Breakdown of the Blood-Brain Barrier during Tick-Borne Encephalitis in Mice Is Not Dependent on CD8+ T-Cells

Abstract

Tick-borne encephalitis (TBE) virus causes severe encephalitis with serious sequelae in humans. The disease is characterized by fever and debilitating encephalitis that can progress to chronic illness or fatal infection. In this study, changes in permeability of the blood-brain barrier (BBB) in two susceptible animal models (BALB/c, and C57Bl/6 mice) infected with TBE virus were investigated at various days after infection by measuring fluorescence in brain homogenates after intraperitoneal injection of sodium fluorescein, a compound that is normally excluded from the central nervous system. We demonstrate here that TBE virus infection, in addition to causing fatal encephalitis in mice, induces considerable breakdown of the BBB. The permeability of the BBB increased at later stages of TBE infection when high virus load was present in the brain (i.e., BBB breakdown was not necessary for TBE virus entry into the brain), and at the onset of the first severe clinical symptoms of the disease, which included neurological signs associated with sharp declines in body weight and temperature. The increased BBB permeability was in association with dramatic upregulation of proinflammatory cytokine/chemokine mRNA expression in the brain. Breakdown of the BBB was also observed in mice deficient in CD8+ T-cells, indicating that these cells are not necessary for the increase in BBB permeability that occurs during TBE. These novel findings are highly relevant to the development of future therapies designed to control this important human infectious disease.

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

“…There is circumstantial evidence that astrocytes contribute to the second wave of WNV neuroinvasion through the upregulation of MMPs, which disrupt the BBB, and proinflammatory cytokines, which recruit infected leukocytes (5,41,52,53). Indeed, propagation within astrocytes, neurons, and glial cells prior to the breakdown of the BBB is believed to be a common strategy of neuroinvasive viruses, including tick-borne encephalitis virus and HIV, to enhance dissemination within the CNS (54,55). Therefore, the inability of WNV-MAD78 to replicate in astrocytes may limit the capacity of the virus to undergo a second round of entry into the CNS (32,33).…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…In a model of WNV infection using insect cell-derived WNV, BBB disruption coincided with peripheral infection and preceded CNS entry [152,157]. However, recent studies using mice infected with JEV [151], WNV [158,159], and tick-borne encephalitis virus (TBEV) [160] have demonstrated that CNS entry of virus can occur before BBB disruption. Paracellular entry under these conditions may contribute to a second phase of CNS infection.…”

Tick-Borne Encephalitis Virus: A General Overview

“…The increased BBB permeability is in association with dramatic upregulation of proinflammatory cytokine/chemokine mRNA expression in the brain. Breakdown of the BBB can be also observed in mice deficient in CD8 + T-cells, indicating, that these cells are not necessary for the increase in BBB permeability that occurs during TBE (Růžek et al, 2011).…”