|
1
|
Kiflu AB. The Immune Escape Strategy of Rabies Virus and Its Pathogenicity Mechanisms. Viruses 2024; 16:1774. [PMID: 39599888 PMCID: PMC11598914 DOI: 10.3390/v16111774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/01/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences in the immune responses to laboratory-attenuated RABV and wild-type rabies virus infections. Various investigations showed that whilst laboratory-attenuated RABV elicits an innate immune response, wild-type RABV evades detection. Pathogenic RABV infection bypasses immune response by antagonizing interferon induction, which prevents downstream signal activation and impairs antiviral proteins and inflammatory cytokines production that could eliminate the virus. On the contrary, non-pathogenic RABV infection leads to immune activation and suppresses the disease. Apart from that, through recruiting leukocytes into the central nervous system (CNS) and enhancing the blood-brain barrier (BBB) permeability, which are vital factors for viral clearance and protection, cytokines/chemokines released during RABV infection play a critical role in suppressing the disease. Furthermore, early apoptosis of neural cells limit replication and spread of avirulent RABV infection, but street RABV strains infection cause delayed apoptosis that help them spread further to healthy cells and circumvent early immune exposure. Similarly, a cellular regulation mechanism called autophagy eliminates unused or damaged cytoplasmic materials and destroy microbes by delivering them to the lysosomes as part of a nonspecific immune defense mechanism. Infection with laboratory fixed RABV strains lead to complete autophagy and the viruses are eliminated. But incomplete autophagy during pathogenic RABV infection failed to destroy the viruses and might aid the virus in dodging detection by antigen-presenting cells, which could otherwise elicit adaptive immune activation. Pathogenic RABV P and M proteins, as well as high concentration of nitric oxide, which is produced during rabies virus infection, inhibits activities of mitochondrial proteins, which triggers the generation of reactive oxygen species, resulting in oxidative stress, contributing to mitochondrial malfunction and, finally, neuron process degeneration.
Collapse
Affiliation(s)
- Abraha Bahlbi Kiflu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530004, China;
- College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, China
| |
Collapse
|
|
2
|
Ben Hamed S, Myers JF, Chandwani A, Wirblich C, Kurup D, Paran N, Schnell MJ. Toward the Development of a Pan-Lyssavirus Vaccine. Viruses 2024; 16:1107. [PMID: 39066269 PMCID: PMC11281706 DOI: 10.3390/v16071107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/24/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
In addition to the rabies virus (RABV), 16 more lyssavirus species have been identified worldwide, causing a disease similar to RABV. Non-rabies-related human deaths have been described, but the number of cases is unknown, and the potential of such lyssaviruses causing human disease is unpredictable. The current rabies vaccine does not protect against divergent lyssaviruses such as Mokola virus (MOKV) or Lagos bat virus (LBV). Thus, a more broad pan-lyssavirus vaccine is needed. Here, we evaluate a novel lyssavirus vaccine with an attenuated RABV vector harboring a chimeric RABV glycoprotein (G) in which the antigenic site I of MOKV replaces the authentic site of rabies virus (RABVG-cAS1). The recombinant vaccine was utilized to immunize mice and analyze the immune response compared to homologous vaccines. Our findings indicate that the vaccine RABVG-cAS1 was immunogenic and induced high antibody titers against both RABVG and MOKVG. Challenge studies with different lyssaviruses showed that replacing a single antigenic site of RABV G with the corresponding site of MOKV G provides a significant improvement over the homologous RABV vaccine and protects against RABV, Irkut virus (IRKV), and MOKV. This strategy of epitope chimerization paves the way towards a pan-lyssavirus vaccine to safely combat the diseases caused by these viruses.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Matthias J. Schnell
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA (N.P.)
| |
Collapse
|
|
3
|
Perraud V, Vanderhoydonck B, Bouvier G, Dias de Melo G, Kilonda A, Koukni M, Jochmans D, Rogée S, Ben Khalifa Y, Kergoat L, Lannoy J, Van Buyten T, Izadi-Pruneyre N, Chaltin P, Neyts J, Marchand A, Larrous F, Bourhy H. Mechanism of action of phthalazinone derivatives against rabies virus. Antiviral Res 2024; 224:105838. [PMID: 38373533 DOI: 10.1016/j.antiviral.2024.105838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 02/21/2024]
Abstract
Rabies, a viral zoonosis, is responsible for almost 59,000 deaths each year, despite the existence of an effective post-exposure prophylaxis. Indeed, rabies causes acute encephalomyelitis, with a case-fatality rate of 100 % after the onset of neurological clinical signs. Therefore, the development of therapies to inhibit the rabies virus (RABV) is crucial. Here, we identified, from a 30,000 compound library screening, phthalazinone derivative compounds as potent inhibitors of RABV infection and more broadly of Lyssavirus and even Mononegavirales infections. Combining in vitro experiments, structural modelling, in silico docking and in vivo assays, we demonstrated that phthalazinone derivatives display a strong inhibition of lyssaviruses infection by acting directly on the replication complex of the virus, and with noticeable effects in delaying the onset of the clinical signs in our mouse model.
Collapse
Affiliation(s)
- Victoire Perraud
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | - Bart Vanderhoydonck
- Center for Innovation and Stimulation of Drug Discovery (Cistim) Leuven, Belgium
| | - Guillaume Bouvier
- Institut Pasteur, Université Paris Cité, CNRS UMR3528, Structural Bioinformatics Unit, F-75015, Paris, France
| | - Guilherme Dias de Melo
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | - Amuri Kilonda
- Center for Innovation and Stimulation of Drug Discovery (Cistim) Leuven, Belgium
| | - Mohamed Koukni
- Center for Innovation and Stimulation of Drug Discovery (Cistim) Leuven, Belgium
| | | | - Sophie Rogée
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | - Youcef Ben Khalifa
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | - Lauriane Kergoat
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | - Julien Lannoy
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France
| | | | - Nadia Izadi-Pruneyre
- Institut Pasteur, Université Paris Cité, CNRS UMR3528, Bacterial Transmembrane Systems Unit, F-75015, Paris, France
| | - Patrick Chaltin
- Center for Innovation and Stimulation of Drug Discovery (Cistim) Leuven, Belgium; Centre for Drug Design and Discovery (CD3), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Johan Neyts
- Katholieke Universiteit Leuven, Leuven, Belgium
| | - Arnaud Marchand
- Center for Innovation and Stimulation of Drug Discovery (Cistim) Leuven, Belgium
| | - Florence Larrous
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France.
| | - Hervé Bourhy
- Institut Pasteur, Université Paris Cité, Unité Lyssavirus, Epidémiologie et Neuropathologie, WHO Collaborating Centre for Reference and Research on Rabies, F-75015, Paris, France.
| |
Collapse
|
|
4
|
Lacy M, Phasuk N, Scholand SJ. Human Rabies Treatment-From Palliation to Promise. Viruses 2024; 16:160. [PMID: 38275970 PMCID: PMC10819634 DOI: 10.3390/v16010160] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/19/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Rabies encephalitis has plagued humankind for thousands of years. In developed countries, access to preventive care, both pre-exposure and post-exposure, has significantly reduced the burden of suffering and disease. However, around the world, rabies remains a neglected tropical disease, largely due to uncontrolled dog rabies, and tens of thousands perish each year. Currently, the standard of care for management of rabies encephalitis is palliation. Heroic attempts to treat human rabies patients over the last few decades have yielded glimpses into our understanding of pathophysiology, opening the door to the development of new antiviral therapies and modalities of treatment. Researchers continue to investigate new compounds and approaches to therapy, yet there remain real challenges given the complexity of the disease. We explore and review some of the promising therapies on the horizon in pursuit of a salvage treatment for rabies.
Collapse
Affiliation(s)
- Marian Lacy
- College of Medicine, University of Arizona, Tucson, AZ 85721, USA;
| | - Nonthapan Phasuk
- School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand;
| | | |
Collapse
|
|
5
|
Bai Y, Yu EY, Liu Y, Jin H, Liu X, Wu X, Zhang M, Feng N, Huang P, Zhang H, Kwok RTK, Xia X, Li Y, Tang BZ, Wang H. Molecular Engineering of AIE Photosensitizers for Inactivation of Rabies Virus. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2303542. [PMID: 37431212 DOI: 10.1002/smll.202303542] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/30/2023] [Indexed: 07/12/2023]
Abstract
Rabies is a zoonotic neurological disease caused by the rabies virus (RABV) that is fatal to humans and animals. While several post-infection treatment have been suggested, developing more efficient and innovative antiviral methods are necessary due to the limitations of current therapeutic approaches. To address this challenge, a strategy combining photodynamic therapy and immunotherapy, using a photosensitizer (TPA-Py-PhMe) with high type I and type II reactive oxygen species (ROS) generation ability is proposed. This approach can inactivate the RABV by killing the virus directly and activating the immune response. At the cellular level, TPA-Py-PhMe can reduce the virus titer under preinfection prophylaxis and postinfection treatment, with its antiviral effect mainly dependent on ROS and pro-inflammatory factors. Intriguingly, when mice are injected with TPA-Py-PhMe and exposed to white light irradiation at three days post-infection, the onset of disease is delayed, and survival rates improved to some extent. Overall, this study shows that photodynamic therapy and immunotherapy open new avenues for future antiviral research.
Collapse
Affiliation(s)
- Yujie Bai
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Eric Y Yu
- Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, China
| | - Yongsai Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Hongli Jin
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Xingqi Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Xiaoyu Wu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Mengyao Zhang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Na Feng
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China
| | - Pei Huang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Haili Zhang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Ryan T K Kwok
- Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, China
| | - Xianzhu Xia
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China
| | - Yuanyuan Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Ben Zhong Tang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Shenzhen, Guangdong, 518172, China
| | - Hualei Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| |
Collapse
|
|
6
|
Guo M, Xie S, Wang J, Zhang Y, He X, Luo P, Deng J, Zhou C, Qin J, Huang C, Zhang L. The difference in the composition of gut microbiota is greater among bats of different phylogenies than among those with different dietary habits. Front Microbiol 2023; 14:1207482. [PMID: 37577418 PMCID: PMC10419214 DOI: 10.3389/fmicb.2023.1207482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
Bats have a very long evolutionary history and are highly differentiated in their physiological functions. Results of recent studies suggest effects of some host factors (e.g., phylogeny and dietary habit) on their gut microbiota. In this study, we examined the gut microbial compositions of 18 different species of bats. Results showed that Firmicutes, Gammaproteobacteria, and Actinobacteria were dominant in all fecal samples of bats. However, the difference in the diversity of gut microbiota among bats of different phylogenies was notable (p = 0.06). Various species of Firmicutes, Actinobacteria, and Gammaproteobacteria were found to contribute to the majority of variations in gut microbiota of all bats examined, and Aeromonas species were much more abundant in bats that feed on both insects and fish than in those of insectivores. The abundance of various species of Clostridium, Euryarchaeota, and ancient bacterial phyla was found to vary among bats of different phylogenies, and various species of Vibrio varied significantly among bats with different dietary habits. No significant difference in the number of genes involved in various metabolic pathways was detected among bats of different phylogenies, but the abundance of genes involved in 5 metabolic pathways, including transcription; replication, recombination, and repair; amino acid transport and metabolism; and signal transduction mechanisms, was different among bats with different dietary habits. The abundance of genes in 3 metabolic pathways, including those involved in stilbenoid, diarylheptanoid, and gingerol biosynthesis, was found to be different between insectivorous bats and bats that feed on both insects and fish. Results of this study suggest a weak association between dietary habit and gut microbiota in most bats but a notable difference in gut microbiota among bats of different phylogenies.
Collapse
Affiliation(s)
- Min Guo
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Siwei Xie
- College of Mathematics and Informatics, South China Agricultural University, Guangzhou, China
| | - Junhua Wang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Yuzhi Zhang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xiangyang He
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Pengfei Luo
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jin Deng
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
- College of Life Sciences, South China Normal University, Guangzhou, China
| | - Chunhui Zhou
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jiao Qin
- Institute of Plant Protection, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Chen Huang
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
| | - Libiao Zhang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| |
Collapse
|
|
7
|
Motta GH, Guimarães LP, Fernandes ER, Guedes F, de Sá LRM, Dos Ramos Silva S, Ribeiro OG, Katz ISS. Rabies virus isolated from insectivorous bats induces different inflammatory responses in experimental model. J Neuroimmunol 2022; 373:577974. [PMID: 36270078 DOI: 10.1016/j.jneuroim.2022.577974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/18/2022] [Accepted: 09/28/2022] [Indexed: 01/12/2023]
Abstract
Rabies virus (RABV) is a neurotropic virus that causes fatal neuroinflammation in mammals. The insectivorous bat RABV strains are less pathogenic for mice than strains associated with other reservoirs. We characterized the tissue inflammatory response in the CNS of RABV isolated from insectivorous bats. Eptesicus furinalis (EPBRV)-infected mice had a robust inflammatory response and a greater amount of IL-1β, IL-6 and TNF-α, while Myotis nigricans (MNBRV)-infected mice showed a higher expression of IL-17 and greater activation of IFN-β. New approaches to understand the inflammatory response to different mechanisms of action may provide insights for the development of novel therapies for rabies.
Collapse
Affiliation(s)
| | | | | | - Fernanda Guedes
- Pasteur Institute, Av. Paulista 393, São Paulo CEP 01311-000, Brazil
| | | | | | - Orlando Garcia Ribeiro
- Laboratory of Immunogenetics, Butantan Institute, Av. Vital Brasil 1500, São Paulo CEP 05503-900, Brazil
| | | |
Collapse
|
|
8
|
Lab-Attenuated Rabies Virus Facilitates Opening of the Blood-Brain Barrier by Inducing Matrix Metallopeptidase 8. J Virol 2022; 96:e0105022. [PMID: 36005758 PMCID: PMC9472762 DOI: 10.1128/jvi.01050-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Infection with laboratory-attenuated rabies virus (RABV), but not wild-type (wt) RABV, can enhance the permeability of the blood-brain barrier (BBB), which is considered a key determinant for RABV pathogenicity. A previous study showed that the enhancement of BBB permeability is directly due not to RABV infection but to virus-induced inflammatory molecules. In this study, the effect of the matrix metallopeptidase (MMP) family on the permeability of the BBB during RABV infection was evaluated. We found that the expression level of MMP8 was upregulated in mice infected with lab-attenuated RABV but not with wt RABV. Lab-attenuated RABV rather than wt RABV activates inflammatory signaling pathways mediated by the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Activated NF-κB (p65) and AP-1 (c-Fos) bind to the MMP8 promoter, resulting in upregulation of its transcription. Analysis of mouse brains infected with the recombinant RABV expressing MMP8 indicated that MMP8 enhanced BBB permeability, leading to infiltration of inflammatory cells into the central nervous system (CNS). In brain-derived endothelial cells, treatment with MMP8 recombinant protein caused the degradation of tight junction (TJ) proteins, and the application of an MMP8 inhibitor inhibited the degradation of TJ proteins after RABV infection. Furthermore, an in vivo experiment using an MMP8 inhibitor during RABV infection demonstrated that BBB opening was diminished. In summary, our data suggest that the infection of lab-attenuated RABV enhances the BBB opening by upregulating MMP8. IMPORTANCE The ability to change BBB permeability was associated with the pathogenicity of RABV. BBB permeability was enhanced by infection with lab-attenuated RABV instead of wt RABV, allowing immune cells to infiltrate into the CNS. We found that MMP8 plays an important role in enhancing BBB permeability by degradation of TJ proteins during RABV infection. Using an MMP8 selective inhibitor restores the reduction of TJ proteins. We reveal that MMP8 is upregulated via the MAPK and NF-κB inflammatory pathways, activated by lab-attenuated RABV infection but not wt RABV. Our findings suggest that MMP8 has a critical role in modulating the opening of the BBB during RABV infection, which provides fresh insight into developing effective therapeutics for rabies and infection with other neurotropic viruses.
Collapse
|
|
9
|
Knobel DL, Jackson AC, Bingham J, Ertl HCJ, Gibson AD, Hughes D, Joubert K, Mani RS, Mohr BJ, Moore SM, Rivett-Carnac H, Tordo N, Yeates JW, Zambelli AB, Rupprecht CE. A One Medicine Mission for an Effective Rabies Therapy. Front Vet Sci 2022; 9:867382. [PMID: 35372555 PMCID: PMC8967983 DOI: 10.3389/fvets.2022.867382] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.
Collapse
Affiliation(s)
- Darryn L. Knobel
- Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre, Saint Kitts and Nevis
- Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
- Canine Rabies Treatment Initiative, Salt Rock, South Africa
| | - Alan C. Jackson
- Department of Medicine, Northern Consultation Centre, Thompson General Hospital, Thompson, MB, Canada
- Department of Medicine, Lake of the Woods District Hospital, Kenora, ON, Canada
| | - John Bingham
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Australian Animal Health Laboratory at the Australian Centre for Disease Preparedness, Geelong, VIC, Australia
| | | | - Andrew D. Gibson
- Division of Genetics and Genomics, Easter Bush Veterinary Centre, The Roslin Institute and the Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, United Kingdom
| | - Daniela Hughes
- Canine Rabies Treatment Initiative, Salt Rock, South Africa
| | - Kenneth Joubert
- Veterinary Anaesthesia, Analgesia and Critical Care Services, Lonehill, South Africa
| | - Reeta S. Mani
- Department of Neurovirology, WHO Collaborating Centre for Reference and Research in Rabies, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Bert J. Mohr
- Canine Rabies Treatment Initiative, Salt Rock, South Africa
- Centre for Animal Research, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
| | - Susan M. Moore
- Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, MO, United States
| | | | - Noël Tordo
- Institut Pasteur de Guinée, Conakry, Guinea
| | | | | | | |
Collapse
|
|
10
|
Feige L, Zaeck LM, Sehl-Ewert J, Finke S, Bourhy H. Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis. Viruses 2021; 13:2364. [PMID: 34960633 PMCID: PMC8708193 DOI: 10.3390/v13122364] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/19/2022] Open
Abstract
The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood-brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.
Collapse
Affiliation(s)
- Lena Feige
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
| | - Luca M. Zaeck
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Julia Sehl-Ewert
- Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany;
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Hervé Bourhy
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
| |
Collapse
|
|
11
|
Zhao P, Hou K, Zhong Z, Guo S, Yang S, Xia X. Quantitative characterization of the T cell receptor repertoires of human immunized by rabies virus vaccine. Hum Vaccin Immunother 2021; 17:2530-2537. [PMID: 33823121 PMCID: PMC8475554 DOI: 10.1080/21645515.2021.1893575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 02/03/2021] [Accepted: 02/16/2021] [Indexed: 02/05/2023] Open
Abstract
Cellular immunity is crucial for an efficient host immune response against rabies virus (RABV) infection. But the T cell receptor (TCR) repertoire in human after RABV vaccine immunization remained unclear. In this study, we conducted high-throughput sequencing of TCR β chain complementarity determining region 3(CDR3) repertoires in 4 healthy volunteers before and after immunization with RABV vaccine. Our data showed that RABV vaccination changed the TCR diversity and the usage of V/J gene segments, as well as V-J pairing. The high-frequency clonotypes that altered after vaccination were identified. These results may provide us with new insights into T cell receptor condition after RABV vaccination.
Collapse
Affiliation(s)
- Pingsen Zhao
- Department of Laboratory Medicine, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, China
- Shaoguan Municipal Quality Control Center for Laboratory Medicine, Yuebei People’s Hospital, Shaoguan, China
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, China
- CONTACT Pingsen Zhao ; Head & Professor, Department of Laboratory Medicine, Yuebei People’s Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan512025, P. R. China
| | - Kaijian Hou
- Department of Endocrine and Metabolic Diseases, Longhu Hospital, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Zhixiong Zhong
- Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, China
| | - Sharula Guo
- Department of Infection Control, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, China
| | - Songtao Yang
- Academy of Military Medical Sciences, Institute of Military Veterinary, Changchun, China
| | - Xianzhu Xia
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, China
- Academy of Military Medical Sciences, Institute of Military Veterinary, Changchun, China
| |
Collapse
|
|
12
|
Luo J, Zhang Y, Wang Y, Liu Q, Li J, He H, Luo Y, Huang S, Guo X. Artesunate and Dihydroartemisinin Inhibit Rabies Virus Replication. Virol Sin 2021; 36:721-729. [PMID: 33661488 PMCID: PMC7930525 DOI: 10.1007/s12250-021-00349-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/16/2020] [Indexed: 12/25/2022] Open
Abstract
Rabies is caused by infection of rabies virus (RABV) and remains a serious threat to the global public health. Except for the requirement for cold chain and high cost of human rabies immune globulin, no small molecule drugs are currently available for clinical treatment of rabies. So, it is of great importance to identify novel compounds that can effectively inhibit RABV infection. Artesunate (ART) and dihydroartemisinin (DHA), two derivatives of artemisinin, are widely used for treatment of malaria in adults and children, showing high safety. In this study, we found that both ART and DHA were able to inhibit RABV replication in host cells at a low concentration (0.1 μmol/L). The antiviral effects of ART and DHA were independent of viral strains and cell lines. Pre-treatment with ART or DHA for 2 h in vitro did not affect the viral replication in host cells, implying that ART and DHA neither reduced the viability of RABV directly nor inhibited the binding and entrance of the virus to host cells. Further studies revealed that ART and DHA inhibited RABV genomic RNA synthesis and viral gene transcription. Treatment with ART or DHA (5 mg/kg) by intramuscular injection improved, to some extent, the survival rate of RABV-challenged mice. Combination treatment with derivatives of artemisinin and mannitol significantly improved the survival rate of RABV-challenged mice. The results suggest that ART and DHA have a great potential to be explored as new anti-rabies agents for treatment of rabies.
Collapse
Affiliation(s)
- Jun Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yue Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yang Wang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Qing Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Jiesen Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Hongling He
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yongwen Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA. .,Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
| | - Xiaofeng Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
| |
Collapse
|
|
13
|
Lebrun A, Kean RB, Hooper DC. Brain tissue-resident immune memory cells are required for long-term protection against CNS infection with rabies virus. Future Virol 2020; 15:755-761. [PMID: 33343683 DOI: 10.2217/fvl-2020-0132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 11/17/2020] [Indexed: 12/25/2022]
Abstract
Immune memory cells residing in previously infected, nonlymphoid tissues play a role in immune surveillance. In the event that circulating antibodies fail to prevent virus spread to the tissues in a secondary infection, these memory cells provide an essential defense against tissue reinfection. CNS tissues are isolated from circulating immune cells and antibodies by the blood-brain barrier, making the presence of tissue-resident immune memory cells particularly needed to combat recurrent infection by neurotropic viruses. Wild-type and laboratory-engineered rabies viruses are neurotropic, differ in pathogenicity, and have varying effects on BBB functions. These viruses have proven invaluable tools in demonstrating the importance of tissue-resident immune memory cells in the reinfection of CNS tissues. Only Type 1 immune memory is effective at therapeutically clearing a secondary infection with wild-type rabies viruses from the CNS and does so despite the maintenance of blood-brain barrier integrity.
Collapse
Affiliation(s)
- Aurore Lebrun
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Rhonda B Kean
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - D Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
14
|
Luo J, Zhang B, Wu Y, Guo X. Amino Acid Mutation in Position 349 of Glycoprotein Affect the Pathogenicity of Rabies Virus. Front Microbiol 2020; 11:481. [PMID: 32308648 PMCID: PMC7145897 DOI: 10.3389/fmicb.2020.00481] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/05/2020] [Indexed: 12/25/2022] Open
Abstract
Rabies, caused by rabies virus (RABV), is a zoonotic disease infecting mammals including humans. Studies have confirmed that glycoprotein (G) is most related to RABV pathogenicity. In the present study, to discover more amino acid sites related to viral pathogenicity, artificial mutants have been constructed in G of virulent strain GD-SH-01 backbone. Results showed that pathogenicity of GD-SH-01 significantly decreased when Gly349 was replaced by Glu349 through in vivo assays. Gly349→Glu349 of G did not significantly influence viral growth and spread in NA cells. Gly349→Glu349 of G increased the immunogenicity of GD-SH-01 in periphery and induced more expression of interferon alpha (IFN-α) in the brain in mice. It was observed that Gly349→Glu349 of G led to enhanced blood–brain barrier (BBB) permeability at day 5 postinfection. All together, these data revealed that Gly349→Glu349 of G mutation decreased RABV pathogenicity through enhanced immune response and increased BBB permeability. This study provides a new referenced site G349 that could attenuate pathogenicity of RABV.
Collapse
Affiliation(s)
- Jun Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Boyue Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yuting Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Xiaofeng Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| |
Collapse
|
|
15
|
Long T, Zhang B, Fan R, Wu Y, Mo M, Luo J, Chang Y, Tian Q, Mei M, Jiang H, Luo Y, Guo X. Phosphoprotein Gene of Wild-Type Rabies Virus Plays a Role in Limiting Viral Pathogenicity and Lowering the Enhancement of BBB Permeability. Front Microbiol 2020; 11:109. [PMID: 32153520 PMCID: PMC7045047 DOI: 10.3389/fmicb.2020.00109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/17/2020] [Indexed: 12/14/2022] Open
Abstract
Enhancement of blood–brain barrier (BBB) permeability is necessary for clearing virus in the central nervous system (CNS). It has been reported that only laboratory-attenuated rabies virus (RABV) induces inflammatory response to lead BBB transient breakdown rather than wild-type (wt) strains. As a component of ribonucleoprotein (RNP), phosphoprotein (P) of RABV plays a key role in viral replication and pathogenicity. To our knowledge, the function of RABV P gene during RABV invasion was unclear so far. In order to determine the role of RABV P gene during RABV infection, we evaluated the BBB permeability in vivo after infection with wt RABV strain (GD-SH-01), a lab-attenuated RABV strain (HEP-Flury), and a chimeric RABV strain (rHEP-SH-P) whose P gene cloned from GD-SH-01 was expressed in the genomic backbone of HEP-Flury. We found that rHEP-SH-P caused less enhancement of BBB permeability and was less pathogenic to adult mice than GD-SH-01 and HEP-Flury. In an effort to investigate the mechanism, we found that the replication of rHEP-SH-P has been limited due to the suppressed P protein expression and induced less response to maintain BBB integrity. Our data indicated that the P gene of wt RABV was a potential determinant in hampering viral replication in vivo, which kept BBB integrity. These findings provided an important foundation for understanding the viral invasion and development of novel vaccine.
Collapse
Affiliation(s)
- Teng Long
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Boyue Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Ruqi Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yuting Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Meijun Mo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Jun Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yiran Chang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Qin Tian
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Mingzhu Mei
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - He Jiang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yongwen Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Xiaofeng Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| |
Collapse
|
|
16
|
Gold S, Donnelly CA, Nouvellet P, Woodroffe R. Rabies virus-neutralising antibodies in healthy, unvaccinated individuals: What do they mean for rabies epidemiology? PLoS Negl Trop Dis 2020; 14:e0007933. [PMID: 32053628 PMCID: PMC7017994 DOI: 10.1371/journal.pntd.0007933] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Rabies has been a widely feared disease for thousands of years, with records of rabid dogs as early as ancient Egyptian and Mesopotamian texts. The reputation of rabies as being inevitably fatal, together with its ability to affect all mammalian species, contributes to the fear surrounding this disease. However, the widely held view that exposure to the rabies virus is always fatal has been repeatedly challenged. Although survival following clinical infection in humans has only been recorded on a handful of occasions, a number of studies have reported detection of rabies-specific antibodies in the sera of humans, domestic animals, and wildlife that are apparently healthy and unvaccinated. These 'seropositive' individuals provide possible evidence of exposure to the rabies virus that has not led to fatal disease. However, the variability in methods of detecting these antibodies and the difficulties of interpreting serology tests have contributed to an unclear picture of their importance. In this review, we consider the evidence for rabies-specific antibodies in healthy, unvaccinated individuals as indicators of nonlethal rabies exposure and the potential implications of this for rabies epidemiology. Our findings indicate that whilst there is substantial evidence that nonlethal rabies exposure does occur, serology studies that do not use appropriate controls and cutoffs are unlikely to provide an accurate estimate of the true prevalence of nonlethal rabies exposure.
Collapse
Affiliation(s)
- Susannah Gold
- Institute of Zoology, Zoological Society of London, London, United Kingdom
- MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom
| | - Christl A. Donnelly
- MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom
- Department of Statistics, University of Oxford, Oxford, United Kingdom
| | - Pierre Nouvellet
- School of Life Sciences, University of Sussex, Falmer, United Kingdom
| | - Rosie Woodroffe
- Institute of Zoology, Zoological Society of London, London, United Kingdom
| |
Collapse
|
|
17
|
Yamada K, Noguchi K, Kimitsuki K, Kaimori R, Saito N, Komeno T, Nakajima N, Furuta Y, Nishizono A. Reevaluation of the efficacy of favipiravir against rabies virus using in vivo imaging analysis. Antiviral Res 2019; 172:104641. [PMID: 31672666 DOI: 10.1016/j.antiviral.2019.104641] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/13/2019] [Accepted: 10/23/2019] [Indexed: 12/30/2022]
Abstract
Rabies virus (RABV) is a highly neurotropic virus and the causative agent of rabies, an encephalitis with an almost 100% case-fatality rate that remains incurable after the onset of symptoms. Favipiravir (T-705), a broad-spectrum antiviral drug against RNA viruses, has been shown to be effective against RABV in vitro but ineffective in vivo. We hypothesized that favipiravir is effective in infected mice when RABV replicates in the peripheral tissues/nerves but not after virus neuroinvasion. We attempted to clarify this point in this study using in vivo bioluminescence imaging. We generated a recombinant RABV from the field isolate 1088, which expressed red firefly luciferase (1088/RFLuc). This allowed semiquantitative detection and monitoring of primary replication at the inoculation site and viral spread in the central nervous system (CNS) in the same mice. Bioluminescence imaging revealed that favipiravir (300 mg/kg/day) treatment commencing 1 h after intramuscular inoculation of RABV efficiently suppressed viral replication at the inoculation site and the subsequent replication in the CNS. However, virus replication in the CNS was not inhibited when the treatment began 2 days after inoculation. We also found that higher doses (600 or 900 mg/kg/day) of favipiravir could suppress viral replication in the CNS even when administration started 2 days after inoculation. These results support our hypothesis and suggest that a highly effective drug-delivery system into the CNS and/or the enhancement of favipiravir conversion to its active form are required to improve favipiravir treatment of rabies. Furthermore, the bioluminescence imaging system established in this study will facilitate the development of treatment for symptomatic rabies.
Collapse
Affiliation(s)
- Kentaro Yamada
- Research Promotion Institute, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan
| | - Kazuko Noguchi
- Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan; Department of Food Science and Technology, Minami Kyushu University, 5-1-2 Kirishima, Miyazaki City, Miyazaki, 880-0031, Japan
| | - Kazunori Kimitsuki
- Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan
| | - Ryo Kaimori
- Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan
| | - Nobuo Saito
- Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan
| | - Takashi Komeno
- FUJIFILM Toyama Chemical Co.,Ltd, 2-4-1 Shimookui, Toyama City, Toyama, 930-8508, Japan
| | - Nozomi Nakajima
- FUJIFILM Toyama Chemical Co.,Ltd, 2-4-1 Shimookui, Toyama City, Toyama, 930-8508, Japan
| | - Yousuke Furuta
- FUJIFILM Toyama Chemical Co.,Ltd, 2-4-1 Shimookui, Toyama City, Toyama, 930-8508, Japan
| | - Akira Nishizono
- Research Promotion Institute, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan; Department of Microbiology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, 879-5593, Japan.
| |
Collapse
|
|
18
|
Nyctinomops laticaudatus bat-associated Rabies virus causes disease with a shorter clinical period and has lower pathogenic potential than strains isolated from wild canids. Arch Virol 2019; 164:2469-2477. [PMID: 31297587 DOI: 10.1007/s00705-019-04335-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/02/2019] [Indexed: 10/26/2022]
Abstract
Rabies is a lethal viral disease that can affect a wide range of mammals. Currently, Rabies virus (RABV) in some European and American countries is maintained primarily in wild species. The regulation of viral replication is one of the critical mechanisms involved in RABV pathogenesis. However, the relationship between replication and the pathogenesis of RABV isolated from wild animals remains poorly understood. In the present study, we evaluated the pathogenicity of the street viruses Nyctinomops laticaudatus bat-associated RABV (NYBRV) and Cerdocyon thous canid-associated RABV (CECRV). Infection of mice with NYBRV led to 33% mortality with rapid disease evolution and marked histopathological changes in the CNS. In contrast, infection with CECRV led to 67% mortality and caused mild neuropathological lesions. The proportion of RABV antigen was significantly higher in the cytoplasm of neuronal cells of the cerebral cortex and in the meninges of mice infected with CECRV and NYBRV, respectively. Moreover, the replication rate of NYBRV was significantly higher (p < 0.001) than that of CECRV in neuroblastoma cells. However, CECRV replicated to a significantly higher titer in epithelial cells. Our results indicate that NYBRV infection results in rapid disease progression accompanied by frequent and intense histopathological alterations in the CNS in mice, and in a high replication rate in neuroblastoma cells. Although, CECRV is more pathogenic in mice, it caused milder histopathological changes in the CNS and replicated more efficiently in epithelial cells. Our data point to a correlation between clinical aspects of disease and the replication of RABV in different cell lines.
