Timothy Vartanian

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 ß-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.  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.  Many questions remain unanswered and are ongoing projects in our lab discussed below.  Our ultimate goal is to prevent new MS disease activity by inhibiting toxin production or function. 

Colonization of the gut microbiome by C. perfringens types B or D.  We know that people with Multiple Sclerosis harbor epsilon toxin producing strains of C. perfringens, but we know very little about how the MS gut microbiome gets colonized by these pathogenic strains or what drives their growth.  Our lab is interested in understanding how the taxonomic and metabolic structure of the microbiome influences colonization by and growth of C. perfringens types B or D.  We are investigating how host genetics effect colonization?  We are working to determine what role exogenous factors such as antibiotic use and diet have in colonization and growth of C. perfringens types B and D. 

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.  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.  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.    

Role of epsilon toxin in oligodendrocyte death and demyelination.  When MS lesions initially form in the white matter, there is no significant inflammatory infiltrate.  Instead, this earliest stage of lesion evolution is characterized by blood-brain barrier permeability, early signs of injury to oligodendrocytes and their myelin, and early microglial activation.  In these nascent lesions oligodendrocyte show varying degrees of swelling and apoptosis, whereas myelin reveals swelling and pallor.  In dissociated and organotypic cultures, our lab was the first to show that epsilon toxin directly causes oligodendrocyte death and demyelination leaving other neural elements untouched.  How epsilon toxin induces oligodendrocyte and myelin injury is currently unknown and investigation into relevant mechanisms is an active project in our lab.    

Current Projects: