Date Published: August 20, 2015
Publisher: Public Library of Science
Author(s): Clement W. Gnanadurai, Yang Yang, Ying Huang, Zhenguang Li, Christina M. Leyson, Tanya L. Cooper, Simon R. Platt, Stephen B. Harvey, Douglas C. Hooper, Milosz Faber, Zhen F. Fu, Charles E Rupprecht. http://doi.org/10.1371/journal.pntd.0004023
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.
Partial Text: 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. Despite the advances in the development of rabies biologicals, rabies remains a public health threat, causing more than 55,000 human deaths every year around the globe . A hallmark of wild-type (wt) RABV is its unique ability to invade the central nervous system (CNS) from the peripheral inoculation/bite sites through the neuromuscular junction via motor or sensory neurons [2, 3].
Rabies is a highly lethal but preventable disease caused by the neurotropic RABV [38, 39]. RABV infects the CNS, causing fatal encephalitis and death . However, the mechanism of rabies pathogenesis is still not completely understood. For the past several years, remarkable advances have been made in elucidating the pathogenesis of rabies. Animals infected with wt-RABVs do not develop VNA, whereas attenuated RABVs induce high levels of VNA. In this present study, we compared the immune responses in dogs after infection with an attenuated TriGAS that is non-pathogenic in nature or a wt DRV-NG11 which is a highly pathogenic virus isolated from a rabid dog . Consistent with a previous report in mice , our study shows IM infection of TriGAS in dogs induced a high level of serum VNA. However, wt RABV infection in dogs did not induce any VNA production in the serum or CSF. Similarly, the inability of wt RABV to induce VNA responses has also been reported in other animal species such as mice  and skunks . Also, it is well known that rabies patients rarely develop rabies VNA . Furthermore, TriGAS infection in dogs induced antibodies against RABV including its G protein, whereas the DRV-NG11 infection induced anti-RABV antibodies but was neither significantly different from the TriGAS infected dogs nor from the uninfected controls. However, DRV-NG11 did not induce any antibodies against rabies G protein.