Collapse
|
|
19
|
Smith SP, Wu G, Fooks AR, Ma J, Banyard AC. Trying to treat the untreatable: experimental approaches to clear rabies virus infection from the CNS. J Gen Virol 2019; 100:1171-1186. [PMID: 31237530 DOI: 10.1099/jgv.0.001269] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Rabies virus causes an invariably fatal encephalitis following the onset of clinical disease. Despite the availability of safe and effective vaccines, the clinical stages of rabies encephalitis remain untreatable, with few survivors being documented. A principal obstacle to the treatment of rabies is the neurotropic nature of the virus, with the blood-brain barrier size exclusion limit rendering the delivery of antiviral drugs and molecules to the central nervous system inherently problematic. This review focuses on efforts to try and overcome barriers to molecule delivery to treat clinical rabies and overviews current progress in the development of experimental live rabies virus vaccines that may have future applications in the treatment of clinical rabies, including the attenuation of rabies virus vectors through either the duplication or mutation of existing genes or the incorporation of non-viral elements within the genome. Rabies post-infection treatment (PIT) remains the holy grail of rabies research.
Collapse
Affiliation(s)
- Samuel P Smith
- Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal and Plant Health Agency (APHA), Addlestone, Surrey, KT15 3NB, UK.,Institute for Infection and Immunity, St George's Hospital Medical School, University of London, London, UK
| | - Guanghui Wu
- Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal and Plant Health Agency (APHA), Addlestone, Surrey, KT15 3NB, UK
| | - Anthony R Fooks
- Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal and Plant Health Agency (APHA), Addlestone, Surrey, KT15 3NB, UK.,Institute for Infection and Immunity, St George's Hospital Medical School, University of London, London, UK.,Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
| | - Julian Ma
- Institute for Infection and Immunity, St George's Hospital Medical School, University of London, London, UK
| | - Ashley C Banyard
- Institute for Infection and Immunity, St George's Hospital Medical School, University of London, London, UK.,School of Life Sciences, University of West Sussex, Falmer, West Sussex, UK.,Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal and Plant Health Agency (APHA), Addlestone, Surrey, KT15 3NB, UK
| |
Collapse
|
|
20
|
Monette A, Mouland AJ. T Lymphocytes as Measurable Targets of Protection and Vaccination Against Viral Disorders. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 342:175-263. [PMID: 30635091 PMCID: PMC7104940 DOI: 10.1016/bs.ircmb.2018.07.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Continuous epidemiological surveillance of existing and emerging viruses and their associated disorders is gaining importance in light of their abilities to cause unpredictable outbreaks as a result of increased travel and vaccination choices by steadily growing and aging populations. Close surveillance of outbreaks and herd immunity are also at the forefront, even in industrialized countries, where previously eradicated viruses are now at risk of re-emergence due to instances of strain recombination, contractions in viral vector geographies, and from their potential use as agents of bioterrorism. There is a great need for the rational design of current and future vaccines targeting viruses, with a strong focus on vaccine targeting of adaptive immune effector memory T cells as the gold standard of immunity conferring long-lived protection against a wide variety of pathogens and malignancies. Here, we review viruses that have historically caused large outbreaks and severe lethal disorders, including respiratory, gastric, skin, hepatic, neurologic, and hemorrhagic fevers. To observe trends in vaccinology against these viral disorders, we describe viral genetic, replication, transmission, and tropism, host-immune evasion strategies, and the epidemiology and health risks of their associated syndromes. We focus on immunity generated against both natural infection and vaccination, where a steady shift in conferred vaccination immunogenicity is observed from quantifying activated and proliferating, long-lived effector memory T cell subsets, as the prominent biomarkers of long-term immunity against viruses and their associated disorders causing high morbidity and mortality rates.
Collapse
|
|
21
|
Fuoco NL, Fernandes ER, Dos Ramos Silva S, Luiz FG, Ribeiro OG, Santos Katz IS. Street rabies virus strains associated with insectivorous bats are less pathogenic than strains isolated from other reservoirs. Antiviral Res 2018; 160:94-100. [PMID: 30393124 DOI: 10.1016/j.antiviral.2018.10.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/16/2018] [Accepted: 10/25/2018] [Indexed: 01/08/2023]
Abstract
Rabies is a fatal and viral zoonosis that causes acute, progressive encephalitis and remains an important concern in public health. In the last few years, there has been a change in the epidemiological profile of rabies after implementing canine rabies control in the Americas, which has led to a significant increase in both human and pet cases of rabies associated with insectivorous bats. Thus, it is important to understand the pathogenesis caused by Rabies virus (RABV) isolates from insectivorous bats. Viral growth kinetics, cell-to-cell spread and virus uptake in vitro were analyzed for RABV isolates from Eptesicus furiralis and Myotis nigricans. For pathogenesis evaluation, mice were inoculated with RABV isolates from Eptesicus furiralis and Myotis nigricans, and clinical signs were observed for 40 days. We observed that the insectivorous bat strains showed a higher replication rate, faster cell-to-cell spread and delayed virus uptake in N2a cells. Furthermore, after the first sign of a clinical infection, mice infected with Myotis nigricans and Eptesicus furiralis isolates succumbed rapidly (6 ± 9 days) compared with RABV strains associated with other reservoirs. Our results show that the insectivorous bat RABV strains are less pathogenic for mice than strains associated with other reservoirs. In addition, this study also indicates that the differences in the biological characteristics of the RABV strains are important to their pathogenicity. An enhanced understanding of rabies pathogenesis may be important for the development of novel therapies for humans and in the implementation of rabies control strategies.
Collapse
|
|
22
|
Gnanadurai CW, Fu ZF. CXCL10 and blood-brain barrier modulation in rabies virus infection. Oncotarget 2018; 7:10694-5. [PMID: 26895109 PMCID: PMC4905431 DOI: 10.18632/oncotarget.7428] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Indexed: 12/17/2022] Open
Affiliation(s)
- Clement W Gnanadurai
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Zhen F Fu
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.,State-Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| |
Collapse
|
|
23
|
Garcia SA, Lebrun A, Kean RB, Craig Hooper D. Clearance of attenuated rabies virus from brain tissues is required for long-term protection against CNS challenge with a pathogenic variant. J Neurovirol 2018; 24:606-615. [PMID: 29987584 DOI: 10.1007/s13365-018-0655-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 05/23/2018] [Accepted: 05/31/2018] [Indexed: 12/25/2022]
Abstract
Rabies virus is a neurotropic lyssavirus which is 100% fatal in its pathogenic form when reaching unprotected CNS tissues. Death can be prevented by mechanisms delivering appropriate immune effectors across the blood-brain barrier which normally remains intact during pathogenic rabies virus infection. One therapeutic approach is to superinfect CNS tissues with attenuated rabies virus which induces blood-brain barrier permeability and immune cell entry. Current thinking is that peripheral rabies immunization is sufficient to protect against a challenge with pathogenic rabies virus. While this is undoubtedly the case if the virus is confined to the periphery, what happens if the virus reaches the CNS is less well-understood. In the current study, we find that peripheral immunization does not fully protect mice long-term against an intranasal challenge with pathogenic rabies virus. Protection is significantly better in mice that have cleared attenuated virus from the CNS and is associated with a more robust CNS recall response evidently due to the presence in CNS tissues of elevated numbers of lymphocytes phenotypically resembling long-term resident immune cells. Adoptive transfer of cells from rabies-immune mice fails to protect against CNS challenge with pathogenic rabies virus further supporting the concept that long-term resident immune cell populations must be established in brain tissues to protect against a subsequent CNS challenge with pathogenic rabies virus.
Collapse
Affiliation(s)
- Samantha A Garcia
- Department of Cancer Biology, Thomas Jefferson University, 1020 Locust Street, JAH Rm 452, Philadelphia, PA, 19107-6731, USA
| | - Aurore Lebrun
- Department of Cancer Biology, Thomas Jefferson University, 1020 Locust Street, JAH Rm 452, Philadelphia, PA, 19107-6731, USA
| | - Rhonda B Kean
- Department of Cancer Biology, Thomas Jefferson University, 1020 Locust Street, JAH Rm 452, Philadelphia, PA, 19107-6731, USA
| | - D Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, 1020 Locust Street, JAH Rm 452, Philadelphia, PA, 19107-6731, USA. .,Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.
| |
Collapse
|
|
24
|
Recombinant rabies virus expressing interleukin-6 enhances the immune response in mouse brain. Arch Virol 2018; 163:1889-1895. [PMID: 29594364 DOI: 10.1007/s00705-018-3808-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 02/15/2018] [Indexed: 12/25/2022]
Abstract
Rabies, which is caused by the rabies virus (RABV), is an ancient zoonosis that has a high mortality rate. Previous studies have indicated that recombinant RABV expressing canine interleukin-6 (rHEP-CaIL6), induced more virus-neutralizing antibodies than parental RABV in mice following intramuscular immunization. To investigate the immune response induced in the CNS by rHEP-CaIL6 after intranasal or intracranial administration in mice, the permeability of the blood-brain barrier (BBB), the infiltration of CD3 T cells, and innate immune response-related effector molecules in the CNS were examined. It was observed that infection of rHEP-CaIL6 led to enhanced BBB permeability following intranasal infection. More CD3 T cells infiltrated into the central nervous system (CNS) in mice infected with rHEP-CaIL6 than in those infected with the HEP-Flury strain. Furthermore, rHEP-CaIL6 induced an increased expression of innate immune response-related effector molecules, compared with the parental HEP-Flury strain, within the CNS. Taken together, these findings suggest that rHEP-CaIL6 induced stronger immune responses in mice brains, which is more beneficial for virus clearance. These results may also partly illustrate the role of IL6 in RABV infection.
