BackgroundRabies is known to be lethal in human. Treatment with passive immunity for the rabies is effective only when the patients have not shown the central nerve system (CNS) signs. The blood–brain barrier (BBB) is a complex functional barrier that may compromise the therapeutic development in neurological diseases. The goal of this study is to determine the change of BBB integrity and to assess the therapeutic possibility of enhancing BBB permeability combined with passive immunity in the late stage of rabies virus infection.MethodsThe integrity of BBB permeability in rats was measured by quantitative ELISA for total IgG and albumin levels in the cerebrospinal fluid (CSF) and by exogenously applying Evans blue as a tracer. Western blotting of occludin and ZO-1, two tight junction proteins, was used to assess the molecular change of BBB structure.The breakdown of BBB with hypertonic arabinose, recombinant tumor necrosis factor-alpha (rTNF-γ), and focused ultrasound (FUS) were used to compare the extent of BBB disruption with rabies virus infection. Specific humoral immunity was analyzed by immunofluorescent assay and rapid fluorescent focus inhibition test. Virus-neutralizing monoclonal antibody (mAb) 8-10E was administered to rats with hypertonic breakdown of BBB as a passive immunotherapy to prevent the death from rabies.ResultsThe BBB permeability was altered on day 7 post-infection. Increased BBB permeability induced by rabies virus infection was observed primarily in the cerebellum and spinal cord. Occludin was significantly decreased in both the cerebral cortex and cerebellum. The rabies virus-specific antibody was not strongly elicited even in the presence of clinical signs. Disruption of BBB had no direct association with the lethal outcome of rabies. Passive immunotherapy with virus-neutralizing mAb 8-10E with the hypertonic breakdown of BBB prolonged the survival of rabies virus-infected rats.ConclusionsWe demonstrated that the BBB permeability was altered in a rat model with rabies virus inoculation. Delivery of neutralizing mAb to the infected site in brain combined with effective breakdown of BBB could be an aggressive but feasible therapeutic mode in rabies when the CNS infection has been established.
Rodent parvoviruses are among the most prevalent infectious agents in laboratory rodents and have been shown to interfere with in vivo and in vitro research. A newly recognized rat parvovirus (RPV) that is distinct from the prototypic RPV was recently identified in naturally infected laboratory rats in Taiwan. Nucleotide and amino acid sequence comparisons showed that this newly identified variant of RPV is most closely related to rat parvovirus type 1a (RPV-1a) and type 1b (RPV-1b) and is distinctly different from type UT (RPV/UT) and other rodent parvoviruses. This variant was designated rat parvovirus type National Taiwan University 1 (RPV-NTU1). Phylogenetic and sequence analyses revealed that RPV-NTU1 contains conserved open reading frames with an overall genome organization similar to known RPV-1. RPV-NTU1 is the second RPV-1 variant whose full-length molecular characterization has been performed.
Rodent parvovirus infection is one of the common viral problems in laboratory rodent colonies. In this study, two new parvoviruses were identified in naturally-infected rats from two different research colonies in Taiwan. The genomic nucleotide sequences and the predicted amino acid sequences of proteins for these two viruses were compared to the previously characterized rodent parvoviruses. The two newly identified viruses were most closely related to each other, also closely related to two variants of rat minute virus (RMV; RMV-1 and RMV-2), and distinct from but closely related to Kilham rat virus and H-1 virus. These two viruses were significantly different from variants of rat parvovirus (RPV; RPV-1 and RPV-NTU1). Phylogenetic data also supported that these two new viruses are variants of the RMV species. These two newly identified viruses were designated RMV type National Taiwan University 1 (RMV-NTU1) and RMV type National Taiwan University 2 (RMV-NTU2). RMV-NTUs are the first molecularly characterized RMV variants identified in Asia.
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