The virus that causes COVID-19, SARS-CoV-2, is a highly transmissible member of the Coronavirinae subfamily, and the related spread of infection has been declared a pandemic by the World Health Organization.1 Because this virus causes potentially devastating health consequences, in addition to identifying effective treatments, determining the different routes of viral entry into the body will be useful in prevention efforts. Although aerosolized transmission of the virus has attracted the most attention,2 transmission through other routes such as the skin merits further investigation.

Many recent studies have reported skin manifestations in patients with COVID-19 and suggested possible mechanisms for these signs and symptoms. The group of dermatologic complications seen in these patients includes generalized or localized morbilliform, urticarial eruptions; vesicular eruptions; and chilblain-like lesions.3 In addition, hair loss has been seen in patients with COVID-19.4 With a better understanding of the possible pathophysiologic mechanisms of these manifestations, the presence of the virus in the skin and the infection of skin cells or consequences of infection such as the cytokine storm may be delayed.

To examine this issue more closely, it is possible to use studies investigating other members of this virus family, such as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). According to Ding et al,5 SARS-CoV can infect sweat glands; accordingly, this virus may be present in sweat. Similarly, the infection of a healthcare worker with MERS-CoV during CPR may have resulted from transmission through sweat.6 Unsurprisingly, given these previous studies, the expression of angiotensin-converting enzyme 2 (ACE2) as a receptor for SARS-CoV-2 also has been noted in sweat glands.7

In another interesting study, Liu and colleagues8 found that SARS-CoV-2 can infect keratin (Krt) 7+ secretory luminal cells (major target cells), and Krt5^-/Krt7^- epithelial cells were found in sweat ducts in skin autopsy samples from patients with COVID-19. Because severe sweating has been observed in a significant number of patients with COVID-19, the presence of the virus in the sweat of these patients is a salient detail.9

In addition to the possibility of infection spread through sweat, it is necessary to examine the possibility of infection via the skin. To do so, the expression of SARS-CoV-2 receptors should be discussed. The expression of ACE2 has been noted in sebaceous gland cells, basal epidermal layers, and hair follicle cells in normal skin.10 In addition, the high expression of ACE2 in keratinocytes and their apoptosis in patients with COVID-19 has been demonstrated.11 Interestingly, a higher expression of ACE2 in visceral and subcutaneous adipose tissues (versus lung tissue) is associated with COVID-19-related mortality in patients with obesity.12

Transmembrane serine protease 2 is required for SARS-CoV-2 entry in to cells through ACE2 and is expressed in skin tissue.13 Another SARS-CoV-2 receptor, cluster of differentiation 147, is expressed in skin and associated with several immune system disorders such as psoriatic dermatitis.14 In addition, SARS-CoV has been shown to infect Langerhans cells, although no data are available yet on the relationship of these cells to SARS-CoV-2.15 In patients with COVID-19 and chilblains-like lesions, infected endothelial cells have been detected in immunohistochemistry studies. Further, SARS-CoV-2 particles have been found in endothelial cell' cytoplasm using electron microscopy.16 Finally, small blood vessels in the skin are important targets for SARS-CoV-2, and lymphocyte skin infiltration in patients with COVID-19 provides evidence that the virus enters the skin through blood vessels after systemic infection.8

In addition to the direct infection of endothelial cells by SARS-CoV-2, indirect infection is possible following viral entry into skin. Previously, these authors reviewed the effect of elevated levels of angiotensin II (Ang II) followed by ACE2 downregulation in patients with COVID-19.17 Increased Ang II levels were associated with increased endothelial cell permeability, which induced lymphocyte infiltration; that said, the effect of Ang II on the entry of SARS-CoV-2 into different tissues such as skin should be examined.18 However, it is likely that the entry of the virus into subcutaneous layers paves the way for viral proliferation on a large scale.

Although the superficial layers of skin prevent viral entry under normal conditions, given skin disruptions such as wounds and the long viability of the virus on the surface of skin, there exists a possibility of contamination of underlying tissues.

The Figure represents the probable mechanism of SARS-CoV-2-induced skin lesions and possible cell routes for the virus to multiply in the skin. These authors eagerly anticipate the publication of future studies on this topic to help illuminate the transmission of SARS-CoV-2 via skin.

Figure.

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