Modulatory effect of perforin gene dosage during pathogen associatated blood brain barrier (BBB) disruption

Abstract

Abstract Neuroinflammation is a putative mechanism of pathogen associated blood brain barrier (BBB) disruption. However, mechanisms of immune mediated vascular permeability remain an active topic of research. Our lab has defined a role for CD8 T cells and perforin in BBB tight junction protein alterations during neuroinflammation. Within the human population, perforin is highly polymorphic, the significance of which is unknown. Therefore, we investigated the capacity of T cells with a single perforin allele, which reduces perforin mRNA and protein expression by half, in modulating BBB disruption in a murine model. We also conducted a genetic analysis to determine the significance of perforin polymorphisms in humans. In vivo, we assessed perforin+/+, perforin+/− and perforin−/− mice using the peptide induced fatal syndrome (PIFS) model for CD8 T cell mediated BBB disruption. Using 3D volumetric analysis of gadolinium enhanced, T1 weighted MRI we determined that perforin alleles are additive in increasing BBB disruption. This finding was not the result of differing immune cell infiltration or virus load. In parallel, we conducted a population genetic analysis of the human perforin allele. Using the Exome Aggregation Consortium and primary literature, we categorized over 450 perforin polymorphisms. Perforin polymorphism rates directly correlated with equatorial distance and environmental pathogen richness. Therefore, our studies demonstrate a single perforin allele alters BBB disruption severity. We hypothesize that diversity at the human perforin allele is a form of inclusive fitness by contributing to differential susceptibility to pathogen associated CNS vascular permeability.