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Preferential uptake of SARS-CoV-2 by pericytes potentiates vascular damage and permeability in an organoid model of the microvasculature

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posted on 2023-03-14, 14:40 authored by Abdullah O. Khan, Jasmeet S. Reyat, Harriet Hill, Joshua H. Bourne, Martina Colicchia, Maddy L. Newby, Joel D. Allen, Max Crispin, Esther Youd, Paul MurrayPaul Murray, Graham Taylor, Zania Stamataki, Alex G. Richter, Adam F. Cunningham, Matthew Pugh, Julie Rayes

Aims: Thrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection; however, the mechanisms inducing endotheliitis and the disruption of endothelial integrity in the microcirculation are poorly understood. We hypothesized that within the vessel wall, pericytes preferentially take up viral particles and mediate the subsequent loss of vascular integrity.

Methods and results: Immunofluorescence of post-mortem patient sections was used to assess pathophysiological aspects of COVID-19 infection. The effects of COVID-19 on the microvasculature were assessed using a vascular organoid model exposed to live viral particles or recombinant viral antigens. We find increased expression of the viral entry receptor angiotensin-converting enzyme 2 on pericytes when compared to vascular endothelium and a reduction in the expression of the junctional protein CD144, as well as increased cell death, upon treatment with both live virus and/or viral antigens. We observe a dysregulation of genes implicated in vascular permeability, including Notch receptor 3, angiopoietin-2, and TEK. Activation of vascular organoids with interleukin-1β did not have an additive effect on vascular permeability.  Spike antigen was detected in some patients’ lung pericytes, which was associated with a decrease in CD144 expression and increased platelet recruitment and von Willebrand factor (VWF) deposition in the capillaries of these patients, with thrombi in large vessels rich in VWF and fibrin.

Conclusion: Together, our data indicate that direct viral exposure to the microvasculature modelled by organoid infection and viral antigen treatment results in pericyte infection, detachment, damage, and cell death, disrupting pericyte-endothelial cell crosstalk and increasing microvascular endothelial permeability, which can promote thrombotic and bleeding complications in the microcirculation.


Funding

Engineering a novel human bone marrow organoid to target myelofibrosis.

Wellcome Trust

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Novel mechanism of platelet activation in haemolytic diseases

British Heart Foundation

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Accelerator Award (round 1)

British Heart Foundation

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History

Publication

Cardiovascular Research, 118, 3085–3096

Publisher

Oxford University Press / European Society of Cardiology

Other Funding information

A.O.K. is a Henry Wellcome fellow (218649/Z/19/Z). J.R. is a British Heart Foundation Intermediate Fellow (FS/IBSRF/20/25039). This research was supported by BHF Accelerator Awards to J.S.R. and A.O.K. (AA/18/2/34218). This research was funded, in whole or in part, by the Wellcome Trust (218649/Z/19/Z), British Heart Foundation (AA/18/2/34218), and COMPARE. A CC BY or equivalent licence is applied to AAM arising from this submission, in accordance with the grant’s open access conditions. M.C. was supported by the University of Southampton Coronavirus Response Fund. M.C. was also supported by the International AIDS Vaccine Initiative (IAVI) through grant INV-008352/OPP1153692 and the IAVI Neutralizing Antibody Center through the Collaboration for AIDS Vaccine Discovery grant INV-008813/OPP1196345, both funded by the Bill and Melinda Gates Foundation.

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