Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs

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 Findings

The 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/Significance

IM 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.

Author Summary

Remarkable advances have been made in elucidating the pathogenesis of rabies. One of the hallmarks of rabies infection is that human patients do not develop VNA. In this present study, 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. IM infection of dogs with TriGAS induced early activation of DCs and B cells in the blood, and production of VNA in the periphery, whereas, IT infection with TriGAS induced a high level of VNA not only in the serum but also in the CSF. On the contrary, infection of dogs with DRV-NG11 failed to elicit VNA. As a result, none of the dogs infected with wt DRV-NG11 survived. The ability of DRV-NG11 to replicate and spread without triggering an immune response to glycoprotein is evidently an important facet of its pathogenicity.