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Autophagy Apr 2024Lyssaviruses are well-known worldwide and often cause fatal encephalitis. Previous studies have shown that autophagy is beneficial for the replication of rabies virus...
Lyssaviruses are well-known worldwide and often cause fatal encephalitis. Previous studies have shown that autophagy is beneficial for the replication of rabies virus (RABV), the representative lyssavirus, but the detailed mechanism remains obscure. In this study, we showed that the rabies virus matrix protein (RABV-M) used its PPxY motif to interact with the E3 ubiquitin-protein ligase NEDD4. NEDD4 then recruited MAP1LC3/LC3 via its LC3-interacting region (LIR). Interestingly, after binding to the ubiquitinated RABV-M, NEDD4 could bind more LC3 and enhance autophagosome accumulation, while NEDD4 knockdown significantly reduced M-induced autophagosome accumulation. Further study revealed that RABV-M prevented autophagosome-lysosome fusion and facilitated viral budding. Inhibition of RABV-M-induced autophagosome accumulation reduced the production of extracellular virus-like particles. We also found that M proteins of most lyssaviruses share the same mechanism to accumulate autophagosome by hijacking NEDD4. Collectively, this study revealed a novel strategy for lyssaviruses to achieve efficient viral replication by exploiting the host autophagy system. ABLV: Australian bat lyssavirus; ATG5: autophagy related 5; Baf A1:bafilomycin A;co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI:4',6-diamidino-2'-phenylindole; DMSO: dimethyl sulfoxide; EBLV:European bat lyssavirus; GFP: green fluorescent protein; GST:glutathione S-transferase; hpi: hours post-infection; hpt: hourspost-transfection; LIR: LC3-interactingregion;MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mCherry:red fluorescent protein; MOI: multiplicity of infection; NC: negativecontrol; MVB: multivesicular body; NEDD4: neural precursorcell-expressed developmentally down-regulated 4; RABV: rabies virus;SQSTM1/p62: sequestosome 1; VLP: virus-like particle; VPS4B: vacuolarprotein sorting 4B; TEM: transmission electron microscopy; WB:western blotting; WT: wild-type; μm: micrometer; μM: micromole.
PubMed: 38566321
DOI: 10.1080/15548627.2024.2338575 -
Antiviral Research May 2024Despite the availability of effective preventative vaccines and potent small-molecule antiviral drugs, effective non-toxic prophylactic and therapeutic measures are... (Review)
Review
Despite the availability of effective preventative vaccines and potent small-molecule antiviral drugs, effective non-toxic prophylactic and therapeutic measures are still lacking for many viruses. The use of monoclonal and polyclonal antibodies in an antiviral context could fill this gap and provide effective virus-specific medical interventions. In order to develop these therapeutic antibodies, preclinical animal models are of utmost importance. Due to the variability in viral pathogenesis, immunity and overall characteristics, the most representative animal model for human viral infection differs between virus species. Therefore, throughout the years researchers sought to find the ideal preclinical animal model for each virus. The most used animal models in preclinical research include rodents (mice, ferrets, …) and non-human primates (macaques, chimpanzee, ….). Currently, antibodies are tested for antiviral efficacy against a variety of viruses including different hepatitis viruses, human immunodeficiency virus (HIV), influenza viruses, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rabies virus. This review provides an overview of the current knowledge about the preclinical animal models that are used for the evaluation of therapeutic antibodies for the abovementioned viruses.
Topics: Animals; Mice; Ferrets; Antibodies, Viral; Respiratory Syncytial Virus, Human; SARS-CoV-2; Disease Models, Animal; Antiviral Agents
PubMed: 38548022
DOI: 10.1016/j.antiviral.2024.105843 -
The European Journal of Neuroscience May 2024The posterior parietal cortex (PPC) integrates multisensory and motor-related information for generating and updating body representations and movement plans. We used...
Pathways from the superior colliculus and the nucleus of the optic tract to the posterior parietal cortex in macaque monkeys: Functional frameworks for representation updating and online movement guidance.