Collapse
|
|
25
|
Tian B, Zhou M, Yang Y, Yu L, Luo Z, Tian D, Wang K, Cui M, Chen H, Fu ZF, Zhao L. Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway. Front Immunol 2018; 8:2011. [PMID: 29403485 PMCID: PMC5785723 DOI: 10.3389/fimmu.2017.02011] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 12/27/2017] [Indexed: 12/25/2022] Open
Abstract
Rabies is an ancient disease but remains endemic in most parts of the world and causes approximately 59,000 deaths annually. The mechanism through which the causative agent, rabies virus (RABV), evades the host immune response and infects the host central nervous system (CNS) has not been completely elucidated thus far. Our previous studies have shown that lab-attenuated, but not wild-type (wt), RABV activates the innate immune response in the mouse and dog models. In this present study, we demonstrate that lab-attenuated RABV causes abortive infection in astrocytes, the most abundant glial cells in the CNS. Furthermore, we found that lab-attenuated RABV produces more double-stranded RNA (dsRNA) than wt RABV, which is recognized by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5). Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Notably, lab-attenuated RABV replicates in a manner identical to that of wt RABV in MAVS−/− astrocytes. It was also found that lab-attenuated, but not wt, RABV induces the expression of inflammatory cytokines via the MAVS- p38/NF-κB signaling pathway. These inflammatory cytokines increase the blood–brain barrier permeability and thus enable immune cells and antibodies infiltrate the CNS parenchyma, resulting in RABV control and elimination. In contrast, wt RABV restricts dsRNA production and thus evades innate recognition by RIG-I/MDA5 in astrocytes, which could be one of the mechanisms by which wt RABV evades the host immune response in resident CNS cells. Our findings suggest that astrocytes play a critical role in limiting the replication of lab-attenuated RABV in the CNS.
Collapse
Affiliation(s)
- Bin Tian
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Ming Zhou
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Yu Yang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Lan Yu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Zhaochen Luo
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Dayong Tian
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Ke Wang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Min Cui
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Huanchun Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China.,College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhen F Fu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.,Department of Pathology, University of Georgia, Athens, GA, United States
| | - Ling Zhao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China.,College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| |
Collapse
|
|
26
|
Manesh A, Mani RS, Pichamuthu K, Jagannati M, Mathew V, Karthik R, Abraham OC, Chacko G, Varghese GM. Case Report: Failure of Therapeutic Coma in Rabies Encephalitis. Am J Trop Med Hyg 2018; 98:207-210. [PMID: 29141755 PMCID: PMC5928693 DOI: 10.4269/ajtmh.17-0153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 08/31/2017] [Indexed: 12/25/2022] Open
Abstract
Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti-exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense protocol have not been successful. In this article, we report the failure of the protocol in Indian patients with canine-acquired rabies and elucidate the potential explanations for the failure of the protocol in our patients.
Collapse
Affiliation(s)
- Abi Manesh
- Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
| | - Reeta Subramaniam Mani
- Department of Neurovirology, WHO Collaborating Centre for Reference and Research on Rabies, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India
| | - Kishore Pichamuthu
- Division of Critical Care, Christian Medical College, Vellore, Tamil Nadu, India
| | - Manjeera Jagannati
- Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| | - Vivek Mathew
- Department of Neurological Sciences, Neurology Unit, Christian Medical College, Vellore, Tamil Nadu, India
| | - Rajiv Karthik
- Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Geeta Chacko
- Section of Neuropathology, Department of Neurological Sciences & Pathology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
| | - George M. Varghese
- Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
| |
Collapse
|
|
27
|
Fooks AR, Cliquet F, Finke S, Freuling C, Hemachudha T, Mani RS, Müller T, Nadin-Davis S, Picard-Meyer E, Wilde H, Banyard AC. Rabies. Nat Rev Dis Primers 2017; 3:17091. [PMID: 29188797 DOI: 10.1038/nrdp.2017.91] [Citation(s) in RCA: 196] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Rabies is a life-threatening neglected tropical disease: tens of thousands of cases are reported annually in endemic countries (mainly in Africa and Asia), although the actual numbers are most likely underestimated. Rabies is a zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which are transmitted via the saliva of an infected animal. Dogs are the most important reservoir for rabies viruses, and dog bites account for >99% of human cases. The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system. Once clinical disease develops, it is almost certainly fatal. Primary prevention involves dog vaccination campaigns to reduce the virus reservoir. If exposure occurs, timely post-exposure prophylaxis can prevent the progression to clinical disease and involves appropriate wound care, the administration of rabies immunoglobulin and vaccination. A multifaceted approach for human rabies eradication that involves government support, disease awareness, vaccination of at-risk human populations and, most importantly, dog rabies control is necessary to achieve the WHO goal of reducing the number of cases of dog-mediated human rabies to zero by 2030.
Collapse
Affiliation(s)
- Anthony R Fooks
- Animal and Plant Health Agency (APHA), Wildlife Zoonoses and Vector Borne Diseases Research Group, (WHO Collaborating Centre for the Characterisation of Rabies and Rabies-Related Viruses, World Organisation for Animal Health (OIE) Reference Laboratory for Rabies), Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK.,Institute of Infection &Global Health, University of Liverpool, Liverpool, UK.,Institute for Infection and Immunity, St. George's Hospital Medical School, University of London, London, UK
| | - Florence Cliquet
- French Agency for Food, Environmental and Occupational Health &Safety (ANSES)-Nancy Laboratory for Rabies and Wildlife (European Union Reference Laboratory for Rabies, WHO Collaborating Centre for Research and Management in Zoonoses Control, OIE Reference Laboratory for Rabies, European Union Reference Institute for Rabies Serology), Technopôle Agricole et Vétérinaire de Pixérécourt, Malzéville, France
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology (WHO Collaborating Centre for Rabies Surveillance and Research, OIE Reference Laboratory for Rabies), Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Conrad Freuling
- Institute of Molecular Virology and Cell Biology (WHO Collaborating Centre for Rabies Surveillance and Research, OIE Reference Laboratory for Rabies), Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Thiravat Hemachudha
- Department of Medicine (Neurology) and (WHO Collaborating Centre for Research and Training on Viral Zoonoses), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Thai Red Cross Emerging Infectious Disease-Health Science Centre, Thai Red Cross Society, Bangkok, Thailand
| | - Reeta S Mani
- Department of Neurovirology (WHO Collaborating Centre for Reference and Research in Rabies), National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Thomas Müller
- Institute of Molecular Virology and Cell Biology (WHO Collaborating Centre for Rabies Surveillance and Research, OIE Reference Laboratory for Rabies), Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Susan Nadin-Davis
- Ottawa Laboratory Fallowfield, Canadian Food Inspection Agency (WHO Collaborating Centre for Control, Pathogenesis and Epidemiology of Rabies in Carnivores), Ottawa, Ontario, Canada
| | - Evelyne Picard-Meyer
- French Agency for Food, Environmental and Occupational Health &Safety (ANSES)-Nancy Laboratory for Rabies and Wildlife (European Union Reference Laboratory for Rabies, WHO Collaborating Centre for Research and Management in Zoonoses Control, OIE Reference Laboratory for Rabies, European Union Reference Institute for Rabies Serology), Technopôle Agricole et Vétérinaire de Pixérécourt, Malzéville, France
| | - Henry Wilde
- Department of Medicine (Neurology) and (WHO Collaborating Centre for Research and Training on Viral Zoonoses), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Ashley C Banyard
- Animal and Plant Health Agency (APHA), Wildlife Zoonoses and Vector Borne Diseases Research Group, (WHO Collaborating Centre for the Characterisation of Rabies and Rabies-Related Viruses, World Organisation for Animal Health (OIE) Reference Laboratory for Rabies), Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
| |
Collapse
|
|
28
|
Zhang G, Wang J, Yao G, Shi B. Downregulation of CCL2 induced by the upregulation of microRNA-206 is associated with the severity of HEV71 encephalitis. Mol Med Rep 2017; 16:4620-4626. [PMID: 28765968 PMCID: PMC5647018 DOI: 10.3892/mmr.2017.7142] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 02/20/2017] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRNAs) have been investigated widely as key regulators of gene expression in different diseases by affecting the miRNA‑mediated regulatory function. Human enterovirus 71 (HEV71) can cause a series of human diseases, including encephalitis. Chemokine (C‑C motif) ligand 2 (CCL2) is one of the important genes involved in regulating inflammation. However, the mechanisms underlying HEV71 encephalitis mediated by CCL2 remain to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression level of miR‑206 and the mRNA expression of CCL2 in samples. Western blot analysis was used to detect the protein levels of CCL2. A luciferase assay was used to verify the miR‑206 target site in CCL2. A CCK‑8 assay and flow cytometry were used to determine cell proliferation and apoptosis. The results demonstrated that miR‑206 was downregulated in severe HEV71 encephalitis. Using bioinformatics analysis, miR‑206 was predicted to target the human CCL2 3'‑untranslated region (3'‑UTR). A dual‑luciferase assay demonstrated that miR‑206 downregulated the expression of CCL2 by directly targeting its 3'‑UTR, whereas CCL2 3'‑UTR mutations completely eliminated its interaction with miR‑206. The expression levels of miR‑206 and CCL2 were inversely correlated in cerebrospinal fluid. The expression of exogenous miRNA, which mimicked miR‑206 miRNA, decreased the protein and mRNA levels of CCL2, whereas the suppression of endogenous miR‑206 resulted in an increase of the protein and mRNA levels of CCL2. The present study also found that miR‑206 promoted NPC cell proliferation and reduced the apoptosis of NPC cells via CCL2. The mechanism is likely to involve suppression of the expression of miR‑206 and upregulation of the expression of CCL2, important in regulating the progress of HEV71 encephalitis. In conclusion, miR‑206 may be useful in the prognosis and treatment of HEV71 encephalitis.
Collapse
Affiliation(s)
- Guangyou Zhang
- Department of Pediatrics, Taian Central Hospital, Taian, Shandong 271000, P.R. China
| | - Jiwen Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Guo Yao
- Department of Pediatrics, Taian Central Hospital, Taian, Shandong 271000, P.R. China
| | - Baohai Shi
- Department of Pediatrics, Taian Central Hospital, Taian, Shandong 271000, P.R. China
| |
Collapse
|
|
29
|
Immunological aspects of rabies: a literature review. Arch Virol 2017; 162:3251-3268. [PMID: 28726129 DOI: 10.1007/s00705-017-3484-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/27/2017] [Indexed: 02/08/2023]
Abstract
Rabies is a lethal disease caused by the neurotropic virus rabies virus (RABV), and it remains an important public health problem globally. It is known that the host immune response is important for control of viral infection and promoting viral clearance. In this context, it is well documented that, in addition to RABV neutralizing antibody, interferons and cell-mediated immunity also have an important role in preventing the establishment of disease. On the other hand, RABV suppresses host immunity through different mechanisms, for example, direct inhibition of host gene expression, sequestration of pathogen-associated molecular patterns, or modification of cytokine signalling pathways, which hinder the protective host immune responses to RABV infection. Here, we review the immunological aspects of rabies, highlighting innate and adaptive immunity, as well as the host evasion immune mechanisms used by the virus. Finally, we briefly discuss how this knowledge can direct new research and be harnessed for future therapeutic strategies.
Collapse
|
|
30
|
Lebrun A, Garcia S, Li J, Kean RB, Hooper DC. Protection Against CNS-Targeted Rabies Virus Infection is Dependent upon Type-1 Immune Mechanisms Induced by Live-Attenuated Rabies Vaccines. Trop Med Infect Dis 2017; 2:E22. [PMID: 30270881 PMCID: PMC6082098 DOI: 10.3390/tropicalmed2030022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022] Open
Abstract
Rabies remains a major public health issue worldwide, especially in developing countries where access to medical care can represent a real challenge. While there is still no cure for rabies, it is a vaccine-preventable disease with pre- and post-exposure prophylaxis regimens approved by the World Health Organization (WHO). However, many rabies-exposed individuals have limited access to vaccines and virus-neutralizing antibodies approved for post-exposure prophylaxis. Unfortunately, any delay in the administration of these reagents can have lethal consequences. This highlights the need to develop cost-effective immunological reagents with a greater window of efficacy. Live-attenuated vaccine strains of rabies virus presents a potential treatment in filling this gap. We show here that immunization with live-attenuated vaccines provide long-lasting rabies immunity, superior to the protection induced by inactivated vaccines. In the absence of an immunostimulatory adjuvant, vaccination with multiple doses of inactivated rabies virus induces a type-2 immune response. This type of immunity is highly effective at inducing neutralizing antibody but has limited efficacy in clearing the virus from central nervous system (CNS) tissues. In contrast, a single infection with live-attenuated rabies vaccine safely drives a type-1 immune response, associated with both the production of a neutralizing antibody and the clearance of wild-type rabies virus from CNS tissues. These results indicate that live-attenuated rabies strains have the potential to be more effective in post-exposure prophylaxis than conventional inactivated vaccines.
Collapse
Affiliation(s)
- Aurore Lebrun
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19017, USA.
| | - Samantha Garcia
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19017, USA.
| | - Jianwei Li
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19017, USA.
| | - Rhonda B Kean
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19017, USA.
| | - D Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19017, USA.
- Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA 19017, USA.
| |
Collapse
|
|
31
|
Impact of caspase-1/11, -3, -7, or IL-1 β/IL-18 deficiency on rabies virus-induced macrophage cell death and onset of disease. Cell Death Discov 2017; 3:17012. [PMID: 28280602 PMCID: PMC5339016 DOI: 10.1038/cddiscovery.2017.12] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 01/27/2017] [Indexed: 12/17/2022] Open
Abstract
Rabies virus is a highly neurovirulent RNA virus, which causes about 59000 deaths in humans each year. Previously, we described macrophage cytotoxicity upon infection with rabies virus. Here we examined the type of cell death and the role of specific caspases in cell death and disease development upon infection with two laboratory strains of rabies virus: Challenge Virus Standard strain-11 (CVS-11) is highly neurotropic and lethal for mice, while the attenuated Evelyn–Rotnycki–Abelseth (ERA) strain has a broader cell tropism, is non-lethal and has been used as an oral vaccine for animals. Infection of Mf4/4 macrophages with both strains led to caspase-1 activation and IL-1β and IL-18 production, as well as activation of caspases-3, -7, -8, and -9. Moreover, absence of caspase-3, but not of caspase-1 and -11 or -7, partially inhibited virus-induced cell death of bone marrow-derived macrophages. Intranasal inoculation with CVS-11 of mice deficient for either caspase-1 and -11 or -7 or both IL-1β and IL-18 led to general brain infection and lethal disease similar to wild-type mice. Deficiency of caspase-3, on the other hand, significantly delayed the onset of disease, but did not prevent final lethal outcome. Interestingly, deficiency of caspase-1/11, the key executioner of pyroptosis, aggravated disease severity caused by ERA virus, whereas wild-type mice or mice deficient for either caspase-3, -7, or both IL-1β and IL-18 presented the typical mild symptoms associated with ERA virus. In conclusion, rabies virus infection of macrophages induces caspase-1- and caspase-3-dependent cell death. In vivo caspase-1/11 and caspase-3 differently affect disease development in response to infection with the attenuated ERA strain or the virulent CVS-11 strain, respectively. Inflammatory caspases seem to control attenuated rabies virus infection, while caspase-3 aggravates virulent rabies virus infection.
Collapse
|
|
32
|
Expression of interleukin-6 by a recombinant rabies virus enhances its immunogenicity as a potential vaccine. Vaccine 2017; 35:938-944. [DOI: 10.1016/j.vaccine.2016.12.069] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/20/2016] [Accepted: 12/20/2016] [Indexed: 11/13/2022]
|
|
33
|
Zhu S, Guo C. Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential. Viruses 2016; 8:v8110279. [PMID: 27801824 PMCID: PMC5127009 DOI: 10.3390/v8110279] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 10/17/2016] [Accepted: 10/20/2016] [Indexed: 12/25/2022] Open
Abstract
Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals. Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans. In the search for novel rabies control and treatment strategies, live-attenuated viruses have recently emerged as a practical and promising approach for immunizing and controlling rabies. Unlike the conventional, inactivated rabies vaccine, live-attenuated viruses are genetically modified viruses that are able to replicate in an inoculated recipient without causing adverse effects, while still eliciting robust and effective immune responses against rabies virus infection. A number of viruses with an intrinsic capacity that could be used as putative candidates for live-attenuated rabies vaccine have been intensively evaluated for therapeutic purposes. Additional novel strategies, such as a monoclonal antibody-based approach, nucleic acid-based vaccines, or small interfering RNAs (siRNAs) interfering with virus replication, could further add to the arena of strategies to combat rabies. In this review, we highlight current advances in rabies therapy and discuss the role that they might have in the future of rabies treatment. Given the pronounced and complex impact of rabies on a patient, a combination of these novel modalities has the potential to achieve maximal anti-rabies efficacy, or may even have promising curative effects in the future. However, several hurdles regarding clinical safety considerations and public awareness should be overcome before these approaches can ultimately become clinically relevant therapies.
Collapse
Affiliation(s)
- Shimao Zhu
- Shenzhen Weiguang Biological Products Co., Ltd., Shenzhen 518107, China.
| | - Caiping Guo
- Shenzhen Weiguang Biological Products Co., Ltd., Shenzhen 518107, China.
| |
Collapse
|
|
34
|
Miao FM, Zhang SF, Wang SC, Liu Y, Zhang F, Hu RL. Comparison of immune responses to attenuated rabies virus and street virus in mouse brain. Arch Virol 2016; 162:247-257. [PMID: 27722994 DOI: 10.1007/s00705-016-3081-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 09/19/2016] [Indexed: 12/25/2022]
Abstract
Rabies is a lethal neurological disease caused by the neurotropic rabies virus (RABV). To investigate the innate immune response in the brain during rabies infection, key gene transcripts indicative of innate immunity in a mouse model system were measured using real-time RT-PCR. Mice were infected via the intracerebral or intramuscular route with either attenuated rabies virus (SRV9) or pathogenic rabies virus (BD06). Infection with SRV9 resulted in the early detection of viral replication and the rapid induction of innate immune response gene expression in the brain. BD06 infection elicited innate immune response gene expression during only the late stage of infection. We measured Na-fluorescein uptake to assess blood-brain barrier (BBB) permeability, which was enhanced during the early stage of SRV9 infection and significantly enhanced during the late stage of BD06 infection. Furthermore, early SRV9 replication increased the maturation and differentiation of dendritic cells (DCs) and B cells in the inguinal lymph nodes and initiated the generation of virus-neutralizing antibodies (VNAs), which cooperate with the innate immune response to eliminate virus from the CNS. However, BD06 infection did not stimulate VNA production; thus, the virus was able to evade the host immune response and cause encephalitis. The rabies virus phosphoprotein has been reported to counteract IFN activation. In an in vitro study of the relationship between IFN antagonism and RABV pathogenicity, we demonstrated that SRV9 more strongly antagonized IFN activity than did BD06. Therefore, there is no positive relationship between the IFN antagonist activity of the virus and its pathogenicity.
Collapse
Affiliation(s)
- Fa-Ming Miao
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China
| | - Shou-Feng Zhang
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China
| | - Shu-Chao Wang
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China
| | - Ye Liu
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China
| | - Fei Zhang
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China
| | - Rong-Liang Hu
- Laboratory of Epidemiology, Institute of Military Veterinary, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, 666 Liuying West Road, Changchun, 130122, Jilin, China.
| |
Collapse
|
|
35
|
Zhang D, He F, Bi S, Guo H, Zhang B, Wu F, Liang J, Yang Y, Tian Q, Ju C, Fan H, Chen J, Guo X, Luo Y. Genome-Wide Transcriptional Profiling Reveals Two Distinct Outcomes in Central Nervous System Infections of Rabies Virus. Front Microbiol 2016; 7:751. [PMID: 27242764 PMCID: PMC4871871 DOI: 10.3389/fmicb.2016.00751] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 05/03/2016] [Indexed: 12/15/2022] Open
Abstract
Rabies remains a major public health concern in many developing countries. The precise neuropathogenesis of rabies is unknown, though it is hypothesized to be due to neuronal death or dysfunction. Mice that received intranasal inoculation of an attenuated rabies virus (RABV) strain HEP-Flury exhibited subtle clinical signs, and eventually recovered, which is different from the fatal encephalitis caused by the virulent RABV strain CVS-11. To understand the neuropathogenesis of rabies and the mechanisms of viral clearance, we applied RNA sequencing (RNA-Seq) to compare the brain transcriptomes of normal mice vs. HEP-Flury or CVS-11 intranasally inoculated mice. Our results revealed that both RABV strains altered positively and negatively the expression levels of many host genes, including genes associated with innate and adaptive immunity, inflammation and cell death. It is found that HEP-Flury infection can activate the innate immunity earlier through the RIG-I/MDA-5 signaling, and the innate immunity pre-activated by HEP-Flury or Newcastle disease virus (NDV) infection can effectively prevent the CVS-11 to invade central nervous system (CNS), but fails to clear the CVS-11 after its entry into the CNS. In addition, following CVS-11 infection, genes implicated in cell adhesion, blood vessel morphogenesis and coagulation were mainly up-regulated, while the genes involved in synaptic transmission and ion transport were significantly down-regulated. On the other hand, several genes involved in the MHC class II-mediated antigen presentation pathway were activated to a greater extent after the HEP-Flury infection as compared with the CVS-11 infection suggesting that the collaboration of CD4+ T cells and MHC class II-mediated antigen presentation is critical for the clearance of attenuated RABV from the CNS. The differentially regulated genes reported here are likely to include potential therapeutic targets for expanding the post-exposure treatment window for RABV infection.
Collapse
Affiliation(s)
- Daiting Zhang
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Feilong He
- College of Veterinary Medicine, South China Agricultural University Guangzhou, China
| | - Shuilian Bi
- School of Food Science, Guangdong Pharmaceutical University Zhongshan, China
| | - Huixia Guo
- College of Veterinary Medicine, South China Agricultural University Guangzhou, China
| | - Baoshi Zhang
- College of Veterinary Medicine, South China Agricultural University Guangzhou, China
| | - Fan Wu
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Jiaqi Liang
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Youtian Yang
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Qin Tian
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Chunmei Ju
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Huiying Fan
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Jinding Chen
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Xiaofeng Guo
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| | - Yongwen Luo
- College of Veterinary Medicine, South China Agricultural UniversityGuangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural UniversityGuangzhou, China
| |
Collapse
|
|
36
|
Ito N, Moseley GW, Sugiyama M. The importance of immune evasion in the pathogenesis of rabies virus. J Vet Med Sci 2016; 78:1089-98. [PMID: 27041139 PMCID: PMC4976263 DOI: 10.1292/jvms.16-0092] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Rabies is a zoonotic disease caused by the Lyssavirus rabies virus
(RABV) that can infect most mammals, including humans, where it has a case-fatality rate
of almost 100%. Although preventable by vaccination, rabies causes c. 59,000 human
fatalities every year worldwide. Thus, there exists an urgent need to establish an
effective therapy and/or improve dissemination of vaccines for humans and animals. These
outcomes require greater understanding of the mechanisms of RABV pathogenesis to identify
new molecular targets for the development of therapeutics and/or live vaccines with high
levels of safety. Importantly, a number of studies in recent years have indicated that
RABV specifically suppresses host immunity through diverse mechanisms and that this is a
key process in pathogenicity. Here, we review current understanding of immune modulation
by RABV, with an emphasis on its significance to pathogenicity and the potential
exploitation of this knowledge to develop new vaccines and antivirals.
Collapse
Affiliation(s)
- Naoto Ito
- Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan
| | | | | |
Collapse
|
|
37
|
Appolinário CM, Allendorf SD, Peres MG, Ribeiro BD, Fonseca CR, Vicente AF, Antunes JMADP, Megid J. Profile of Cytokines and Chemokines Triggered by Wild-Type Strains of Rabies Virus in Mice. Am J Trop Med Hyg 2015; 94:378-83. [PMID: 26711511 DOI: 10.4269/ajtmh.15-0361] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 11/02/2015] [Indexed: 12/25/2022] Open
Abstract
Rabies is a lethal infectious disease that causes 55,000 human deaths per year and is transmitted by various mammalian species, such as dogs and bats. The host immune response is essential for avoiding viral progression and promoting viral clearance. Cytokines and chemokines are crucial in the development of an immediate antiviral response; the rabies virus (RABV) attempts to evade this immune response. The virus's capacity for evasion is correlated with its pathogenicity and the host's inflammatory response, with highly pathogenic strains being the most efficient at hijacking the host's defense mechanisms and thereby decreasing inflammation. The purpose of this study was to evaluate the expression of a set of cytokine and chemokine genes that are related to the immune response in the brains of mice inoculated intramuscularly or intracerebrally with two wild-type strains of RABV, one from dog and the other from vampire bat. The results demonstrated that the gene expression profile is intrinsic to the specific rabies variant. The prompt production of cytokines and chemokines seems to be more important than their levels of expression for surviving a rabies infection.
Collapse
Affiliation(s)
- Camila Michele Appolinário
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Susan Dora Allendorf
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Marina Gea Peres
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Bruna Devidé Ribeiro
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Clóvis R Fonseca
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Acácia Ferreira Vicente
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - João Marcelo A de Paula Antunes
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Jane Megid
- Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Science, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| |
Collapse
|
|
38
|
Johnson N, Cunningham AF. Interplay between rabies virus and the mammalian immune system. World J Clin Infect Dis 2015; 5:67-76. [DOI: 10.5495/wjcid.v5.i4.67] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/23/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
Rabies is a disease caused following infection of the brain by the rabies virus (RABV). The principle mechanism of transmission is through a bite wound. The virus infects peripheral nerves and moves to the central nervous system (CNS). There appears to be little involvement of other organ systems and little detectable immune stimulation prior to infection of the CNS. This failure of the mammalian immune system to respond to rabies virus infection leads, in the overwhelming majority of cases, to death of the host. To some extent, this failure is likely due to the exclusive replication of RABV in neurons and the limited ability to generate, sufficiently rapidly, an anti-viral antibody response in situ. This is reflected in the ability of post-exposure vaccination, when given early after infection, to prevent disease. The lack of immune stimulation during RABV infection preceding neural invasion is the Achilles heel of the immune response. Whilst many viruses infect the brain, causing encephalitis and neuronal deficit, none are as consistently fatal to the host as RABV. This is in part due to prior replication of many viruses in peripheral, non-neural tissue by other viruses that allows timely activation of the immune response before the host is overwhelmed. Our current understanding of the correlates of protection for rabies suggests that it is the action of neutralising antibodies that prevent infection and control spread of RABV. Furthermore, it tells us that the induction of immunity can protect and understanding how and why this happens is critical to controlling infection. However, the paradigm of antibody development suggests that antigen presentation overwhelmingly occurs in lymphoid tissue (germinal and non-germinal centres) and these are external to the CNS. In addition, the blood-brain-barrier may provide a block to the delivery of immune effectors (antibodies/plasma B-cells) entering where they are needed. Alternatively, there may be insufficient antigen exposure after natural infection to mount an effective response or the virus actively suppresses immune function. To improve our ability to treat this fatal infection it is imperative to understand how immunity to RABV develops and functions so that parameters of protection are better defined.
Collapse
|
|
39
|
Critical Role of K1685 and K1829 in the Large Protein of Rabies Virus in Viral Pathogenicity and Immune Evasion. J Virol 2015; 90:232-44. [PMID: 26468538 DOI: 10.1128/jvi.02050-15] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/04/2015] [Indexed: 12/24/2022] Open
Abstract
UNLABELLED Rabies, one of the oldest infectious diseases, still presents a public health threat in most parts of the world today. Its pathogen, rabies virus (RABV), can utilize its viral proteins, such as the nucleoprotein and phosphorylation protein, to subvert the host innate immune system. For a long time, the large (L) protein was believed to be essential for RABV transcription and replication, but its role in viral pathogenicity and immune evasion was not known. Recent studies have found that the conserved K-D-K-E tetrad motif in the L protein is related to the methyltransferase (MTase) activity in the viral mRNA process. In the present study, a series of RABV mutations in this motif was constructed with the recombinant CVS-B2c (rB2c) virus. Two of these mutants, rB2c-K1685A and rB2c-K1829A, were found to be stable and displayed an attenuated phenotype in both in vitro growth and in vivo pathogenicity in adult and suckling mice. Further studies demonstrated that these two mutants were more sensitive to the expression of the interferon-stimulated gene product IFIT2 than the parent virus. Taken together, our results suggest that K1685 and K1829 in the L protein play important roles in pathogenicity and immune evasion during RABV infection. IMPORTANCE Rabies continues to present a public health threat in most areas of the world, especially in the developing countries of Asia and Africa. The pathogenic mechanisms for rabies are not well understood. In the present study, it was found that the recombinant rabies viruses rB2c-K1685A and rB2c-K1829A, carrying mutations at the predicted MTase catalytic sites in the L protein, were highly attenuated both in vitro and in vivo. Further studies showed that these mutants were more sensitive to the expression of the interferon-stimulated gene product IFIT2 than the parent virus. These findings improve our understanding of rabies pathogenesis, which may help in developing potential therapeutics and an avirulent rabies vaccine.
Collapse
|
|
40
|
Lebrun A, Portocarrero C, Kean RB, Barkhouse DA, Faber M, Hooper DC. T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue. THE JOURNAL OF IMMUNOLOGY 2015; 195:4358-68. [PMID: 26408670 DOI: 10.4049/jimmunol.1501274] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 09/02/2015] [Indexed: 12/25/2022]
Abstract
Much of our understanding of CNS immunity has been gained from models involving pathological inflammation. Attenuated rabies viruses (RABV) are unique tools to study CNS immunity in the absence of conventional inflammatory mechanisms, as they spread from the site of inoculation to the CNS transaxonally, thereby bypassing the blood-brain barrier (BBB), and are cleared without neutrophil or monocyte infiltration. To better understand the role of CD4 T cell subsets in the clearance of the virus from CNS tissues, we examined the development of antiviral immunity in wild-type (WT) and T-bet knockout mice (T-bet(-/-)), which lack Th1 cells. Early control of RABV replication in the CNS tissues of WT mice is associated with the production of IFN-γ, with antiviral effects likely mediated through the enhanced expression of type I IFNs. Of interest, IFN-α and -γ are overexpressed in the infected T-bet(-/-) by comparison with WT CNS tissues, and the initial control of RABV infection is similar. Ultimately, attenuated RABV are cleared from the CNS tissues of WT mice by Ab locally produced by the activities of infiltrating T and B cells. Although T and B cell infiltration into the CNS of infected T-bet(-/-) mice is comparable, their activities are not, the consequence being delayed, low-level Ab production and prolonged RABV replication. More importantly, neither T-bet(-/-) mice immunized with an attenuated virus, nor WT mice with Th2 RABV-specific immunity induced by immunization with inactivated virus, are protected in the long term against challenge with a pathogenic RABV.
Collapse
Affiliation(s)
- Aurore Lebrun
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Carla Portocarrero
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Rhonda B Kean
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Darryll A Barkhouse
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Milosz Faber
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107; and
| | - D Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107; Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA 19107
| |
Collapse
|
|
41
|
Davis BM, Rall GF, Schnell MJ. Everything You Always Wanted to Know About Rabies Virus (But Were Afraid to Ask). Annu Rev Virol 2015; 2:451-71. [PMID: 26958924 DOI: 10.1146/annurev-virology-100114-055157] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The cultural impact of rabies, the fatal neurological disease caused by infection with rabies virus, registers throughout recorded history. Although rabies has been the subject of large-scale public health interventions, chiefly through vaccination efforts, the disease continues to take the lives of about 40,000-70,000 people per year, roughly 40% of whom are children. Most of these deaths occur in resource-poor countries, where lack of infrastructure prevents timely reporting and postexposure prophylaxis and the ubiquity of domestic and wild animal hosts makes eradication unlikely. Moreover, although the disease is rarer than other human infections such as influenza, the prognosis following a bite from a rabid animal is poor: There is currently no effective treatment that will save the life of a symptomatic rabies patient. This review focuses on the major unanswered research questions related to rabies virus pathogenesis, especially those connecting the disease progression of rabies with the complex dysfunction caused by the virus in infected cells. The recent applications of cutting-edge research strategies to this question are described in detail.
Collapse
Affiliation(s)
| | - Glenn F Rall
- Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
| | - Matthias J Schnell
- Department of Microbiology and Immunology and.,Jefferson Vaccine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107; .,Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
| |
Collapse
|
|
42
|
Abstract
Rabies is a highly lethal disease caused by the neurotropic rabies virus (RABV), and it remains an important public health problem globally. Effective vaccines have been developed for pre- and post-exposure prophylaxis (PEP). PEP is only effective if it is initiated promptly after recognizing exposure. Once neurological symptoms develop, however, it is widely accepted that there is no effective treatment available. Recent studies indicate that the presence of RABV-specific immunity (i.e. Virus neutralizing antibodies, VNA) and the transient enhancement of the BBB permeability are absolutely required for effective virus clearance from the CNS. In principle, it has been shown in mice using various live-attenuated RABVs or recombinant RABVs expressing three copies of the G or expressing chemokine/cytokines, which can induce high levels of VNA in the serum and also capable of transiently enhancing the BBB permeability that it is possible to clear the virus from CNS. Also, it has been demonstrated that, intravenous administration of VNA together with MCP-1 (shown to transiently open up BBB) can clear RABV from the CNS in both immunocompetent and immunocompromised mice, as late as 5 days after lethal challenge. Novel therapeutic approaches aimed at allowing the peripheral VNA to cross the BBB by administration of the VNA in combination with biological or chemical agents that can transiently open up the BBB would be useful to establish an effective therapy for rabies in humans. In this review, we focus on the some of the approaches that can be used to meet the challenges in the field of rabies treatment.
Collapse
Affiliation(s)
- C W Gnanadurai
- Department of Pathology, College of Veterinary Medicine, University of Georgia Athens, USA
| | - C T Huang
- Department of Pathology, College of Veterinary Medicine, University of Georgia Athens, USA
| | - D Kumar
- Department of Pathology, College of Veterinary Medicine, University of Georgia Athens, USA
| | - Zhen F Fu
- Department of Pathology, College of Veterinary Medicine, University of Georgia Athens, USA; State-key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, China
| |
Collapse
|
|
43
|
Roy S, Patil D, Ghadigaonkar S, Roy R, Mukherjee S, Chowdhary A, Deshmukh R. A preliminary study of recombinant human interferon-α-2a activity against rabies virus in murine model. Indian J Med Microbiol 2015; 33:132-5. [PMID: 25560017 DOI: 10.4103/0255-0857.148412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Rabies remains an important public health problem in the world due to uncontrolled enzootic rabies. Although rabies associated fatalities may be prevented with timely immunoprophylaxis, but till date a therapeutic molecule has remained elusive. We investigated the role of rhuIFN α-2a in murine model challenged with rabies virus. Titre of 10(4.25) LD50/0.03 ml of 10% w/v RV CVS stock suspension were obtained. Based on 1LD50 titre, challenge dose of 50 LD 50 was administered along with rhuIFN α-2a with pre-exposure (primed) and post-exposure with the rabies virus. Both showed increased survival time as compared with the virus controls. These findings suggest that the rhuIFN α-2a might have some anti-viral activity, which can be used for the treatment of rabies infection. Further research on the efficacy of interferon along with anti-viral drugs for the treatment will be helpful in designing combination therapy against the disease.
Collapse
Affiliation(s)
- S Roy
- Department of Virology, Haffkine Institute, Department of Virology, Haffkine Institute for Training, research and Testing, Aacharya Donde Marg, Parel, Mumbai, Maharashtra - 400 012, India
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Chai Q, She R, Huang Y, Fu ZF. Expression of neuronal CXCL10 induced by rabies virus infection initiates infiltration of inflammatory cells, production of chemokines and cytokines, and enhancement of blood-brain barrier permeability. J Virol 2015; 89:870-6. [PMID: 25339777 PMCID: PMC4301165 DOI: 10.1128/jvi.02154-14] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 10/14/2014] [Indexed: 12/25/2022] Open
Abstract
It has been shown that enhancement of blood-brain barrier (BBB) permeability is modulated by the expression of chemokines/cytokines and reduction of tight junction (TJ) proteins in the brains of mice infected with rabies virus (RABV). Since CXCL10 was found to be the most highly expressed chemokine, its temporal and spatial expression were determined in the present study. The expression of the chemokine CXCL10 was initially detected in neurons as early as 3 days postinfection (p.i.) in the brains of RABV-infected mice, after which it was detected in microglia (6 days p.i.) and astrocytes (9 days p.i.). Neutralization of CXCL10 by treatment with anti-CXCL10 antibodies reduced gamma interferon (IFN-γ) production and Th17 cell infiltration, as well as restoring TJ protein expression and BBB integrity. Together, these data suggest that it is the neuronal CXCL10 that initiates the cascade that leads to the activation of microglia/astrocytes, infiltration of inflammatory cells, expression of chemokines/cytokines, reduction of TJ protein expression, and enhancement of the BBB permeability.
Collapse
Affiliation(s)
- Qingqing Chai
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Ruiping She
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Ying Huang
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Zhen F Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| |
Collapse
|
|
45
|
Barkhouse DA, Garcia SA, Bongiorno EK, Lebrun A, Faber M, Hooper DC. Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon. J Virol 2015; 89:312-22. [PMID: 25320312 PMCID: PMC4301114 DOI: 10.1128/jvi.01572-14] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 10/07/2014] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED Previous animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(-) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50) more than 100-fold greater than SPBN(-). In vitro and in vivo mouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR(-/-)) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-γ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus.
Collapse
Affiliation(s)
- Darryll A Barkhouse
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Samantha A Garcia
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Emily K Bongiorno
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Aurore Lebrun
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Milosz Faber
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - D Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
46
|
Libbey JE, Fujinami RS. Adaptive immune response to viral infections in the central nervous system. HANDBOOK OF CLINICAL NEUROLOGY 2014. [PMID: 25015488 DOI: 10.1016/b978-0-444-0.00010-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Jane E Libbey
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Robert S Fujinami
- Department of Pathology, University of Utah, Salt Lake City, UT, USA.
| |
Collapse
|
|
47
|
Libbey JE, Fujinami RS. Adaptive immune response to viral infections in the central nervous system. HANDBOOK OF CLINICAL NEUROLOGY 2014; 123:225-47. [PMID: 25015488 DOI: 10.1016/b978-0-444-53488-0.00010-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Jane E Libbey
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Robert S Fujinami
- Department of Pathology, University of Utah, Salt Lake City, UT, USA.
| |
Collapse
|
|
48
|
Huang CT, Li Z, Huang Y, Zhang G, Zhou M, Chai Q, Wu H, Fu ZF. Enhancement of blood-brain barrier permeability is required for intravenously administered virus neutralizing antibodies to clear an established rabies virus infection from the brain and prevent the development of rabies in mice. Antiviral Res 2014; 110:132-41. [PMID: 25108172 PMCID: PMC4171353 DOI: 10.1016/j.antiviral.2014.07.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 07/21/2014] [Accepted: 07/23/2014] [Indexed: 02/06/2023]
Abstract
Rabies virus (RABV) is a neurotropic virus that causes fatal disease in humans and animals. Currently there is no cure for rabies once clinical signs appear. It is believed that once RABV enters the central nervous system (CNS), virus neutralizing antibodies (VNAs) in the periphery cannot pass through the blood-brain barrier (BBB) and into the CNS. Furthermore, it has been hypothesized that VNAs produced in the CNS by invading B cells, rather than those produced in the periphery and then transported into the CNS, are important in clearing RABV from the CNS. In the present study, mouse serum containing VNA was administered intravenously into mice after infection with wild-type RABV. Our studies demonstrate that exogenous administration of VNAs is crucial in the clearance of RABV from the brain and prevent the development of rabies in both immunocompetent and immunocompromised mice as long as the BBB permeability remains enhanced. This present study therefore provides a foundation for the possibility of developing VNA therapy for clinical rabies in humans.
Collapse
Affiliation(s)
- Chien-Tsun Huang
- Department of Pathology, University of Georgia, Athens, GA 30602, USA
| | - Zhenguang Li
- Department of Pathology, University of Georgia, Athens, GA 30602, USA; State Key Laboratory of Special Economic Animal Molecular Biology, Institute of Special Economic Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130122, China
| | - Ying Huang
- Department of Pathology, University of Georgia, Athens, GA 30602, USA
| | - Guoqing Zhang
- Department of Pathology, University of Georgia, Athens, GA 30602, USA
| | - Ming Zhou
- Department of Pathology, University of Georgia, Athens, GA 30602, USA
| | - Qingqing Chai
- Department of Pathology, University of Georgia, Athens, GA 30602, USA
| | - Hua Wu
- State Key Laboratory of Special Economic Animal Molecular Biology, Institute of Special Economic Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130122, China
| | - Zhen F Fu
- Department of Pathology, University of Georgia, Athens, GA 30602, USA; State Key Laboratory of Agricultural Microbiology, Key Laboratory of Development of Veterinary Diagnostic Products, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| |
Collapse
|
|
49
|
Chai Q, He WQ, Zhou M, Lu H, Fu ZF. Enhancement of blood-brain barrier permeability and reduction of tight junction protein expression are modulated by chemokines/cytokines induced by rabies virus infection. J Virol 2014; 88:4698-710. [PMID: 24522913 PMCID: PMC3993813 DOI: 10.1128/jvi.03149-13] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 02/05/2014] [Indexed: 12/25/2022] Open
Abstract
UNLABELLED Infection with laboratory-attenuated rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and zonula occludens-1) were decreased in mice infected with laboratory-attenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that gamma interferon (IFN-γ) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-γ reduced both the disruption of BBB permeability in vivo and the downregulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are due not to RABV infection per se but to virus-induced inflammatory chemokines/cytokines. IMPORTANCE Previous studies have shown that infection with only laboratory-attenuated, not wild-type, rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, allowing immune effectors to enter the central nervous system (CNS) and clear RABV from the CNS. This study investigated the mechanism by which RABV infection enhances BBB permeability. It was found that RABV infection enhances BBB permeability by downregulation of tight junction (TJ) protein expression in the brain microvasculature. It was further found that it is not RABV infection per se but the chemokines/cytokines induced by RABV infection that downregulate the expression of TJ proteins and enhance BBB permeability. Blocking some of these cytokines, such as IFN-γ, ameliorated both the disruption of BBB permeability and the downregulation of TJ protein expression. These studies may provide a foundation for developing therapeutics for clinical rabies, such as medication that could be used to enhance BBB permeability.
Collapse
Affiliation(s)
- Qingqing Chai
- State-Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Wen Q. He
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Ming Zhou
- State-Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Huijun Lu
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Zhen F. Fu
- State-Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| |
Collapse
|
|
50
|
Schutsky K, Portocarrero C, Hooper DC, Dietzschold B, Faber M. Limited brain metabolism changes differentiate between the progression and clearance of rabies virus. PLoS One 2014; 9:e87180. [PMID: 24763072 PMCID: PMC3998930 DOI: 10.1371/journal.pone.0087180] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 12/19/2013] [Indexed: 12/25/2022] Open
Abstract
Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.
Collapse
Affiliation(s)
- Keith Schutsky
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Carla Portocarrero
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - D. Craig Hooper
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Bernhard Dietzschold
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Milosz Faber
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
| |
Collapse
|