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Testing the effect of PAR1 inhibitors on Plasmodium falciparum-induced loss of endothelial cell barrier function

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Storm, Janet ORCID: https://orcid.org/0000-0001-7812-4220, Wu, Yang, Davies, Jill, Moxon, Christopher A. and Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 (2020) 'Testing the effect of PAR1 inhibitors on Plasmodium falciparum-induced loss of endothelial cell barrier function'. Wellcome Open Research, Vol 5, Issue 34.

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Abstract

Background:
Sequestration and cytoadherence of Plasmodium falciparum
-infected erythrocytes (IE) to microvascular endothelium alters endothelial barrier function and plays a role in the pathogenesis of severe malaria. Binding of IE is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) and the PfEMP1 variants that binds to endothelial protein C receptor (EPCR) have, in particular, been associated with the dysregulation of the coagulation/inflammation pathways in endothelial cells. This has prompted speculation about the role of protease-activated receptor-1 (PAR1) activation and signalling in causing endothelial activation and loss of barrier function in cerebral malaria.
Methods:
We used a co-culture of primary human brain microvascular endothelial cells (HBMEC) with P. falciparum material, recombinant PfEMP1 or lysates from IE, and measured barrier function by transendothelial electrical resistance (TEER). A selection of PAR1 inhibitors was tested for their ability to reverse the P. falciparum and thrombin induced decrease in barrier function.
Results:
An initial screen in the presence of recombinant PfEMP1 identified a few inhibitors that were able to reduce the rapid thrombin-induced barrier disruption even when activated protein C (aPC) was unable to do so. However, in the IE lysate co-culture system we identified a echanism that slowly reduces barrier function and which is insensitive to PAR1 inhibitors.
Conclusions:
The selected PAR1 inhibitors were able to reverse the disruption of barrier function by thrombin but did not reverse the IE lysate induced disruption of barrier function, implicating a different PAR1-independent mechanism. These findings have implications for the
design of adjunct therapies to reduce brain swelling in cerebral malaria.

Item Type: Article
Subjects: QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.12688/wellcomeopenres.15602.3
Depositing User: Cathy Waldron
Date Deposited: 20 Feb 2020 16:36
Last Modified: 03 Aug 2020 10:10
URI: https://archive.lstmed.ac.uk/id/eprint/13794

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