Blood brain barrier (BBB) disruption is an integral feature of neurological diseases as diverse as multiple sclerosis, acute hemorrhagic leukoencephalitis (AHLE), traumatic brain injury, stroke, cerebral malaria, viral hemorrhagic fevers, epilepsy, glioblastoma, alzheimer's disease, and HIV dementia. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. This lack of understanding currently undermines therapeutic approaches to treat neurological disease in which uncontrolled BBB disruption contributes to pathology. My research program was the first to demonstrate that CD8 T cells have the capacity to disrupt BBB tight junctions using a novel murine model. Using this model, we have developed a tractable approach to dissect immune-mediated mechanisms of vascular endothelial growth factor (VEGF) mediated BBB disruption using a variation of Theiler's Murine Encephalomyelitis Virus (TMEV) and the Plasmodium berghei ANKA (PbA) model systems. Our central hypothesis is CD8 T cells promote neuronal expression of VEGF which results in disruption of cerebral endothelial cell tight junctions and vascular permeability. We will test our central hypothesis through the following aims:
Specific Aim #1 ? Determine the extent direct engagement of antigen specific CD8 T cells with neurons promotes VEGF expression and ensuing vascular changes.
Specific Aim #2 ? Determine the extent neuronal expression of VEGF and its receptors contribute to CD8 T cell-initiated BBB disruption.
Specific Aim #3 ? Evaluate the contribution of neuronal VEGF to CD8 T cell-mediated BBB disruption in the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria. To our knowledge, no other laboratories have a similar mouse as PIFS that capitalizes on readily inducible acute CNS vascular permeability mediated by a well-defined immune cell type. Confirming the existence of homologous inflammatory mechanisms in humans would be the first step toward therapeutic intervention of neurological diseases in which neuroinflammation induced CNS vascular permeability plays a significant part. To accomplish these aims, we will employ: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy and immunohistochemistry, (d) 2-photon intravital microscopy (e) protein biochemistry, and (f) small mammal MRI.

Public Health Relevance

Blood brain barrier (BBB) disruption is a common feature of numerous neurological diseases as diverse as multiple sclerosis, HIV dementia, epilepsy, multiple sclerosis, stroke, cerebral malaria, and viral hemorrhagic fevers. However, the contribution of immune cells and relevant chemical messengers that contribute to BBB disruption remain largely undefined. In this proposal, we will evaluate the contribution of CD8 T cells and neuronal expressed vascular endothelial growth factor (VEGF) on BBB disruption in vivo using our novel Peptide Induced Fatal Syndrome (PIFS) and the Plasmodium berghei ANKA (PbA) model systems.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bosetti, Francesca
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Mayo Clinic, Rochester
United States
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Willenbring, Robin C; Ikeda, Yasuhiro; Pease, Larry R et al. (2018) Human perforin gene variation is geographically distributed. Mol Genet Genomic Med 6:44-55
Malo, Courtney S; Huggins, Matthew A; Goddery, Emma N et al. (2018) Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses. Nat Commun 9:633
Willenbring, Robin C; Johnson, Aaron J (2017) Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease. Int J Mol Sci 18: