Title | Clostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Adler D, Linden JR, Shetty SV, Ma Y, Bokori-Brown M, Titball RW, Vartanian T |
Journal | iScience |
Volume | 15 |
Pagination | 39-54 |
Date Published | 2019 May 31 |
ISSN | 2589-0042 |
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. |
DOI | 10.1016/j.isci.2019.04.016 |
Alternate Journal | iScience |
PubMed ID | 31030181 |
PubMed Central ID | PMC6487375 |
Grant List | R01 NS104350 / NS / NINDS NIH HHS / United States |