Clostridium perfringens epsilon toxin in Multiple Sclerosis

C. perfringens epsilon toxin is an extraordinary molecule possessing all the features of an environmental agent capable of initiating new lesion formation in multiple sclerosis (MS).  Epsilon toxin is a pore-forming toxin in the aerolysin family of b-pore-forming toxins and is produced by C. perfringens types B or D.  The primary cellular targets of epsilon toxin are CNS endothelial cells, oligodendrocytes/myelin, and T cells – three cell types that are center stage in MS pathogenesis.  Timothy Murrell first hypothesized that C. perfringens may play a role in MS pathogenesis published in 1986 in Medical Hypotheses.  Our lab was the first to show that people with MS are more likely than healthy individuals to be colonized by C. perfringens types B or D in the gut microbiome. The abundance of these strains in people with MS is unusually high relative to other, non-pathogenic C. perfringens strains.  We and others showed that people with MS have a higher frequency of circulating antibodies to epsilon toxin compared to healthy individuals.  The presence of epsilon toxin producing strains of C. perfringens in the MS gut microbiome, along with antibodies to epsilon toxin in blood, indicates a high rate of translation of epsilon toxin and its entry into circulation.  Many questions remain unanswered.  What makes people with MS susceptible to colonization by C. perfringens types B or D?  What factors influences growth of these strains and accompanying epsilon toxin production?  How does epsilon toxin cross the gut epithelium and enter the bloodstream?  What levels of epsilon toxin in blood are required to cause new lesion formation.  Most of all, can new MS disease activity be prevented by targeting epsilon toxin?  These and other questions are actively being investigated in our lab.

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Function of epsilon and other bacterial toxins on immune privilege at CNS barriers 

Three major barriers function to maintain CNS homeostasis: the blood-brain, blood-CSF, and blood-meningeal barriers.  These barriers markedly restrict transport of ions, small molecules, macromolecules, and leukocytes into the CNS to maintain a milieu suitable for neuronal function.  Our lab was the first to show that blood borne epsilon toxin selectively binds to the luminal surface of CNS endothelial cells but not to endothelial cells comprising the vascular beds of other organ systems – this accounts, in part, for the neurotropism of epsilon toxin.  Epsilon toxin induces blood-brain barrier dysfunction, which has multiple consequences.  Others and we showed that epsilon toxin induces permeability of the blood-brain barrier to molecules such as immunoglobulins.  A central function of CNS barriers is to maintain immune privilege and our lab was the first to show that epsilon toxin is sufficient to overcome CNS immune privilege in the context of activated myelin autoreactive lymphocytes.  The mechanism by which epsilon toxin and other bacterial toxins function to overcome CNS immune privilege is an ongoing project in our lab.