Abstract Number: PB0745
Meeting: ISTH 2021 Congress
Background: PfEMP1 variants containing EPCR binding CIDRα1 domains are associated with severe malaria complications. The inhibition of activated protein C (APC) binding to EPCR by CIDRα1 domains and thereby APC’s cytoprotective activities is considered to be a major contributing factor for the development of cerebral malaria (CM). However, purified CIDRα1 domains administered to a humanized EPCR (hEPCR) mouse accumulated predominantly in the lung with only minor accumulation in the brain, raising new questions how infected erythrocytes sequester in the brain vasculature.
Aims: To characterize the specific EPCR-dependent sequestration of CIDRα1.1-derivatized 2 μm fluorescent microspheres, mimicking infected erythrocytes, in the brain vasculature in a hEPCR mouse model.
Methods: Streptavidin coated fluorescent microspheres were labeled with biotinylated anti-V5 antibody and V5-tagged CIDRα1 domains and administered in the carotid artery of wild-type and hEPCR mice.
Results: In vivo, injection of CIDRa1.1+ microspheres in the ascendant carotid artery resulted in significant accumulation of beads into the brain microvasculature of hEPCR transgenic mice compared to WT. The carotid artery inoculation resulted in a dose and time dependent sequestration of CIDRa1.1+ microspheres peaking at 1 hour post injection. Accumulation was predominant in the brain hemisphere fed by the injected carotid artery even though microsphere distribution was also observed in the contralateral one especially in hEPCR transgenic mice.
Conclusions: In vivo, accumulation of CIDRa1.1+ microspheres in the brain of mice expressing hEPCR was much more efficient than that of purified CIDRa1.1 domains. This model provides an effective method for the analysis of EPCR-targeting treatments during severe malaria and to determine the effect of brain edema, a hall mark of cerebral malaria, on the EPCR-dependent sequestration of infected erythrocytes in the brain vasculature.
To cite this abstract in AMA style:Aiolfi R, Cowan PJ, Gock H, Weiler H, Turner L, Lavstsen T, Mosnier LO. Endothelial Protein C Receptor (EPCR)-dependent Sequestration of P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1)-derived Fluorescent Microspheres in the Brain Vasculature of a Humanized Mouse [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/endothelial-protein-c-receptor-epcr-dependent-sequestration-of-p-falciparum-erythrocyte-membrane-protein-1-pfemp1-derived-fluorescent-microspheres-in-the-brain-vasculature-of-a-humanized-mouse/. Accessed December 6, 2023.
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