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

Adler, Drew; Linden, Jennifer R.; Shetty, Samantha V.; Ma, Yanlin; Bokori-Brown, Monika; Titball, Richard W.; Vartanian, Timothy

doi:10.1016/j.isci.2019.04.016

Cited by 14 publications

(13 citation statements)

References 86 publications

(132 reference statements)

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“…ETX does not bind to wild-type zebrafish endothelial cells and, consequently, the toxin has no effect. However, a humanized zebrafish model expressing human MAL in endothelial cells binds to ETX and responds by producing blood–brain barrier leakage, blood vessel stenosis, perivascular edema and blood stasis [ 157 ]. In mice, MAL expression was found in the endothelium of some lung vessels, supporting the hypothesis that MAL is a key element in the ETX-induced perivascular edema in the lungs [ 158 ].…”

Section: Mal and The Clostridial Epsilon Toxinmentioning

confidence: 99%

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

Rubio-Ramos

Labat-de-Hoz

Correas

et al. 2021

Cells

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The MAL gene encodes a 17-kDa protein containing four putative transmembrane segments whose expression is restricted to human T cells, polarized epithelial cells and myelin-forming cells. The MAL protein has two unusual biochemical features. First, it has lipid-like properties that qualify it as a member of the group of proteolipid proteins. Second, it partitions selectively into detergent-insoluble membranes, which are known to be enriched in condensed cell membranes, consistent with MAL being distributed in highly ordered membranes in the cell. Since its original description more than thirty years ago, a large body of evidence has accumulated supporting a role of MAL in specialized membranes in all the cell types in which it is expressed. Here, we review the structure, expression and biochemical characteristics of MAL, and discuss the association of MAL with raft membranes and the function of MAL in polarized epithelial cells, T lymphocytes, and myelin-forming cells. The evidence that MAL is a putative receptor of the epsilon toxin of Clostridium perfringens, the expression of MAL in lymphomas, the hypermethylation of the MAL gene and subsequent loss of MAL expression in carcinomas are also presented. We propose a model of MAL as the organizer of specialized condensed membranes to make them functional, discuss the role of MAL as a tumor suppressor in carcinomas, consider its potential use as a cancer biomarker, and summarize the directions for future research.

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Section: Mal and The Clostridial Epsilon Toxinmentioning

confidence: 99%

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

Rubio-Ramos

Labat-de-Hoz

Correas

et al. 2021

Cells

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“…However, there is no absolute relationship between molecular weight and BBB penetration [ 36 ]. A recent study revealed that the epsilon toxin (ETX) can cross the BBB by binding to the lymphocyte protein (MAL) on the luminal surface of endothelial cells [ 37 ]. Thus, macromolecules with high molecular weights are also likely to cross the BBB in a unique way.…”

Section: Discussionmentioning

confidence: 99%

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

Wang

Lee

et al. 2023

Toxins

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Toxin-like proteins and peptides of skin secretions from amphibians play important physiological and pathological roles in amphibians. βγ-CAT is a Chinese red-belly toad-derived pore-forming toxin-like protein complex that consists of aerolysin domain, crystalline domain, and trefoil factor domain and induces various toxic effects via its membrane perforation process, including membrane binding, oligomerization, and endocytosis. Here, we observed the death of mouse hippocampal neuronal cells induced by βγ-CAT at a concentration of 5 nM. Subsequent studies showed that the death of hippocampal neuronal cells was accompanied by the activation of Gasdermin E and caspase-1, suggesting that βγ-CAT induces the pyroptosis of hippocampal neuronal cells. Further molecular mechanism studies revealed that the pyroptosis induced by βγ-CAT is dependent on the oligomerization and endocytosis of βγ-CAT. It is well known that the damage of hippocampal neuronal cells leads to the cognitive attenuation of animals. The impaired cognitive ability of mice was observed after intraperitoneal injection with 10 μg/kg βγ-CAT in a water maze assay. Taken together, these findings reveal a previously unknown toxicological function of a vertebrate-derived pore-forming toxin-like protein in the nerve system, which triggers the pyroptosis of hippocampal neuronal cells, ultimately leading to hippocampal cognitive attenuation.

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“…Several microbes may cause disruption of the integrity of the BBB. Specifically, the bacteria Clostridium perfinges produces Epsilon toxin, which increases BBB permeability in zebrafish [212]. Other bacteria such as Mycobacterium tuberculosis and Mycobacterium marinum can cross the BBB and reach the brain to cause infection [213].…”

Section: Microbial Infectionmentioning

confidence: 99%

Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers

Dunton

Göpel

et al. 2021

IJMS

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The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited ‘scala naturae’ approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research.

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

Cited by 14 publications

References 86 publications

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers

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