Clostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model
| Autor: | Timothy Vartanian, Monika Bokori-Brown, Samantha V. Shetty, Drew Adler, Yinghua Ma, Richard W. Titball, Jennifer R. Linden |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures ved/biology.organism_classification_rank.species 02 engineering and technology Vascular Remodeling Blood–brain barrier Article Pathogenic Organism 03 medical and health sciences Myelin Downregulation and upregulation medicine lcsh:Science Receptor Model organism Zebrafish Multidisciplinary Model Organism biology ved/biology Chemistry Clostridium perfringens epsilon toxin 021001 nanoscience & nanotechnology biology.organism_classification 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure cardiovascular system lcsh:Q Molecular Mechanism of Behavior 0210 nano-technology Blood vessel |
| Zdroj: | iScience iScience, Vol 15, Iss, Pp 39-54 (2019) |
| ISSN: | 2589-0042 |
| DOI: | 10.1016/j.isci.2019.04.016 |
| Popis: | 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. Graphical Abstract Highlights • 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 |
| Databáze: | OpenAIRE |
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