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Iranian Biomedical Journal Jul 2021Viruses are obligatory intracellular parasites that use cell proteins to take the control of the cell functions in order to accomplish their life cycle. Studying the... (Review)
Review
Viruses are obligatory intracellular parasites that use cell proteins to take the control of the cell functions in order to accomplish their life cycle. Studying the viral-host interactions would increase our knowledge of the viral biology and mechanisms of pathogenesis. Studies on pathogenesis mechanisms of lyssaviruses, which are the causative agents of rabies, have revealed some important host protein partners for viral proteins, especially for most studied species, i.e. Rabies virus. In this review article, the key physical lyssavirus-host protein interactions, their contributions to rabies infection, and their exploitation are discussed to improve the knowledge about rabies pathogenesis.
Topics: Animals; Host Microbial Interactions; Humans; Lyssavirus; Phagocytosis; Protein Binding; Rabies; Rabies virus
PubMed: 34217155
DOI: 10.52547/ibj.25.4.226 -
Human Vaccines & Immunotherapeutics Dec 2022Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure... (Review)
Review
Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure prophylaxis should be administered as soon as possible. Monoclonal antibodies (mAbs) neutralizing the rabies virus could be better in human rabies post-exposure prophylaxis than equine or human rabies immune globulin in terms of supply, cost, and efficacy. This article reviews anti-rabies mAbs produced by multiple techniques, and the results of clinical trials for anti-rabies mAbs cocktails recognizing non-overlapping epitopes are also discussed.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antineoplastic Agents, Immunological; Horses; Neutralization Tests; Post-Exposure Prophylaxis; Rabies; Rabies Vaccines; Rabies virus
PubMed: 35172707
DOI: 10.1080/21645515.2022.2026713 -
Animal Models and Experimental Medicine Oct 2022Rabies virus (RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people... (Review)
Review
Rabies virus (RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people and public safety. It is well known that innate immunity is the critical first line of host defense against viral infection. It monitors the invading pathogens by recognizing the pathogen-associated molecular patterns and danger-associated molecular patterns through pattern-recognition receptors, leading to the production of type I interferons (IFNα/β), inflammatory cytokines, and chemokines, or the activation of autophagy or apoptosis to inhibit virus replication. In the case of RABV, the innate immune response is usually triggered when the skin or muscle is bitten or scratched. However, RABV has evolved many ways to escape or even hijack innate immune response to complete its own replication and eventually invades the central nervous system (CNS). Once RABV reaches the CNS, it cannot be wiped out by the immune system or any drugs. Therefore, a better understanding of the interplay between RABV and innate immunity is necessary to develop effective strategies to combat its infection. Here, we review the innate immune responses induced by RABV and illustrate the antagonism mechanisms of RABV to provide new insights for the control of rabies.
Topics: Animals; Humans; Rabies virus; Rabies; Immunity, Innate; Cytokines; Chemokines
PubMed: 36138548
DOI: 10.1002/ame2.12273 -
Cell Host & Microbe Mar 2020Rabies virus (RABV), the etiological agent for the lethal disease of rabies, is a deadly zoonotic pathogen. The RABV glycoprotein (RABV-G) is a key factor mediating...
Rabies virus (RABV), the etiological agent for the lethal disease of rabies, is a deadly zoonotic pathogen. The RABV glycoprotein (RABV-G) is a key factor mediating virus entry and the major target of neutralizing antibodies. Here, we report the crystal structures of RABV-G solved in the free form at ∼pH-8.0 and in the complex form with a neutralizing antibody 523-11 at ∼pH-6.5, respectively. RABV-G has three domains, and the basic-to-acidic pH change results in large domain re-orientations and concomitant domain-linker re-constructions, switching it from a bent hairpin conformation into an extended conformation. During such low-pH-induced structural transitions, residues located in the domain-linker are found to play important roles in glycoprotein-mediated membrane fusion. Finally, the antibody interacts with RABV-G mainly through its heavy chain and binds to a bipartite conformational epitope in the viral protein for neutralization. These structures provide valuable information for vaccine and drug design.
Topics: Amino Acid Sequence; Animals; Antibodies, Neutralizing; Antibodies, Viral; Antigens, Viral; Cell Fusion; Cell Line; Cricetinae; Hydrogen-Ion Concentration; Protein Multimerization; Protein Structure, Tertiary; Rabies virus; Viral Envelope Proteins
PubMed: 32004500
DOI: 10.1016/j.chom.2019.12.012 -
Cell Host & Microbe Sep 2022Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus...
Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G's pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies.
Topics: Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Epitopes; Glycoproteins; Humans; Membrane Proteins; Rabies; Rabies Vaccines; Rabies virus
PubMed: 35985336
DOI: 10.1016/j.chom.2022.07.014 -
Nature Communications Jun 2023Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune...
Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune response, and whether responses can be improved using novel vaccine platforms. Here we show that two doses of a lipid nanoparticle-formulated unmodified mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) induces higher levels of RABV-G specific plasmablasts and T cells in blood, and plasma cells in the bone marrow compared to two doses of Rabipur in non-human primates. The mRNA vaccine also generates higher RABV-G binding and neutralizing antibody titers than Rabipur, while the degree of somatic hypermutation and clonal diversity of the response are similar for the two vaccines. The higher overall antibody titers induced by the mRNA vaccine translates into improved cross-neutralization of related lyssavirus strains, suggesting that this platform has potential for the development of a broadly protective vaccine against these viruses.
Topics: Animals; Humans; Rabies; Rabies Vaccines; Broadly Neutralizing Antibodies; RNA, Messenger; Antibodies, Viral; Rabies virus; Glycoproteins
PubMed: 37349310
DOI: 10.1038/s41467-023-39421-5 -
Virology Journal Nov 2022Rabies is a lethal zoonotic disease that is mainly caused by the rabies virus (RABV). Although effective vaccines have long existed, current vaccines take both time and...
Rabies is a lethal zoonotic disease that is mainly caused by the rabies virus (RABV). Although effective vaccines have long existed, current vaccines take both time and cost to produce. Messenger RNA (mRNA) technology is an emergent vaccine platform that supports rapid vaccine development on a large scale. Here, an optimized mRNA vaccine construct (LVRNA001) expressing rabies virus glycoprotein (RABV-G) was developed in vitro and then evaluated in vivo for its immunogenicity and protective capacity in mice and dogs. LVRNA001 induced neutralizing antibody production and a strong Th1 cellular immune response in mice. In both mice and dogs, LVRNA001 provided protection against challenge with 50-fold lethal dose 50 (LD) of RABV. With regards to protective efficiency, an extended dosing interval (14 days) induced greater antibody production than 3- or 7-day intervals in mice. Finally, post-exposure immunization against RABV was performed to evaluate the survival rates of dogs receiving two 25 μg doses of LVRNA001 vs. five doses of inactivated vaccine over the course of three months. Survival rate in the LVRNA001 group was 100%, whereas survival rate in the inactivated vaccine control group was only 33.33%. In conclusion, these results demonstrated that LVRNA001 induced strong protective immune responses in mice and dogs, which provides a new and promising prophylactic strategy for rabies.
Topics: Dogs; Mice; Animals; Rabies Vaccines; Rabies; RNA, Messenger; Antibodies, Viral; Rabies virus; Vaccines, Inactivated; Antibody Formation; mRNA Vaccines
PubMed: 36371169
DOI: 10.1186/s12985-022-01919-7 -
Molecular Therapy : the Journal of the... Mar 2021Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III...
Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
Topics: Animals; Cell Line; Encephalitis Virus, Venezuelan Equine; Fibroblasts; Gene Expression Regulation; HeLa Cells; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunogenicity, Vaccine; Immunoglobulin G; Interferon Regulatory Factor-3; Janus Kinases; Mice; Middle East Respiratory Syndrome Coronavirus; NF-kappa B; Nitriles; Parainfluenza Virus 5; Protein Biosynthesis; Pyrazoles; Pyrimidines; Rabbits; Rabies virus; Rats; STAT Transcription Factors; Signal Transduction; Vaccines, Synthetic; Viral Envelope Proteins; mRNA Vaccines
PubMed: 33352107
DOI: 10.1016/j.ymthe.2020.11.011 -
BMJ Case Reports Apr 2021Rabies is an almost always fatal disease that physicians and patients dread due to its dismal prognosis and limited treatment options. Transmission of this disease...
Rabies is an almost always fatal disease that physicians and patients dread due to its dismal prognosis and limited treatment options. Transmission of this disease occurs through the bite of dogs and wild animals (like jackal in our case). Other rare forms of transmission may be through inhalation in bat-infested caves and human-to-human transmission by infected corneal transplants, solid organ and tissue transplantation, and sometimes in laboratory settings. Its diagnosis is usually clinical in the absence of availability of special laboratory investigations at the point-of-care facility. Few people have described the role of imaging in diagnosis. We hereby report a patient with rabies encephalitis, having a history of jackal bite and classical MRI findings that we can use for early diagnosis in the absence of typical clinical features and specialised diagnostic testing.
Topics: Animals; Bites and Stings; Dogs; Encephalitis; Humans; Magnetic Resonance Imaging; Rabies; Rabies virus
PubMed: 33906884
DOI: 10.1136/bcr-2020-239249 -
Journal of Virology Oct 2020, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory... (Review)
Review
, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV). Unfortunately, no effective vaccines and antiviral therapeutics against many are currently available. Viral polymerases have been attractive and major antiviral therapeutic targets. Therefore, polymerases have been extensively investigated for their structures and functions. mimic RNA synthesis of their eukaryotic counterparts by utilizing multifunctional RNA polymerases to replicate entire viral genomes and transcribe viral mRNAs from individual viral genes as well as synthesize 5' methylated cap and 3' poly(A) tail of the transcribed viral mRNAs. The catalytic subunit large protein (L) and cofactor phosphoprotein (P) constitute the polymerases. In this review, we discuss the shared and unique features of RNA synthesis, the monomeric multifunctional enzyme L, and the oligomeric multimodular adapter P of We outline the structural analyses of the polymerases since the first structure of the vesicular stomatitis virus (VSV) L protein determined in 2015 and highlight multiple high-resolution cryo-electron microscopy (cryo-EM) structures of the polymerases of , namely, VSV, RABV, HRSV, human metapneumovirus (HMPV), and human parainfluenza virus (HPIV), that have been reported in recent months (2019 to 2020). We compare the structures of those polymerases grouped by virus family, illustrate the similarities and differences among those polymerases, and reveal the potential RNA synthesis mechanisms and models of highly conserved We conclude by the discussion of remaining questions, evolutionary perspectives, and future directions.
Topics: Animals; Cryoelectron Microscopy; Humans; Metapneumovirus; Models, Molecular; Mononegavirales; Protein Conformation; RNA, Messenger; RNA, Viral; RNA-Dependent RNA Polymerase; Rabies virus; Respiratory Syncytial Virus, Human; Vesicular stomatitis Indiana virus; Viral Proteins; Virus Replication
PubMed: 32847861
DOI: 10.1128/JVI.00175-20