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

TitleClostridium perfringens Epsilon Toxin Compromises the Blood-Brain Barrier in a Humanized Zebrafish Model.
Publication TypeJournal Article
Year of Publication2019
AuthorsAdler D, Linden JR, Shetty SV, Ma Y, Bokori-Brown M, Titball RW, Vartanian T
JournaliScience
Volume15
Pagination39-54
Date Published2019 May 31
ISSN2589-0042
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.

DOI10.1016/j.isci.2019.04.016
Alternate JournaliScience
PubMed ID31030181
PubMed Central IDPMC6487375
Grant ListR01 NS104350 / NS / NINDS NIH HHS / United States

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