Abstract
Rabies virus (RABV) induces encephalomyelitis in humans and animals. One of the major problems with rabies is that the infected individuals most often do not develop virus neutralizing antibodies (VNA). In this study we have investigated the host immune response to RABV infection in dogs, using a live-attenuated (TriGAS) or a wild-type (wt) (DRV-NG11) RABV isolated from a rabid dog.Methodology/Principal FindingsThe experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS.Conclusions/SignificanceIM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs.
Highlights
Rabies is a neurological disease in humans and other warm-blooded animals caused by rabies virus (RABV)
Immune responses were investigated in dogs after infection with a highly attenuated RABV (TriGAS) or a highly pathogenic, truly wt RABV (DRV-NG11)
DRV-NG11 was isolated from the brain of a rabid dog and has not been passaged in laboratory animals or in cell culture
Summary
Rabies is a neurological disease in humans and other warm-blooded animals caused by rabies virus (RABV) It is transmitted by animal bites or scratches. One of the mechanisms that contribute to rabies immune evasion and pathogenesis, is the low level of viral replication and subsequent preservation of neuronal structures by minimal viral antigen exposure to the host immune system [6]. It has been known for a long time that most of the human rabies patients (>70%) do not develop virus neutralizing antibodies (VNA) prior to or at the time of death [7]. Most of the wt or pathogenic RABVs used in these studies were at least passaged or amplified in suckling mouse brain, which might alter their phenotypes [14, 15]
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