SARS‐CoV‐2 spike protein is present in both endothelial and eccrine cells of a chilblain‐like skin lesion

Gambichler, Thilo; Reuther, J; Stücker, Markus; Stranzenbach, René; Reyes, Christian Rafael Torres; Schlottmann, Renate; Schmidt, Wolfgang E.; Hayajneh, Rami; Sriram, Ashwin; Becker, Juergen C.

doi:10.1111/jdv.16970

Cited by 27 publications

(39 citation statements)

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“…A proposed mechanism of action suggests a direct viral infection of the endothelial cells. Electron microscopy and polymerase chain reaction (PCR) analyses of the skin lesions have supported this hypothesis [ 13 , 20 , 21 ]. It is known that COVID-19 is associated with a wide clinical spectrum of skin lesions including urticarial, vesicular, vasculitic and chilblain‐like lesions.…”

Section: Discussionmentioning

confidence: 99%

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction

et al. 2021

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Background The coronavirus disease 2019 (COVID‐19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain‐like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear. Patients and methods 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database. Results Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals. Conclusion Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.

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Section: Discussionmentioning

confidence: 99%

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction

et al. 2021

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“…Whether vascular complications can be attributed to a systemic inflammatory response or are a direct consequence of the viral infection of endothelial cells is currently under debate. To-date, SARS-CoV-2 has been reported to directly infect vascular organoids in vitro [ 19 ] and first case studies reported endothelial infection in glomerular capillary loops, skin lesions [ 8 , 10 , 30 ], as well as provided evidences for endotheliitis in COVID-19 patients [ 17 , 30 ]. However, the expression of the putative SARS-CoV-2 receptor, i.e., angiotensin-converting enzyme 2 (ACE2) is low in endothelial cells compared to mural cells and recent studies suggest that endothelial cells may not be the primary target of SARS-CoV-2 in the vascular wall [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants

et al. 2021

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Coronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It is unclear whether endothelial dysfunction is caused by direct infection of endothelial cells or is mainly secondary to inflammation. Here, we investigate whether different types of endothelial cells are susceptible to SARS-CoV-2. Human endothelial cells from different vascular beds including umbilical vein endothelial cells, coronary artery endothelial cells (HCAEC), cardiac and lung microvascular endothelial cells, or pulmonary arterial cells were inoculated in vitro with SARS-CoV-2. Viral spike protein was only detected in HCAECs after SARS-CoV-2 infection but not in the other endothelial cells tested. Consistently, only HCAEC expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), required for virus infection. Infection with the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.2 resulted in significantly higher levels of viral spike protein. Despite this, no intracellular double-stranded viral RNA was detected and the supernatant did not contain infectious virus. Analysis of the cellular distribution of the spike protein revealed that it co-localized with endosomal calnexin. SARS-CoV-2 infection did induce the ER stress gene EDEM1, which is responsible for clearance of misfolded proteins from the ER. Whereas the wild type of SARS-CoV-2 did not induce cytotoxic or pro-inflammatory effects, the variant B.1.1.7 reduced the HCAEC cell number. Of the different tested endothelial cells, HCAECs showed highest viral uptake but did not promote virus replication. Effects on cell number were only observed after infection with the variant B.1.1.7, suggesting that endothelial protection may be particularly important in patients infected with this variant.

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“…Polymerase chain reaction testing for SARS-CoV-2 in skin biopsies of chilblains during the COVID-19 pandemic is frequently negative, 61 although one report detected SARS-CoV-2 and increased kallikrein by PCR from a chilblain-like lesion of the thumb. 62 Colmenero et al 56 attributed direct causality to COVID-19 in their patients with chilblains, favoring the hypothesis of widespread endothelial infection by SARS-CoV-2 leading to resultant endothelial damage and thrombosis, contending that this argues against the hypothesis that describes the role of IFN-I in the pathogenesis of COVID-19-associated pernio. These potential mechanisms, however, are not necessarily mutually exclusive and may be interdependent; SARS-CoV-2 is not the necessary cause of pernio because this diagnosis preexisted the COVID-19 pandemic.…”

Section: Severe Acute Respiratory Syndrome Coronavirus 2 Testing In Skin Biopsies Of Covid-19-associated Perniomentioning

confidence: 99%

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms

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Cappel²,

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2021

Mayo Clinic Proceedings

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Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19-associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19-associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19-associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.

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SARS‐CoV‐2 spike protein is present in both endothelial and eccrine cells of a chilblain‐like skin lesion

Cited by 27 publications

References 10 publications

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction

Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms

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