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

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          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.

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          Most cited references44

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          Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system.

          Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-alpha/beta) signaling pathways and inflammatory chemokines. For the IFN-alpha/beta signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2'-5'-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.
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            Concepts in the pathogenesis of rabies.

            Rabies is a zoonotic disease that remains an important public health problem worldwide and causes more than 70,000 human deaths each year. The causative agent of rabies is rabies virus (RV), a negative-stranded RNA virus of the rhabdovirus family. Neuroinvasiveness and neurotropism are the main features that define the pathogenesis of rabies. Although RV pathogenicity is a multigenic trait involving several elements of the RV genome, the RV glycoprotein plays a major role in RV pathogenesis by controlling the rate of virus uptake and trans-synaptic virus spread, and by regulating the rate of virus replication. Pathogenic street RV strains differ significantly from tissue culture-adapted RV strains in their neuroinvasiveness. Whereas street RV strains are highly neuroinvasive, most tissue culture-adapted RV strains have either no or only limited ability to invade the CNS from a peripheral site. The high neuroinvasiveness of pathogenic street RVs is, at least in part, due to their ability to evade immune responses and to conserve the structures of neurons. The finding that tissue culture-adapted RV strains replicate very fast and induce strong innate and adaptive immune responses opens new avenues for therapeutic intervention against rabies.
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              WHO Expert Consultation on rabies.

              (2004)
              More than 99% of all human rabies deaths occur in the developing world, and although effective and economical control measures are available, the disease has not been brought under control throughout most of the affected countries. Given that a major factor in the low level of commitment to rabies control is a lack of accurate data on the true public health impact of the disease, this report of a WHO Expert Consultation begins by providing new data on the estimated burden of the disease and its distribution in the world. It also reviews recent progress in the classification of rabies viruses, rabies pathogenesis and diagnosis, rabies pre- and post-exposure prophylaxis, the management of rabies patients, and canine as well as wildlife rabies prevention and control. Considering the emergence of new lyssaviruses and changes in animal and human rabies epidemiology observed on different continents, the definition of a rabies-free country or area has been revised to assist public health authorities in better assessing the risk of human rabies resulting from contact with animals. Measures aiming at preventing the spread of rabies through the international transfer of animals, mainly with regard to pets, are discussed as well as the new systems in place within and outside WHO to share rabies data and information. As certain tools currently used in rabies prevention and control, such as biologicals, tests for intra vitam and postmortem diagnosis, vaccines and immunoglobulin quality control, need improvement, the report ends by outlining the priorities for basic research, as well as those for operational research for sustainable canine rabies control, including dog population management schemes complying with animal welfare principles. Such operational research is necessary for removing or alleviating the main constraints to rabies control in dogs, as these are the source of most human rabies cases worldwide.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                20 August 2015
                August 2015
                : 9
                : 8
                : e0004023
                Affiliations
                [1 ]Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America
                [2 ]State-key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
                [3 ]Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America
                [4 ]Small Medicine & Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America
                [5 ]Department of Cancer Biology and Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
                The Global Alliance for Rabies Control, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CWG YY YH ZFF. Performed the experiments: CWG YY YH ZL CML TLC. Analyzed the data: CWG YY YH. Contributed reagents/materials/analysis tools: TLC DCH MF. Wrote the paper: CWG YY YH SRP SBH DCH ZFF.

                Article
                PNTD-D-15-00858
                10.1371/journal.pntd.0004023
                4546273
                26292099
                17246115-220b-407b-ae58-d1a90cc600be
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 19 May 2015
                : 31 July 2015
                Page count
                Figures: 5, Tables: 0, Pages: 15
                Funding
                This work was supported by grants AI-051560 and AI-093369, National Institute of Health (NIH), USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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