Regional Differences in Blood-Brain Barrier Permeability Changes and Inflammation in the Apathogenic Clearance of Virus from the Central Nervous System

Abstract

The loss of blood-brain barrier (BBB) integrity in CNS inflammatory responses triggered by infection and autoimmunity has generally been associated with the development of neurological signs. In the present study, we demonstrate that the clearance of the attenuated rabies virus CVS-F3 from the CNS is an exception; increased BBB permeability and CNS inflammation occurs in the absence of neurological sequelae. We speculate that regionalization of the CNS inflammatory response contributes to its lack of pathogenicity. Despite virus replication and the expression of several chemokines and IL-6 in both regions being similar, the up-regulation of MIP-1β, TNF-α, IFN-γ, and ICAM-1 and the loss of BBB integrity was more extensive in the cerebellum than in the cerebral cortex. The accumulation of CD4- and CD19-positive cells was higher in the cerebellum than the cerebral cortex. Elevated CD19 levels were paralleled by κ-L chain expression levels. The timing of BBB permeability changes, κ-L chain expression in CNS tissues, and Ab production in the periphery suggest that the in situ production of virus-neutralizing Ab may be more important in virus clearance than the infiltration of circulating Ab. The data indicate that, with the possible exception of CD8 T cells, the effectors of rabies virus clearance are more commonly targeted to the cerebellum. This is likely the result of differences in the capacity of the tissues of the cerebellum and cerebral cortex to mediate the events required for BBB permeability changes and cell invasion during virus infection.

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

“…Our experiments are consistent with a previous hypothesis that heterogeneity in clearance of alphavirus infection in the CNS might be due to varying abilities of neurons to respond to T cell cytokines (9). Moreover, the experiments provide a functional significance for the differences in chemokine expression and effector cell trafficking that was observed in the cerebella of animals infected with an attenuated rabies virus (27). As CXCL10 expression is variably induced by IFN-␥ and TNF-␣ (69), and neurons may express Th1 cytokines or their receptors (70 -75), the requirement of CXCR3 for effector T cell function within the cerebellum may reflect differential responses of cerebellar neurons to particular viruses.…”

“…Although targeted deletion of CXCR3 or CXCL10 is associated with a reduction in infiltrating mononuclear cells and enhanced mortality from infection of the CNS with mouse hepatitis virus (MHV) 3 (25,26), few studies have examined regional differences in the expression of chemokine ligands during viral encephalitis. Intranasal infection of an attenuated rabies virus resulted in CCL3 levels that were higher in the cortex, and CCL2, CCL4, and CXCL10 levels that were higher in the cerebellum (27). This was associated with higher levels of CD8 mRNAs in the cortex and higher levels of CD4, CD11b, and CD19 mRNAs in the cerebellum, suggesting that region-specific patterns of chemokine expression may direct the differential trafficking of leukocyte subsets.…”

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

“…To estimate the extent of cell infiltration into CNS tissues, the levels of mRNAs specific for the T cell markers CD4 and CD8, as well as the monocyte marker CD11b (Mac-1, integrin-␣ M chain), were determined by real-time quantitative RT-PCR with primers and probes as described in ref. 6. In brief, spinal tissues were collected from transcardially perfused mice at 19-20 days postimmunization and used for RNA isolation with TRIzol B (Life Technologies) and DNA-free agent (Ambion, Austin, TX) or snap-frozen for sections.…”

“…The BBB is a major contributor to the maintenance of the CNS homeostasis by regulating soluble factor and cellular exchange between the CNS and the blood (2), and the loss of BBB integrity has been associated with several neurological diseases such as MS, EAE, ischemic stroke, traumatic brain injury, and others (3)(4)(5). However, enhanced BBB permeability is also associated in mice with the therapeutic clearance of neurotropic virus (6), indicating that the loss of BBB integrity is unlikely to be the sole determinant of pathogenesis in EAE and possibly MS.…”

Efficiency of live attenuated and inactivated rabies viruses in prophylactic and post exposure vaccination against the street virus strain

“…Twenty bp DNA ladder (TaKaRa, Japan) was employed as marker. Assay of blood brain barrier permeability was carried out by a modification of a previously described technique, in which a low molecular weight fluorescent marker (fluorescein of MW 376) was used as tracer (Phares et al, 2006;Fabis et al, 2008;. Briefly, mice were injected with 100 µl of 100 mg/ml Na-fluorescein under anesthesia via intravenous route.…”