Secondary Logo

Journal Logo

DEPARTMENTS: PRACTICE REFLECTIONS

Skin Tissue: A Place for SARS-CoV-2 to Multiply and Transmit?

Khezri, Mohammad Rafi; Ghasemnejad-Berenji, Morteza PhD; Jafari, Reza PhD

Author Information
doi: 10.1097/01.ASW.0000772732.19325.30
  • Free

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.
Figure.:
THE PROBABLE MECHANISM OF SARS-COV-2-INDUCED SKIN LESIONS AND CELL TYPES THAT MAY BE INVOLVED IN VIRAL REPLICATION IN SKIN

REFERENCES

1. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ2020;371:m3862.
2. Li H, Wang Y, Ji M, et al. Transmission routes analysis of SARS-CoV-2: a systematic review and case report. Front Cell Dev Biol2020;8:618.
3. Novak N, Peng W, Naegeli MC, et al. SARS-CoV-2, COVID-19, skin and immunology—what do we know so far?Allergy2021;76(3):698–713.
4. Shanshal M. COVID-19 related anagen effluvium. J Dermatolog Treat2020:1–2.
5. Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol2004;203(2):622–30.
6. Nam H-S, Yeon M-Y, Park JW, Hong J-Y, Son JW. Healthcare worker infected with Middle East respiratory syndrome during cardiopulmonary resuscitation in Korea, 2015. Epidemiol Health2017;39:e2017052.
7. Hamming I, Timens W, Bulthuis M, Lely A, Navis Gv, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol2004;203(2):631–7.
8. Liu J, Li Y, Liu L, et al. Infection of human sweat glands by SARS-CoV-2. Cell Discov2020;6(1):84.
9. Zhang Y. Gastrointestinal tract symptoms in coronavirus disease 2019: analysis of clinical symptoms in adult patients. medRxiv2020;127.
10. Grzegrzolka J, Swiatko K, Pula B, et al. ACE and ACE2 expression in normal and malignant skin lesions. Folia Histochem Cytobiol2013;51(3):232–8.
11. Xue X, Mi Z, Wang Z, Pang Z, Liu H, Zhang F. High expression of ACE2 on keratinocytes reveals skin as a potential target for SARS-CoV-2. J Invest Dermatol2021;141(1):206–9.
12. Al-Benna S. Association of high level gene expression of ACE2 in adipose tissue with mortality of COVID-19 infection in obese patients. Obes Med2020;19:100283.
13. Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS, Kantoff PW. TMPRSS2 and COVID-19: serendipity or opportunity for intervention?Cancer Discov2020;10(6):779–82.
14. Peng C, Zhang S, Lei L, et al. Epidermal CD147 expression plays a key role in IL-22-induced psoriatic dermatitis. Sci Rep2017;7:44172.
15. Liu L, Wei Q, Nishiura K, et al. Spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques. Mucosal Immunol2016;9(4):1089–101.
16. Colmenero I, Santonja C, Alonso-Riaño M, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol2020;183(4):729–37.
17. Khezri MR, Yousefi K, Ghasemnejad-Berenji M. Angiotensin II: a possible target for therapeutic intervention in COVID-19. Biomed Pharmacother2021;139:111564.
18. Bodor C, Nagy JP, Végh B, et al. Angiotensin II increases the permeability and PV-1 expression of endothelial cells. Am J Physiol Cell Physiol2012;302(1):C267–76.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.