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 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.

Molecular characterization of a rabies virus isolated from trade dogs in Plateau State, Nigeria

“…G is the only viral protein exposed on the surface of the virion and plays an essential role in RABV pathogenicity (Lentz et al, 1983;Thoulouze et al, 1998). DRV-NG11 was shown to be highly virulent and caused 100% percent mortality in experimental dogs after intramuscular administration in a lower dose (Gnanadurai et al, 2015). To identify the differences of functional regions between DRV-NG11 and attenuated RABVs, their G protein sequences were aligned.…”

Critical roles of chemokines and cytokines in antiviral innate immune responses during rabies virus infection

“…It has been known for a long time that more than 70% human rabies patients do not develop VNA in the periphery as well as in the cerebrospinal fluid (CSF) at any stage. The same phenomenon, that wt RABV fails to induce protective VNA, is also observed in other animal species, such as mice, dogs and skunks [24][25][26] .…”

“…On the other hand, laboratory-attenuated RABV replicates rapidly and produces a large amount of the glycoprotein and induces strong innate and adaptive immune responses, such as extensive inflammation and neuronal apoptosis, expression of cytokines and chemokines, BBB permeability enhancement and DC activation as well as high level of VNA production [18,24,[27][28][29][30][31][32] . Numerous comparative studies performed in laboratory animals have suggested that the wt RABV evades, while laboratory-attenuated the RABV actives, the host innate immune responses [16,17,23,24,26,33] .…”

Phosphoprotein Gene of Wild-Type Rabies Virus Plays a Role in Limiting Viral Pathogenicity and Lowering the Enhancement of BBB Permeability

“…Actually, we detected strongly elevated expression of cytokines and chemokines in mice brains infected with GD-SH-01 at 6 dpi, which indicated that the mice got fatal encephalitis, and the infected mice did not recover from rabies till it died at 12 dpi (Gnanadurai et al, 2015;Miao et al, 2017). However, the brains infected with rHEP-SH-P presented a relatively low level of T cells and cytokine expression from day 6 due to the less permeability of BBB.…”

“…Although no significant difference between rHEP-SH-P and GD-SH-01 was detected in cerebella BBB permeability changes at 9 dpi, GD-SH-01 caused great increase in BBB permeability in comparison with control. By 12 dpi, BBB permeability increase in both cerebra and cerebella of mice infected with GD-SH-01 continued to be enhanced (more than threefold increase of NaF uptake); at this time point, majority of mice infected with GD-SH-01 developed severe neurological signs or died owing to rabies (Figures 2A,B), indicating that BBB was destroyed when rabies reached the final stage (Gnanadurai et al, 2015;Miao et al, 2017). However, the BBB of the mice infected with HEP-Flury recovered generally from transient breakdown, and those infected with rHEP-SH-P kept relative integrity in the course of infection.…”