The posterior parietal cortex (PPC) integrates multisensory and motor-related information for generating and updating body representations and movement plans. We used retrograde transneuronal transfer of rabies virus combined with a conventional tracer in macaque monkeys to identify direct and disynaptic pathways to the arm-related rostral medial intraparietal area (MIP), the ventral lateral intraparietal area (LIPv), belonging to the parietal eye field, and the pursuit-related lateral subdivision of the medial superior temporal area (MSTl). We found that these areas receive major disynaptic pathways via the thalamus from the nucleus of the optic tract (NOT) and the superior colliculus (SC), mainly ipsilaterally. NOT pathways, targeting MSTl most prominently, serve to process the sensory consequences of slow eye movements for which the NOT is the key sensorimotor interface. They potentially contribute to the directional asymmetry of the pursuit and optokinetic systems. MSTl and LIPv receive feedforward inputs from SC visual layers, which are potential correlates for fast detection of motion, perceptual saccadic suppression and visual spatial attention. MSTl is the target of efference copy pathways from saccade- and head-related compartments of SC motor layers and head-related reticulospinal neurons. They are potential sources of extraretinal signals related to eye and head movement in MSTl visual-tracking neurons. LIPv and rostral MIP receive efference copy pathways from all SC motor layers, providing online estimates of eye, head and arm movements. Our findings have important implications for understanding the role of the PPC in representation updating, internal models for online movement guidance, eye-hand coordination and optic ataxia.
Topics: Animals; Superior Colliculi; Parietal Lobe; Optic Tract; Male; Movement; Macaca mulatta; Eye Movements
PubMed: 38544445
DOI: 10.1111/ejn.16314 -
Vaccines Mar 2024Rabies, a viral disease spread by infected animal bites that causes encephalitis in humans and other mammals, is a neglected infectious disease present on all continents...
Rabies, a viral disease spread by infected animal bites that causes encephalitis in humans and other mammals, is a neglected infectious disease present on all continents except Antarctica. Spain has been free of terrestrial rabies since 1978. However, due to its geographical situation, it represents a bridge for imported cases from an endemic continent such as Africa to Europe. Rabies vaccination in dogs is an essential preventive tool against this zoonosis. The aim of this study was to determine the state of the immune response against rabies virus in dogs in Spain and to demonstrate whether several factors that have been previously related to the influence of the seroprevalence of this species are involved here. The seroconversion level of this zoonotic virus was assessed in a total of 1060 animals. Indirect ELISA was used to obtain data for statistical analysis to evaluate the studied variables. Working under the concept of One Health, this study provides relevant information to be taken into consideration not only to prevent re-emergence in countries free of this disease but also for prevention and control in endemic countries.
PubMed: 38543927
DOI: 10.3390/vaccines12030293 -
Microorganisms Mar 2024Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous... (Review)
Review
Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous interaction with humans poses a significant threat to the survival and well-being of everyone. Apart from the common cold or seasonal influenza, viruses are also responsible for several important diseases such as polio, rabies, smallpox, and most recently COVID-19. Besides the loss of life and long-term health-related issues, clinical viral infections have significant economic and social impacts. Viral enzymes, especially proteases which are essential for viral multiplication, represent attractive drug targets. As a result, screening of viral protease inhibitors has gained a lot of interest in the development of anti-viral drugs. Despite the availability of anti-viral therapeutics, there is a clear need to develop novel curative agents that can be used against a given virus or group of related viruses. This review highlights the importance of yeasts as an in vivo model for screening viral enzyme inhibitors. We also discuss the advantages of yeast-based screening platforms over traditional assays. Therefore, in the present article, we discuss why yeast is emerging as a model of choice for in vivo screening of anti-viral molecules and why yeast-based screening will become more relevant in the future for screening anti-viral and other molecules of clinical importance.
