiotensin-converting enzyme 2 (ACE2), a critical membrane protein for SARS-CoV-2 that enters a host cell, was recognized to be associated with the risk of SARS-CoV-2 infection. Therefore, tissues that express ACE2 might have the potential to be infected by and transmit SARS-CoV-2. The skin is one such tissue that expresses ACE2. However, unlike the lung that expresses ACE2 on the upper-most epithelial layer, the skin is composed of different layers of cells that function as a barrier, and cells under the top epidermal layer express ACE2. Since the skin barrier is the first line of protection, the typical position of ACE2-expressing cells in the skin implies that the skin barrier function could be the mediator of SARS-CoV-2. In our study, we found that ACE2 could be expressed in the skin, and its expression level is increased in psoriasis, an inflammatory disease of the skin with barrier dysfunction. Additionally, by applying the SARS-CoV-2 pseudovirus on mouse models with or without deteriorated skin barrier, we found that the SARS-CoV-2 pseudovirus could infect the skin and lungs of mouse models, and when the skin barrier was impaired, more SARS-CoV-2-infected cells could be found. Thus, we hypothesized that a deteriorated condition of the skin barrier might increase the risk of SARS-CoV-2 infection through the skin. The skin is one such tissue that expresses ACE2. However, unlike the lung that expresses ACE2 on the upper-most epithelial layer, the skin is composed of different layers of cells that function as a barrier, and cells under the top epidermal layer express ACE2. Since the skin barrier is the first line of protection, the typical position of ACE2expressing cells in the skin implies that the skin barrier function could be the mediator of SARS-CoV-2. In our study, we found that ACE2 could be expressed in the skin, and its expression level is increased in psoriasis, an inflammatory disease of the skin with barrier Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first discovered at the end of 2019, and it spread worldwide [1] . During the coronavirus disease 2019 (COVID-19) pandemic, there were reports that SARS-CoV-2 was transmitted through food cold-chain overpacks [2] , and that SARS-CoV-2 could survive on the skin for more than 9 hours [3] , which brought about the question whether SARS-CoV-2 could transmit through the skin. Considering the fact that the SARS-CoV-2 was present on the skin [11] , we evaluated two hypotheses. Our first hypothesis was that the skin was implicated in SARS CoV-2. Another fact that evoked our further hypothesis was that a well-structured skin barrier is the first line of protection against external microbes. If the skin was implicated in the SARS CoV-2 transmission, the function of the skin barrier could be the mediator. Thus, our second hypothesis was that skin barrier could be the mediator of the impact of SARS-CoV-2 on the skin and the wellstructured skin barrier is a potential weapon against transmission. In other words, SARS-CoV-2 might transmit through the skin while the skin barrier function could be the mediator. There were several indications to support our hypothesis regarding the implication of the skin in SARS-CoV-2 transmission. First, the skin is one of the organs that can express angiotensin-converting enzyme 2 (ACE2) [8] [9] [10] . ACE2 on the cell surface serves as the binding point of SARS-CoV-2, facilitating the entry of the virus and subsequent infection [4, 5] . Thus, ACE2 expression was considered to be associated with susceptibility to SARS-CoV-2 [6] . Secondly, there were reports of coronavirus disease 2019 (COVID-19) patients having dermatological symptoms [11] [12] [13] , such as chilblains-like and pernio-like skin lesions. SARS-CoV-2 particles were found in the skin endothelial cells of the COVID-19 patients through electron microscopy [12] , and a study reported that skin rashes could be an orphan symptom in some patients [14] , for whom SARS-CoV-2 infection was first recognized through only skin-related symptoms, but without respiratory symptoms, which might provoke the thought that the skin was first infected in this patient. When SARS-CoV-2 is transmitted through the respiratory tract, numerous cells, known as alveolar epithelial type II cells, which express ACE2 on the surface of the tract [5] , were infected. This led to severe lung injury, which could eventually result in death. The symptoms on the skin of COVID-19 patients might be caused by systematic response to the SARS-CoV-2 infection, which has not yet been verified. However, with the fact that SARS-CoV-2 virus was detected in the skin, it is more likely that these symptoms were caused by SARS-CoV-2 infecting the skin directly. Thirdly, the SARS-CoV-2 virus was found to be present on cold chain overpacks, and people who work in such cold chain environments could be infected by SARS-CoV-2 as patient zero in certain areas. The skin is the only organ that could directly be in contact with the SARS-CoV-2 contaminated surface in such environments, and SARS-CoV-2 could survive on the skin for over 9 hours. This implied that the skin could be another target of the SARS-CoV-2, and a milieu for SARS-CoV-2 transmission [7] . All of the above support our first hypothesis that the skin is implicated in SARS-CoV-2 transmission. As the "great wall" of the human body, the skin barrier protects us from external microbes. Further, the well-structured skin barrier can also block SARS-CoV-2 from entering the skin. Then, in which circumstances can the SARS-CoV-2 pass the barrier? Unlike the lung, which contains only one layer of epithelial cells as a barrier to the external microbial environment, the skin is composed of tight junctions of keratinocytes and lipids that could be recognized as the "bricks and cement of a wall," respectively. The expression of ACE2 in the normal skin was observed not on the surface, as in the lungs or gut, but on the stratum basale, sweat glands, and blood vessel epithelia, which are located at the bottom or under the skin barrier [7, 9, 10, 12, 19, 20] . Thus, the target ACE2-expressing cells of SARS-CoV-2 can be located in the innermost layer of the "bricks" and in the basement. If there are fractures between the external brick layers of the wall, infectious particles, such as SARS-CoV-2, present on the external layer, gain contact with the vulnerable bricks of the innermost bricklayer ( Figure 1 ). Thus, in certain pre-existing cutaneous conditions with high ACE2 expression and barrier dysfunction, SARS-CoV-2 may be transmitted through the skin, and the well-structured skin barrier can be a potential weapon against transmission while the skin barrier function acts as the mediator. Our hypothesis stands on the fact that the skin could express ACE2, and that skin barrier dysfunction was associated with the skin acting as a weapon against external microbes. We evaluated the skin ACE2 expression in psoriasis and atopic dermatitis (AD), typical skin diseases with barrier dysfunction [26] , and normal skin through RNAseq. Results showed that the skin could express ACE2 in all the three conditions, and patients with psoriasis had the highest expression of ACE2 on the skin among the three conditions ( Figure 2) . We used the [16] . This made us wonder whether the deteriorated skin barrier or skin inflammation could be associated with ACE2 expression. In our study, we could not conclude whether ACE2 was associated with skin barrier function; however, the results implied that the psoriatic form of the skin inflammation with barrier dysfunction might enable a higher risk for SARS-CoV-2 transmission in certain circumstances. However, another article demonstrated that the incidence of COVID-19 in psoriatic patients was not elevated [25] . The expression of ACE2 in the lesion skin of patients with psoriasis and atopic dermatitis as well as the skin of normal control. The percentage of GFP cells in mouse models with induced psoriasis, atopic dermatitis and group control. 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