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Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Vikramjeet Singh, Alexander Beer, Andreas Kraus, Xiaoni Zhang, Jinhua Xue, Dirk M Hermann, View ORCID ProfileMatthias Gunzer
doi: https://doi.org/10.1101/2020.06.24.162941
Vikramjeet Singh
1Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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  • For correspondence: vikramjeet.singh@uni-due.de matthias.gunzer@uni-due.de
Alexander Beer
1Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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Andreas Kraus
1Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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Xiaoni Zhang
3Department of Neurology, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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Jinhua Xue
1Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
3Department of Neurology, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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Dirk M Hermann
3Department of Neurology, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
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Matthias Gunzer
1Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany
2Leibniz-Institut für Analytische Wissenschaften – ISAS -e.V., Dortmund, Germany
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  • ORCID record for Matthias Gunzer
  • For correspondence: vikramjeet.singh@uni-due.de matthias.gunzer@uni-due.de
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Abstract

Background The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.

Methods Mice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.

Results Strikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1β in the lungs. Higher gene expression of cytokines IL-6 and IL-1β was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression.

Conclusions We demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.

Highlights Brain tissue injury increases ACE2 levels in the lungs

Brain injury induces pro-inflammatory cytokine expression in the lungs

Brain injury causes parenchymal inflammation and systemic lymphopenia

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 24, 2020.
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Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs
Vikramjeet Singh, Alexander Beer, Andreas Kraus, Xiaoni Zhang, Jinhua Xue, Dirk M Hermann, Matthias Gunzer
bioRxiv 2020.06.24.162941; doi: https://doi.org/10.1101/2020.06.24.162941
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Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs
Vikramjeet Singh, Alexander Beer, Andreas Kraus, Xiaoni Zhang, Jinhua Xue, Dirk M Hermann, Matthias Gunzer
bioRxiv 2020.06.24.162941; doi: https://doi.org/10.1101/2020.06.24.162941

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