PubMed: 38543629
DOI: 10.3390/microorganisms12030578 -
Animals : An Open Access Journal From... Mar 2024The water buffalo () has great adaptability to rustic environments and more variable conditions than cattle, who generally share the habitat. Diseases carried by... (Review)
Review
The water buffalo () has great adaptability to rustic environments and more variable conditions than cattle, who generally share the habitat. Diseases carried by buffaloes are relatively unknown and ignored and could be transmissible; an imbalance occurs between pathogens, environment, and susceptible hosts, generating a severe animal health problem. Also relevant is the effect of climate change on the populations of vectors that transmit viral diseases. The discovery of new virus variants that can pass from bovine (Bos) to buffalo or vice versa or to humans has highlighted the relevance of viruses crossing the host barrier. This review discusses the clinical viral diseases most reported in the water buffalo, characteristics, epidemiology, and recent findings about disease behavior, interaction with other species, the host, vectors, and pathogens. Diseases reviewed include Foot and Mouth Disease, Rinderpest, Malignant Catarrhal Fever, Infectious Bovine Rhinotracheitis, Bovine Viral Diarrhea, and Rabies. Also, vector-borne diseases include Lumpy Skin Disease, Ephemeral Fever, and Blue Tongue. The review also considers emerging viruses such as Buffalo Pox and Schmallenberg and, finally, other viruses such as papillomatosis. The knowledge and epidemiology of buffalo viral diseases must be constantly reconsidered and updated for adequate prevention and control programs.
PubMed: 38539942
DOI: 10.3390/ani14060845 -
Brazilian Journal of Biology = Revista... 2024The hematophagous bats are usually the main reservoir of sylvatic rabies, being one of the most important viral zoonoses affecting humans and livestock in Latin America.... (Observational Study)
Observational Study
The hematophagous bats are usually the main reservoir of sylvatic rabies, being one of the most important viral zoonoses affecting humans and livestock in Latin America. Despite the most countries have already studied spatio-temporal distribution of bovine rabies, however, in Ecuador, little has been reported about the state of rabies in the country. Aiming to this objective, a descriptive observational study was realized from 2007 to 2020 based on the formal reports by WAHI-OIE and surveillance of bovine rabies retrieved from its official website. During the study period in Ecuador, some 895 cases of rabies were confirmed in cattle. In addition, in the total of bovine rabies cases seen in Andean and Coast regions (185 effected bovines), Loja and Esmeraldas had 95 (6.16% cases per 10,000 animals) and 51 (1.7% cases per 10,000 animals), respectively. Furthermore, the Amazon region indicated higher rabies cases in cattle than to the observed in other regions (710 rabies cases) while it was highly fluctuating with respect to the years (9.74 to 42.82% cases per 10,000 animals). However, Zamora (292 rabies cases), Orellana (115 rabies cases) and Sucumbíos (113 rabies cases) yielded the highest incidence rates than other provinces (9 to 42% cases per 10,000 animals). Based on this evidence, it has been fundamental to assess the current national program for preventing and control of the sylvatic rabies, being also necessary to include concept of the ecology of the vampire bat. Regardless of these results, vaccination is vital for control programs to prevent rabies in livestock and need to be widely increased for limiting their geographic and temporal spread.
Topics: Animals; Cattle; Humans; Chiroptera; Ecuador; Rabies; Rabies virus; Retrospective Studies; Cross-Sectional Studies
PubMed: 38536975
DOI: 10.1590/1519-6984.279112 -
BMC Medicine Mar 2024Synaptic dysfunction with reduced synaptic protein levels is a core feature of Alzheimer's disease (AD). Synaptic proteins play a central role in memory processing,...
BACKGROUND
Synaptic dysfunction with reduced synaptic protein levels is a core feature of Alzheimer's disease (AD). Synaptic proteins play a central role in memory processing, learning, and AD pathogenesis. Evidence suggests that synaptic proteins in plasma neuronal-derived extracellular vesicles (EVs) are reduced in patients with AD. However, it remains unclear whether levels of synaptic proteins in EVs are associated with hippocampal atrophy of AD and whether upregulating the expression of these synaptic proteins has a beneficial effect on AD.
