@entity3168 epsilon toxin (  -toxin) is responsible for a devastating multifocal central nervous system (CNS) @entity62 in ruminant animals. The mechanism by which   -toxin causes white matter damage is poorly understood. In this study, we sought to determine the molecular and cellular mechanisms by which   -toxin causes pathological changes to white matter. In primary CNS cultures,   -toxin binds to and kills oligodendrocytes but not astrocytes, microglia, or neurons. In cerebellar organotypic culture,   -toxin induces @entity17 , which occurs in a time- and dose-dependent manner, while preserving neurons, astrocytes, and microglia.   -Toxin specificity for oligodendrocytes was confirmed using enriched glial culture. Sensitivity to   -toxin is developmentally regulated, as only mature oligodendrocytes are susceptible to   -toxin; oligodendrocyte progenitor cells are not.   -Toxin sensitivity is also dependent on oligodendrocyte expression of the proteolipid myelin and lymphocyte protein (MAL), as @entity17 oligodendrocytes are insensitive to   -toxin. In addition,   -toxin binding to white matter follows the spatial and temporal pattern of MAL expression. A neutralizing antibody against   -toxin inhibits @entity204 and @entity17 . This study provides several novel insights into the action of   -toxin in the CNS. (i)   -Toxin causes selective @entity204 while preserving all other neural elements. (ii)   -Toxin-mediated @entity204 is a cell autonomous effect. (iii) The effects of   -toxin on the oligodendrocyte lineage are restricted to mature oligodendrocytes. (iv) Expression of the developmentally regulated proteolipid MAL is required for the cytotoxic effects. (v) The cytotoxic effects of   -toxin can be abrogated by an   -toxin neutralizing antibody. IMPORTANCE: Our intestinal tract is host to trillions of microorganisms that play an essential role in health and homeostasis. Disruption of this symbiotic relationship has been implicated in influencing or causing disease in distant organ systems such as the brain. Epsilon toxin (  -toxin)-carrying @entity3168 strains are responsible for a devastating @entity62 in ruminant animals that shares similar features with @entity1 @entity15 . In this report, we define the mechanism by which   -toxin causes @entity62 . We find that   -toxin specifically targets the myelin-forming cells of the central nervous system (CNS), oligodendrocytes, leading to cell death. The selectivity of   -toxin for oligodendrocytes is remarkable, as other cells of the CNS are unaffected. Importantly,   -toxin-induced @entity204 results in @entity17 and is dependent on expression of myelin and lymphocyte protein (MAL). These results help complete the mechanistic pathway from bacteria to brain by explaining the specific cellular target of   -toxin within the CNS.

XXXX Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central @entity17 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity17 :: ('MESH:D003711', 'Disease') :: ['demyelination', 'MAL-deficient'] @entity3168 :: ('1502', 'Species') :: ['Clostridium perfringens'] @entity62 :: ('MESH:D056784', 'Disease') :: ['white matter disease'] @entity204 :: ('MESH:D003643', 'Disease') :: ['oligodendrocyte death'] @entity15 :: ('MESH:D009103', 'Disease') :: ['multiple sclerosis']
@entity3168 :: (1502,Species) :: ['Clostridium perfringens']
