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The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier
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Abstract
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 includes 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. 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 expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for 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 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to 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.
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Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884
Clinical characteristics of coronavirus disease 2019 in China
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., Liu, L., Shan, H., Lei, C.-L., Hui, D. S. C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2002032 · Cited by 30,246
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30251-8 · Cited by 11,907
Chan, J. F.-W., Yuan, S., Kok, K.-H., To, K. K.-W., Chu, H., Yang, J., Xing, F., Liu, J., Yip, C. C.-Y., Poon, R. W.-S., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30154-9 · Cited by 8,944
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, Gorbalenya, A. E., Baker, S. C., Baric, R. S., de Groot, R. J., Drosten, C., Gulyaeva, A. A., Haagmans, B. L., Lauber, C., Leontovich, A. M., et al. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0695-z · Cited by 8,403
Endothelial cell infection and endotheliitis in COVID-19
Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., Mehra, M. R., Schuepbach, R. A., Ruschitzka, F., & Moch, H. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30937-5 · Cited by 6,358
Lauer, S. A., Grantz, K. H., Bi, Q., Jones, F. K., Zheng, Q., Meredith, H. R., Azman, A. S., Reich, N. G., & Lessler, J. (2020) · Annals of Internal Medicine · doi:10.7326/m20-0504 · Cited by 5,970
Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H. (2004) · The Journal of Pathology · doi:10.1002/path.1570 · Cited by 5,676
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2015432 · Cited by 5,613
Clinical and immunological features of severe and moderate coronavirus disease 2019
Chen, G., Wu, D., Guo, W., Cao, Y., Huang, D., Wang, H., Wang, T., Zhang, X., Chen, H., Yu, H., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137244 · Cited by 4,750
Research works printed but not linked: 4
- Bradley, 2004, Histopathology and ultrastructural findings of fatal COVID-19 Infections, medRxiv, 2020
- Carod-Artal, 2020, Neurological complications of coronavirus and COVID-19, Rev. Neurol., 70, 311, 10.33588/rn.7009.2020179 · doi:10.33588/rn.7009.2020179
- Marshall, 1988, HIV penetration of the BBB, Neurology, 38, 1000, 10.1212/WNL.38.6.1000-b · doi:10.1212/wnl.38.6.1000-b
- Rissi, 2018, A retrospective study of the neuropathology and diagnosis of naturally occurring feline infectious peritonitis, J. Vet. Diagn. Investig., 30, 392, 10.1177/1040638718755833 · doi:10.1177/1040638718755833
Cited by
Immunity, endothelial injury and complement-induced coagulopathy in COVID-19
Perico, L., Benigni, A., Casiraghi, F., Ng, L. F. P., Renia, L., & Remuzzi, G. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-020-00357-4 · Cited by 607
Greene, C., Connolly, R., Brennan, D., Laffan, A., O’Keeffe, E., Zaporojan, L., O’Callaghan, J., Thomson, B., Connolly, E., Argue, R., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01576-9 · Cited by 429
LaRovere, K. L., Riggs, B. J., Poussaint, T. Y., Young, C. C., Newhams, M. M., Maamari, M., Walker, T. C., Singh, A. R., Dapul, H., Hobbs, C. V., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.0504 · Cited by 396
Morphological, cellular and molecular basis of brain infection in COVID-19 patients
Crunfli, F., Carregari, V. C., Veras, F. P., Vendramini, P. H., Valença, A. G. F., Antunes, A. S. L. M., Brandão-Teles, C., da Silva Zuccoli, G., Reis-de-Oliveira, G., Silva-Costa, L. C., et al. (2020) · doi:10.1101/2020.10.09.20207464 · Cited by 331
Neuropathobiology of COVID-19: The Role for Glia
Tremblay, M.-E., Madore, C., Bordeleau, M., Tian, L., & Verkhratsky, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592214 · Cited by 159
Metadata
- Authors
- Buzhdygan, T. P., DeOre, B. J., Baldwin-Leclair, A., Bullock, T. A., McGary, H. M., Khan, J. A., Razmpour, R., Hale, J. F., Galie, P. A., Potula, R., Andrews, A. M., & Ramirez, S. H.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 146
- Pages
- 105131
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W3092499620
- Cited by
- 507
- References
- 64
- FWCI
- 30.31
- Type
- journal article
- Language
- en
- Open access
- gold
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
- Funders
- TPB (T32 DA007237)
- SHR & RP (5R01DA046833)
- AMA (K01DA046308)
- NIH (5R24HD000836)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
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- Buzhdygan, T. P., DeOre, B. J., Baldwin-Leclair, A., Bullock, T. A., McGary, H. M., Khan, J. A., Razmpour, R., Hale, J. F., Galie, P. A., Potula, R., Andrews, A. M., & Ramirez, S. H. (2020). 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. https://doi.org/10.1016/j.nbd.2020.105131
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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