METHODS
In this study, we included 57 patients with AD and 56 healthy controls. We evaluated their brain atrophy through magnetic resonance imaging using the medial temporal lobe atrophy score. We measured the levels of four synaptic proteins, including synaptosome-associated protein 25 (SNAP25), growth-associated protein 43 (GAP43), neurogranin, and synaptotagmin 1 in both plasma neuronal-derived EVs and cerebrospinal fluid (CSF). We further examined the association of synaptic protein levels with brain atrophy. We also evaluated the levels of these synaptic proteins in the brains of 5×FAD mice. Then, we loaded rabies virus glycoprotein-engineered EVs with messenger RNAs (mRNAs) encoding GAP43 and SNAP25 and administered these EVs to 5×FAD mice. After treatment, synaptic proteins, dendritic density, and cognitive function were evaluated.
RESULTS
The results showed that GAP43, SNAP25, neurogranin, and synaptotagmin 1 were decreased in neuronal-derived EVs but increased in CSF in patients with AD, and the changes corresponded to the severity of brain atrophy. GAP43 and SNAP25 were decreased in the brains of 5×FAD mice. The engineered EVs efficiently and stably delivered these synaptic proteins to the brain, where synaptic protein levels were markedly upregulated. Upregulation of synaptic protein expression could ameliorate cognitive impairment in AD by promoting dendritic density. This marks the first successful delivery of synaptic protein mRNAs via EVs in AD mice, yielding remarkable therapeutic effects.
CONCLUSIONS
Synaptic proteins are closely related to AD processes. Delivery of synaptic protein mRNAs via EVs stands as a promising effective precision treatment strategy for AD, which significantly advances the current understanding of therapeutic approaches for the disease.
Topics: Humans; Mice; Animals; Alzheimer Disease; Synaptotagmin I; Amyloid beta-Peptides; Neurogranin; Cognitive Dysfunction; Extracellular Vesicles; Atrophy; Biomarkers
PubMed: 38528511
DOI: 10.1186/s12916-024-03359-2 -
Biotechnology Journal Mar 2024Production of therapeutic monoclonal antibody (mAb) in transgenic plants has several advantages such as large-scale production and the absence of pathogenic animal...
Production of therapeutic monoclonal antibody (mAb) in transgenic plants has several advantages such as large-scale production and the absence of pathogenic animal contaminants. However, mAb with high mannose (HM) type glycans has shown a faster clearance compared to antibodies produced in animal cells. The neonatal Fc receptor (FcRn) regulates the persistence of immunoglobulin G (IgG) by the FcRn-mediated recycling pathway, which salvages IgG from lysosomal degradation within cells. In this study, Fc-engineering of antirabies virus therapeutic mAb SO57 with the endoplasmic reticulum (ER)-retention peptide signal (Lys-Asp-Glu-Leu; KDEL) (mAbK SO57) in plant cell was conducted to enhance its binding activity to human neonatal Fc receptor (hFcRn), consequently improve its serum half-life. Enzyme-linked immunosorbent assay (ELISA) and Surface plasmon resonance assay showed altered binding affinity of the Fc region of three different mAbK SO57 variants [M252Y/S254T/T256E (MST), M428L/N434S (MN), H433K/N434F (HN)] to hFcRn compared to wild type (WT) of mAbK SO57. Molecular modeling data visualized the structural alterations in these mAbK SO57. All of the mAbK SO57 variants had HM type glycan structures similar to the WT mAbK SO57. In addition, the neutralizing activity of the three variants against the rabies virus CVS-11 was effective as the WT mAbK SO57. These results indicate that the binding affinity of mAbK SO57 variants to hFcRn can be modified without alteration of N-glycan structure and neutralization activity. Taken together, this study suggests that Fc-engineering of antirabies virus mAb can be applied to enhance the efficacy of therapeutic mAbs in plant expression systems.
Topics: Humans; Antibodies, Monoclonal; Histocompatibility Antigens Class I; Immunoglobulin G; Polysaccharides; Receptors, Fc; Protein Engineering; Plants
PubMed: 38528347
DOI: 10.1002/biot.202300552 -
Nature Communications Mar 2024Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we...
Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.
Topics: Animals; Male; Cerebellum; Learning; Purkinje Cells; Prefrontal Cortex; Primates
PubMed: 38514616
DOI: 10.1038/s41467-024-46281-0