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

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 b...

Full description

Saved in:
Bibliographic Details
Published iniScience Vol. 15; pp. 39 - 54
Main Authors Adler, Drew, Linden, Jennifer R., Shetty, Samantha V., Ma, Yinghua, Bokori-Brown, Monika, Titball, Richard W., Vartanian, Timothy
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 31.05.2019
Elsevier
Subjects
Model Organism
Molecular Mechanism of Behavior
Pathogenic Organism
Vascular Remodeling
Vascular Remodeling
Pathogenic Organism
Molecular Mechanism of Behavior
Model Organism
Online AccessGet full text

Cover

More Information
Summary: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. [Display omitted] •ProETX binds specifically to hMAL in live humanized zebrafish•hMAL expression in zebrafish confers susceptibility to ETX-mediated BBB breakdown•Live imaging reveals ETX-mediated edema, hMAL downregulation, stenosis, and stasis•Antibody neutralization abrogates ETX-mediated vascular pathology Pathogenic Organism; Vascular Remodeling; Molecular Mechanism of Behavior; Model Organism
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Lead Contact
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2019.04.016