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iScience. 2019 May 31;15:39-54. doi: 10.1016/j.isci.2019.04.016. Epub 2019 Apr 11.

Clostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model.

Author information

1
Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA; Department of Neurobiology and Behavior, Cornell University, Ithaca, NY 14850, USA.
2
Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
3
Department of Biosciences, University of Exeter, Exeter, Devon EX4 4SB, UK.
4
Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. Electronic address: tiv2002@med.cornell.edu.

Abstract

Clostridium perfringens epsilon toxin (ETX) is hypothesized to mediate blood-brain barrier (BBB) permeability by binding to the myelin and lymphocyte protein (MAL) on the luminal surface of endothelial cells (ECs). However, the kinetics of this interaction and a general understanding of ETX's behavior in a live organism have yet to be appreciated. Here we investigate ETX binding and BBB breakdown in living Danio rerio (zebrafish). Wild-type zebrafish ECs do not bind ETX. When zebrafish ECs are engineered to express human MAL (hMAL), proETX binding occurs in a time-dependent manner. Injection of activated toxin in hMAL zebrafish initiates BBB leakage, hMAL downregulation, blood vessel stenosis, perivascular edema, and blood stasis. We propose a kinetic model of MAL-dependent ETX binding and neurovascular pathology. By generating a humanized zebrafish BBB model, this study contributes to our understanding of ETX-induced BBB permeability and strengthens the proposal that MAL is the ETX receptor.

KEYWORDS:

Model Organism; Molecular Mechanism of Behavior; Pathogenic Organism; Vascular Remodeling

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