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Oncotarget Mar 2016
Topics: Animals; Biological Transport; Blood-Brain Barrier; Chemokine CXCL10; Mice; Rabies; Rabies virus
PubMed: 26895109
DOI: 10.18632/oncotarget.7428 -
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 -
Biology Letters Sep 2022Rabies virus (RABV) transmitted by the common vampire bat () poses a threat to agricultural development and public health throughout the Neotropics. The ecology and... (Review)
Review
Rabies virus (RABV) transmitted by the common vampire bat () poses a threat to agricultural development and public health throughout the Neotropics. The ecology and evolution of rabies host-pathogen dynamics are influenced by two infection-induced behavioural changes. RABV-infected hosts often exhibit increased aggression which facilitates transmission, and rabies also leads to reduced activity and paralysis prior to death. Although several studies document rabies-induced behavioural changes in rodents and other dead-end hosts, surprisingly few studies have measured these changes in vampire bats, the key natural reservoir throughout Latin America. Taking advantage of an experiment designed to test an oral rabies vaccine in captive male vampire bats, we quantify for the first time, to our knowledge, how rabies affects allogrooming and aggressive behaviours in this species. Compared to non-rabid vampire bats, rabid individuals reduced their allogrooming prior to death, but we did not detect increases in aggression among bats. To put our results in context, we review what is known and what remains unclear about behavioural changes of rabid vampire bats (resumen en español, electronic supplementary material, S1).
Topics: Animals; Chiroptera; Male; Rabies; Rabies Vaccines; Rabies virus
PubMed: 36069068
DOI: 10.1098/rsbl.2022.0298 -
Current Opinion in Virology Apr 2019Rabies virus (RABV) constitutes a major social and economic burden associated with 60 000 deaths annually worldwide. Although pre-exposure and post-exposure treatment... (Review)
Review
Rabies virus (RABV) constitutes a major social and economic burden associated with 60 000 deaths annually worldwide. Although pre-exposure and post-exposure treatment options are available, they are efficacious only when initiated before the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNA-dependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.
Topics: Animals; Antibodies, Viral; Antiviral Agents; Humans; Lyssavirus; Mice; Rabies; Rabies virus; Vaccination; Viral Proteins
PubMed: 30753961
DOI: 10.1016/j.coviro.2018.12.009 -
Viruses Apr 2022Rabies is an ancient lethal scourge that has plagued humankind for centuries [...].
Rabies is an ancient lethal scourge that has plagued humankind for centuries [...].
Topics: Humans; Rabies; Rabies virus
PubMed: 35632587
DOI: 10.3390/v14050845 -
Revue Scientifique Et Technique... Aug 2018Rabies is an ancient zoonotic disease caused by infection with the rabies virus (RABV). While the circulation of RABV in domestic dogs has been appreciated for...
Rabies is an ancient zoonotic disease caused by infection with the rabies virus (RABV). While the circulation of RABV in domestic dogs has been appreciated for centuries, the recognition of bat and wild carnivore reservoirs began in the early part of the 20th century. Bats are the ancestral reservoir of RABV and a remarkable diversity of species perpetuate distinct lineages of the virus, despite the fact that circulation in bats is geographically limited to the New World fauna. The circulation of RABV in domestic dogs likely represents a historic shift from a bat reservoir, although the timing and details of such an ancient event have been difficult to resolve from the virus genetic evidence. Since becoming established in the domestic dog population, RABV has undergone repeated host shifts to wild carnivores globally. These shifts have most frequently been to species within families of the Caniformia suborder of carnivores. The circulation of RABV in bats has been linked to host shifts to wild carnivore reservoirs in North and South America. It is clear that RABV has been incredibly successful at exploiting diverse chiropteran and carnivore hosts. With improved control of circulation in domestic dogs, surveillance is likely to yield additional discoveries regarding the diversity of wildlife reservoirs and vectors of RABV.
Topics: Animals; Animals, Domestic; Animals, Wild; Chiroptera; Disease Reservoirs; Dogs; North America; Rabies; Rabies virus; South America; Zoonoses
PubMed: 30747141
DOI: 10.20506/rst.37.2.2808 -
Proceedings of the National Academy of... May 2022Cortical circuit tracing using modified rabies virus can identify input neurons making direct monosynaptic connections onto neurons of interest. However, challenges...
Cortical circuit tracing using modified rabies virus can identify input neurons making direct monosynaptic connections onto neurons of interest. However, challenges remain in our ability to establish the cell type identity of rabies-labeled input neurons. While transcriptomics may offer an avenue to characterize inputs, the extent of rabies-induced transcriptional changes in distinct neuronal cell types remains unclear, and whether these changes preclude characterization of rabies-infected neurons according to established transcriptomic cell types is unknown. We used single-nucleus RNA sequencing to survey the gene expression profiles of rabies-infected neurons and assessed their correspondence with established transcriptomic cell types. We demonstrated that when using transcriptome-wide RNA profiles, rabies-infected cortical neurons can be transcriptomically characterized despite global and cell-type-specific rabies-induced transcriptional changes. Notably, we found differential modulation of neuronal marker gene expression, suggesting that caution should be taken when attempting to characterize rabies-infected cells with single genes or small gene sets.
