Language:

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier

Neurobiology of disease, 2020-12, Vol.146, p.105131-105131, Article 105131 [Peer Reviewed Journal]

2020 The Author(s) ;Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved. ;2020 The Author(s) 2020 ;ISSN: 0969-9961 ;EISSN: 1095-953X ;DOI: 10.1016/j.nbd.2020.105131 ;PMID: 33053430

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier
Author: Buzhdygan, Tetyana P. ; DeOre, Brandon J. ; Baldwin-Leclair, Abigail ; Bullock, Trent A. ; McGary, Hannah M. ; Khan, Jana A. ; Razmpour, Roshanak ; Hale, Jonathan F. ; Galie, Peter A. ; Potula, Raghava ; Andrews, Allison M. ; Ramirez, Servio H.
Subjects: Angiotensin-Converting Enzyme 2 - metabolism ; Blood-brain barrier ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Capillary Permeability - drug effects ; Capillary Permeability - physiology ; Cell Adhesion Molecules - drug effects ; Cell Adhesion Molecules - metabolism ; Cell Survival - drug effects ; Cerebral vascular biology ; COVID-19 ; Dementia - metabolism ; Electric Impedance ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Frontal Lobe - metabolism ; Humans ; Hypertension - metabolism ; In Vitro Techniques ; Inflammation - metabolism ; Intercellular Junctions - metabolism ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Lab-On-A-Chip Devices ; Matrix Metalloproteinases - drug effects ; Matrix Metalloproteinases - metabolism ; Microfluidic chip ; Neuroinflammation ; Primary Cell Culture ; Protein Domains ; Protein Subunits - metabolism ; Protein Subunits - pharmacology ; RNA, Messenger - drug effects ; RNA, Messenger - metabolism ; SARS-CoV-2 ; SARS-CoV-2 - pathogenicity ; Spike Glycoprotein, Coronavirus - pharmacology ; Spike Glycoprotein, Coronavirus - physiology ; Tissue engineering
Is Part Of: Neurobiology of disease, 2020-12, Vol.146, p.105131-105131, Article 105131
Description: As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients. •SARS-CoV-2 is known to bind to ACE2. ACE2 is upregulated in the human brain vasculature of hypertensive and dementia cases.•The SARS-CoV-2 spike protein does not acutely affect the viability of brain endothelial cells.•Blood-brain barrier function is negatively affected by SARS-CoV-2 spike protein subunits.•Brain endothelial cells show a distinct pro-inflammatory response when exposed to various SARS-CoV-2 spike protein subunits.•Mechanistically, barrier disruption may be explained by induction of members of the MMP family of proteins.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0969-9961
EISSN: 1095-953X
DOI: 10.1016/j.nbd.2020.105131
PMID: 33053430
Source: MEDLINE
DOAJ Directory of Open Access Journals

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier

2020 The Author(s) ;Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved. ;2020 The Author(s) 2020 ;ISSN: 0969-9961 ;EISSN: 1095-953X ;DOI: 10.1016/j.nbd.2020.105131 ;PMID: 33053430

Searching Remote Databases, Please Wait