PUBLICATION
Clostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model
- Authors
- Adler, D., Linden, J.R., Shetty, S.V., Ma, Y., Bokori-Brown, M., Titball, R.W., Vartanian, T.
- ID
- ZDB-PUB-190429-7
- Date
- 2019
- Source
- iScience 15: 39-54 (Journal)
- Registered Authors
- Keywords
- Model Organism, Molecular Mechanism of Behavior, Pathogenic Organism, Vascular Remodeling
- MeSH Terms
- none
- PubMed
- 31030181 Full text @ iScience
Citation
Adler, D., Linden, J.R., Shetty, S.V., Ma, Y., Bokori-Brown, M., Titball, R.W., Vartanian, T. (2019) Clostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model. iScience. 15:39-54.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping