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Emerging Infectious Diseases Dec 2020Rabies is a severe zoonotic disease in China, but the circulation and distribution of rabies virus (RABV) within animal reservoirs is not well understood. We report the...
Rabies is a severe zoonotic disease in China, but the circulation and distribution of rabies virus (RABV) within animal reservoirs is not well understood. We report the results of 15 years of surveillance of the first Chinese Rabies Surveillance Plan in animal populations, in which animal brain tissues collected during 2004-2018 were tested for RABV and phylogenetic and spatial-temporal evolutionary analyses performed using obtained RABV sequences. The results have provided the most comprehensive dataset to date on the infected animal species, geographic distribution, transmission sources, and genetic diversity of RABVs in China. In particular, the transboundary transmission of emerging RABV subclades between China and neighboring countries was confirmed. The study highlights the importance of continuous animal rabies surveillance in monitoring the transmission dynamics, and provides updated information for improving current control and prevention strategies at the source.
Topics: Animals; Cat Diseases; Cats; China; Dog Diseases; Dogs; Phylogeny; Population Surveillance; Rabies; Rabies virus
PubMed: 33219645
DOI: 10.3201/eid2612.200303 -
International Journal of Molecular... Jun 2023Rabies, a highly fatal zoonotic disease, is a significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and...
Rabies, a highly fatal zoonotic disease, is a significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and no effective treatment for rabies is available. Increasing evidence shows that the tripartite-motif protein (TRIM) family of proteins participates in the host's regulation of viral replication. Studies have demonstrated the upregulated expression of tripartite-motif protein 21 (TRIM21) in the brain tissue of mice infected with the rabies virus. Related studies have shown that TRIM21 knockdown inhibits RABV replication, while overexpression of TRIM21 exerted the opposite effect. Knockdown of interferon-alpha and interferon-beta modulates the inhibition of RABV replication caused by TRIM21 knockdown and promotes the replication of the virus. Furthermore, our previous study revealed that TRIM21 regulates the secretion of type I interferon during RABV infection by targeting interferon regulatory factor 7 (IRF7). IRF7 knockdown reduced the inhibition of RABV replication caused by the knockdown of TRIM21 and promoted viral replication. TRIM21 regulates RABV replication via the IRF7-IFN axis. Our study identified TRIM21 as a novel host factor required by RABV for replication. Thus, TRIM21 is a potential target for rabies treatment or management.
Topics: Animals; Mice; Rabies virus; Rabies; Interferon Regulatory Factor-7; Tripartite Motif Proteins; Ubiquitination; Virus Replication
PubMed: 37446070
DOI: 10.3390/ijms241310892 -
Vaccine Nov 2023Rabies is a preventable zoonotic disease caused by rabies virus (RABV) with high mortality. Messenger RNA (mRNA) vaccines have opened up new avenues for vaccine...
Rabies is a preventable zoonotic disease caused by rabies virus (RABV) with high mortality. Messenger RNA (mRNA) vaccines have opened up new avenues for vaccine development and pandemic preparedness with potent scalability, which may overcome the only licensed rabies inactived vaccine' shortcoming of time and cost wasting. Here, we designed an RABV mRNA vaccines expressed RABV G protein and capsulated with lipid nanoparticle (LNP) and different nucleic acid immunostimulator (CPG 1018, CPG 2395 and Poly I:C) and then assessed the immunogenicity and protective capacity in mice. While RABV mRNA capsulated with LNP and CPG 1018 could induce more potent humoral response with highest and durable RABV-G specific IgG titers and virus neutralizing titers, but also induced stronger RABV G-specific cell-mediated immunity (CMI) responses, including the highest proportions of interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNFα)- producing CD4+/CD8 + T cells according to a flow cytometry assay in mice. In addition, in the pre- and post-exposure challenge assays, LNP + CPG 1018 capsulated RABV G mRNA induced 100 % protection against 25 LD50 of RABV infection with highest inhibition efficacy of viral replication with the decreased virus genome detected by qRT-PCR. These results showed that RABV G mRNA capsulated with LNP immune-stimulating nucleic acids CPG 1018 showed promise as a safe and economical rabies vaccine candidate.
Topics: Animals; Mice; Rabies; Rabies virus; Antibodies, Viral; Rabies Vaccines; RNA, Messenger
PubMed: 37866995
DOI: 10.1016/j.vaccine.2023.10.019 -
PLoS Pathogens Dec 2022Rabies virus (RABV) transcription and replication take place within viral factories having liquid properties, called Negri bodies (NBs), that are formed by liquid-liquid...
Rabies virus (RABV) transcription and replication take place within viral factories having liquid properties, called Negri bodies (NBs), that are formed by liquid-liquid phase separation (LLPS). The co-expression of RABV nucleoprotein (N) and phosphoprotein (P) in mammalian cells is sufficient to induce the formation of cytoplasmic biocondensates having properties that are like those of NBs. This cellular minimal system was previously used to identify P domains that are essential for biocondensates formation. Here, we constructed fluorescent versions of N and analyzed by FRAP their dynamics inside the biocondensates formed in this minimal system as well as in NBs of RABV-infected cells using FRAP. The behavior of N appears to be different of P as there was no fluorescence recovery of N proteins after photobleaching. We also identified arginine residues as well as two exposed loops of N involved in condensates formation. Corresponding N mutants exhibited distinct phenotypes in infected cells ranging from co-localization with NBs to exclusion from them associated with a dominant-negative effect on infection. We also demonstrated that in vitro, in crowded environments, purified P as well as purified N0-P complex (in which N is RNA-free) form liquid condensates. We identified P domains required for LLPS in this acellular system. P condensates were shown to associate with liposomes, concentrate RNA, and undergo a liquid-gel transition upon ageing. Conversely, N0-P droplets were disrupted upon incubation with RNA. Taken together, our data emphasize the central role of P in NBs formation and reveal some physicochemical features of P and N0-P droplets relevant for explaining NBs properties such as their envelopment by cellular membranes at late stages of infection and nucleocapsids ejections from the viral factories.
Topics: Animals; Rabies virus; Nucleoproteins; Rabies; Nucleocapsid; Phosphoproteins; Virus Replication; Mammals
PubMed: 36480574
DOI: 10.1371/journal.ppat.1011022 -
Frontiers in Immunology 2023Rabies is a serious public health problem worldwide for which an effective treatment method is lacking but can be prevented by vaccines. Current vaccines are produced in...
INTRODUCTION
Rabies is a serious public health problem worldwide for which an effective treatment method is lacking but can be prevented by vaccines. Current vaccines are produced in cell or egg cultures, which are both costly and time consuming.
METHODS
Here, a non-replicating mRNA vaccine (RV021) encoding the rabies virus glycoprotein was developed , and its immunogenicity and protective efficacy against live virus was evaluated in mice.
RESULTS
A two-dose vaccination with 1 μg of RV021 at 7-day intervals induced a protective level of neutralizing antibody that was maintained for at least 260 days. RV021 induced a robust cellular immune response that was significantly superior to that of an inactivated vaccine. Two doses of 1 μg RV021 provided full protection against challenge with CVS of 30~60-fold lethal dose, 50%. Vaccine potency testing (according to the National Institutes of Health) revealed that the potency of RV021 at 15 μg/dose was 7.5 IU/dose, which is substantially higher than the standard for lot release of rabies vaccines for current human use.
CONCLUSION
The mRNA vaccine RV021 induces a strong protective immune response in mice, providing a new and promising strategy for human rabies prevention and control.
Topics: United States; Animals; Humans; Mice; Rabies; Rabies Vaccines; Antibodies, Viral; Antibodies, Neutralizing; Rabies virus
PubMed: 37954577
DOI: 10.3389/fimmu.2023.1288879 -
The Journal of General Virology Dec 2023The zoonotic rabies virus (RABV) is a non-segmented negative-sense RNA virus classified within the family , and is the most common aetiological agent responsible for...
The zoonotic rabies virus (RABV) is a non-segmented negative-sense RNA virus classified within the family , and is the most common aetiological agent responsible for fatal rabies disease. The RABV glycoprotein (G) forms trimeric spikes that protrude from RABV virions and mediate virus attachment, entry and spread, and is a major determinant of RABV pathogenesis. A range of RABV strains exist that are highly pathogenic in part due to their ability to evade host immune detection. However, some strains are disease-attenuated and can be cleared by host defences. A detailed molecular understanding of how strain variation relates to pathogenesis is currently lacking. Here, we reveal key differences in the trafficking profiles of RABV-G proteins from the challenge virus standard strain (CVS-11) and a highly attenuated vaccine strain SAD-B19 (SAD). We show that CVS-G traffics to the cell surface and undergoes rapid internalization through both clathrin- and cholesterol-dependent endocytic pathways. In contrast, SAD-G remains resident at the plasma membrane and internalizes at a significantly slower rate. Through engineering hybrids of CVS-G and SAD-G, we show that the cytoplasmic tail of CVS-G is the key determinant of these different internalization profiles. Alanine scanning further revealed that mutation of Y497 in CVS-G (H497 in SAD-G) could reduce the rate of internalization to SAD-G levels. Together, these data reveal new phenotypic differences between CVS-G and SAD-G proteins that may contribute to altered pathogenicity.
Topics: Humans; Rabies virus; Virus Internalization; Rabies; Rabies Vaccines; Glycoproteins; GTP-Binding Proteins
PubMed: 38063294
DOI: 10.1099/jgv.0.001935 -
Viruses Jul 2023Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog...
Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog populations [...].
Topics: Humans; Animals; Dogs; Rabies; Lyssavirus; Rabies virus; Dog Diseases
PubMed: 37515243
DOI: 10.3390/v15071557 -
The Indian Journal of Medical Research Jan 2024Rabies is a lethal viral disease transmitted through the bite of rabid animals. India has a high burden of rabies, contributing to a significant proportion of the global... (Review)
Review
Rabies is a lethal viral disease transmitted through the bite of rabid animals. India has a high burden of rabies, contributing to a significant proportion of the global deaths. However, under-reporting of the disease is prevalent due to lack of laboratory confirmation. Laboratory diagnosis of rabies plays a crucial role in differentiating the disease from clinical mimics, initiation of appropriate care, implementing infection control measures and informing disease surveillance. This review provides an overview of the recent advancements in laboratory diagnosis of rabies, aimed at updating physicians involved in diagnosis and management of rabies cases in India.
Topics: Animals; Rabies; Rabies virus; Laboratories; India; Clinical Laboratory Techniques; Bites and Stings
PubMed: 38376376
DOI: 10.4103/ijmr.ijmr_131_23 -
Vaccines Nov 2023Nipah virus (NiV) causes severe, lethal encephalitis in humans and pigs. However, there is no licensed vaccine available to prevent NiV infection. In this study, we used...
Nipah virus (NiV) causes severe, lethal encephalitis in humans and pigs. However, there is no licensed vaccine available to prevent NiV infection. In this study, we used the reverse genetic system based on the attenuated rabies virus strain SRV9 to construct two recombinant viruses, rSRV9-NiV-F and rSRV9-NiV-G, which displayed the NiV envelope glycoproteins F and G, respectively. Following three immunizations in BALB/c mice, the inactivated rSRV9-NiV-F and rSRV9-NiV-G alone or in combination, mixed with the adjuvants ISA 201 VG and poly (I:C), were able to induce the antigen-specific cellular and Th1-biased humoral immune responses. The specific antibodies against rSRV9-NiV-F and rSRV9-NiV-G had reactivity with two constructed bacterial-like particles displaying the F and G antigens of NiV. These data demonstrate that rSRV9-NiV-F or rSRV9-NiV-G has the potential to be developed into a promising vaccine candidate against NiV infection.
PubMed: 38140162
DOI: 10.3390/vaccines11121758 -
Journal of Virology May 2023Viral protein assembly and virion budding are tightly regulated to enable the proper formation of progeny virions. At this late stage in the virus life cycle, some...
Viral protein assembly and virion budding are tightly regulated to enable the proper formation of progeny virions. At this late stage in the virus life cycle, some enveloped viruses take advantage of the host endosomal sorting complex required for transport (ESCRT) machinery, which contributes to the physiological functions of membrane modulation and abscission. Bullet-shaped viral particles are unique morphological characteristics of rhabdoviruses; however, the involvement of host factors in rhabdovirus infection and, specifically, the molecular mechanisms underlying virion formation are not fully understood. In the present study, we used a small interfering RNA (siRNA) screening approach and found that the ESCRT-I component TSG101 contributes to the propagation of rabies virus (RABV). We demonstrated that the matrix protein (M) of RABV interacts with TSG101 via the late domain containing the PY and YL motifs, which are conserved in various viral proteins. Loss of the YL motif in the RABV M or the downregulation of host TSG101 expression resulted in the intracellular aggregation of viral proteins and abnormal virus particle formation, indicating a defect in the RABV assembly and budding processes. These results indicate that the interaction of the RABV M and TSG101 is pivotal for not only the efficient budding of progeny RABV from infected cells but also for the bullet-shaped virion morphology. Enveloped viruses bud from cells with the host lipid bilayer. Generally, the membrane modulation and abscission are mediated by host ESCRT complexes. Some enveloped viruses utilize their late (L-) domain to interact with ESCRTs, which promotes viral budding. Rhabdoviruses form characteristic bullet-shaped enveloped virions, but the underlying molecular mechanisms involved remain elusive. Here, we showed that TSG101, one of the ESCRT components, supports rabies virus (RABV) budding and proliferation. TSG101 interacted with RABV matrix protein via the L-domain, and the absence of this interaction resulted in intracellular virion accumulation and distortion of the morphology of progeny virions. Our study reveals that virion formation of RABV is highly regulated by TSG101 and the virus matrix protein.
Topics: Humans; Endosomal Sorting Complexes Required for Transport; Morphogenesis; Rabies; Rabies virus; Viral Proteins; Virion; Virus Release; Cell Line; Animals
PubMed: 37042780
DOI: 10.1128/jvi.00438-23