Blood-brain barrier leakage stems from interferon-induced breakdown of barrier properties during reovirus encephalitis
Stephanie Bonney1,2, Scott Seitz3,4, Caitlin A. Ryan1, Ken Jones5, Penny Clarke4, Kenneth L. Tyler4, Julie A. Siegenthaler1,6 1Department of Pediatrics Section of Developmental Biology, 2Cell Biology, Stem Cells and Development Graduate Program, 3Microbiology Graduate Program, 4Department of Neurology, 5Department of Pediatrics Section of Genetics, University of Colorado, School of Medicine
Blood-brain barrier (BBB) breakdown is a hallmark of many diseases in the central nervous system (CNS). A dysfunctional BBB during CNS diseases, like encephalitis, can result in loss of vascular support, rapid infiltration of immune cells and swelling of the brain that can exacerbate neuronal injury. However the mechanisms underlying BBB breakdown during encephalitis are not known. By utilizing a viral-induced encephalitis mouse model in which perinatal mice are exposed to reovirus we found that BBB leakage occurs at late stages of reovirus-induced encephalitis. The BBB leakage is associated with disorganization in vascular tight junctions and reductions in BBB support cells called pericytes. RNA-sequencing from sorted brain endothelial cells during reovirus infection identified activation of interferon (IFN) signaling within the brain vasculature. Our in vitro studies show that IFNγ is capable of reducing barrier properties in mouse brain endothelial cells most notably through cytoskeletal reorganizations. Neutralization of IFNγ during reovirus infection improved vascular morphology, BBB leakage, and pericyte coverage. Together our results suggest that IFNγ contributes to BBB dysfunction during reovirus infection in the CNS.
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