Topics: DNA Fingerprinting; Humans; Neurons; Rabies; Rabies virus; Sequence Analysis, RNA; Transcription, Genetic; Transcriptome
PubMed: 35609197
DOI: 10.1073/pnas.2203677119 -
PLoS Neglected Tropical Diseases Feb 2020Rabies 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... (Review)
Review
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.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Humans; Rabies; Rabies Vaccines; Rabies virus; Vaccination
PubMed: 32053628
DOI: 10.1371/journal.pntd.0007933 -
ELife Feb 2024Mapping the connectivity of diverse neuronal types provides the foundation for understanding the structure and function of neural circuits. High-throughput and low-cost...
Mapping the connectivity of diverse neuronal types provides the foundation for understanding the structure and function of neural circuits. High-throughput and low-cost neuroanatomical techniques based on RNA barcode sequencing have the potential to map circuits at cellular resolution and a brain-wide scale, but existing Sindbis virus-based techniques can only map long-range projections using anterograde tracing approaches. Rabies virus can complement anterograde tracing approaches by enabling either retrograde labeling of projection neurons or monosynaptic tracing of direct inputs to genetically targeted postsynaptic neurons. However, barcoded rabies virus has so far been only used to map non-neuronal cellular interactions in vivo and synaptic connectivity of cultured neurons. Here we combine barcoded rabies virus with single-cell and in situ sequencing to perform retrograde labeling and transsynaptic labeling in the mouse brain. We sequenced 96 retrogradely labeled cells and 295 transsynaptically labeled cells using single-cell RNA-seq, and 4130 retrogradely labeled cells and 2914 transsynaptically labeled cells in situ. We found that the transcriptomic identities of rabies virus-infected cells can be robustly identified using both single-cell RNA-seq and in situ sequencing. By associating gene expression with connectivity inferred from barcode sequencing, we distinguished long-range projecting cortical cell types from multiple cortical areas and identified cell types with converging or diverging synaptic connectivity. Combining in situ sequencing with barcoded rabies virus complements existing sequencing-based neuroanatomical techniques and provides a potential path for mapping synaptic connectivity of neuronal types at scale.
Topics: Animals; Mice; Rabies virus; Neuroanatomy; Neurons; Sequence Analysis, RNA; RNA
PubMed: 38319699
DOI: 10.7554/eLife.87866 -
PloS One 2021Rabies spreads in both Arctic (Vulpes lagopus) and red foxes (Vulpes vulpes) throughout the Canadian Arctic but limited wildlife disease surveillance, due to the...
Rabies spreads in both Arctic (Vulpes lagopus) and red foxes (Vulpes vulpes) throughout the Canadian Arctic but limited wildlife disease surveillance, due to the extensive landmass of the Canadian north and its small widely scattered human population, undermines our knowledge of disease transmission patterns. This study has explored genetic population structure in both the rabies virus and its fox hosts to better understand factors that impact rabies spread. Phylogenetic analysis of 278 samples of the Arctic lineage of rabies virus recovered over 40 years identified four sub-lineages, A1 to A4. The A1 lineage has been restricted to southern regions of the Canadian province of Ontario. The A2 lineage, which predominates in Siberia, has also spread to northern Alaska while the A4 lineage was recovered from southern Alaska only. The A3 sub-lineage, which was also found in northern Alaska, has been responsible for virtually all cases across northern Canada and Greenland, where it further differentiated into 18 groups which have systematically evolved from a common predecessor since 1975. In areas of Arctic and red fox sympatry, viral groups appear to circulate in both hosts, but both mitochondrial DNA control region sequences and 9-locus microsatellite genotypes revealed contrasting phylogeographic patterns for the two fox species. Among 157 Arctic foxes, 33 mitochondrial control region haplotypes were identified but little genetic structure differentiating localities was detected. Among 162 red foxes, 18 control region haplotypes delineated three groups which discriminated among the Churchill region of Manitoba, northern Quebec and Labrador populations, and the coastal Labrador locality of Cartwright. Microsatellite analyses demonstrated some genetic heterogeneity among sampling localities of Arctic foxes but no obvious pattern, while two or three clusters of red foxes suggested some admixture between the Churchill and Quebec-Labrador regions but uniqueness of the Cartwright group. The limited population structure of Arctic foxes is consistent with the rapid spread of rabies virus subtypes throughout the north, while red fox population substructure suggests that disease spread in this host moves most readily down certain independent corridors such as the northeastern coast of Canada and the central interior. Interestingly the evidence suggests that these red fox populations have limited capacity to maintain the virus over the long term, but they may contribute to viral persistence in areas of red and Arctic fox sympatry.
Topics: Animals; Canada; DNA, Mitochondrial; Foxes; Genotype; Microsatellite Repeats; Phylogeny; Rabies virus
PubMed: 33592018
DOI: 10.1371/journal.pone.0246508