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Viruses Apr 2024Rabies is a fatal encephalitic infectious disease caused by the rabies virus (RABV). RABV is highly neurotropic and replicates in neuronal cell lines . The RABV fixed...
Rabies is a fatal encephalitic infectious disease caused by the rabies virus (RABV). RABV is highly neurotropic and replicates in neuronal cell lines . The RABV fixed strain, HEP-Flury, was produced via passaging in primary chicken embryonic fibroblast cells. HEP-Flury showed rapid adaptation when propagated in mouse neuroblastoma (MNA) cells. In this study, we compared the growth of our previously constructed recombinant HEP (rHEP) strain-based on the sequence of the HEP (HEP-Flury) strain-with that of the original HEP strain. The original HEP strain exhibited higher titer than rHEP and a single substitution at position 80 in the matrix (M) protein M(D80N) after incubation in MNA cells, which was absent in rHEP. , intracerebral inoculation of the rHEP-M(D80N) strain with this substitution resulted in enhanced viral growth in the mouse brain and a significant loss of body weight in the adult mice. The number of viral antigen-positive cells in the brains of adult mice inoculated with the rHEP-M(D80N) strain was significantly higher than that with the rHEP strain at 5 days post-inoculation. Our findings demonstrate that a single amino acid substitution in the M protein M(D80N) is associated with neurovirulence in mice owing to adaptation to mouse neuronal cells.
Topics: Animals; Rabies virus; Mice; Amino Acid Substitution; Virulence; Brain; Viral Matrix Proteins; Rabies; Neurons; Virus Replication; Cell Line
PubMed: 38793581
DOI: 10.3390/v16050699 -
Bioengineering (Basel, Switzerland) May 2024Cell therapy has proven to be a promising treatment for a range of neurological disorders, including Parkinson Disease, drug-resistant epilepsy, and stroke, by restoring... (Review)
Review
Cell therapy has proven to be a promising treatment for a range of neurological disorders, including Parkinson Disease, drug-resistant epilepsy, and stroke, by restoring function after brain damage. Nevertheless, evaluating the true effectiveness of these therapeutic interventions requires a deep understanding of the functional integration of grafted cells into existing neural networks. This review explores a powerful arsenal of molecular techniques revolutionizing our ability to unveil functional integration of grafted cells within the host brain. From precise manipulation of neuronal activity to pinpoint the functional contribution of transplanted cells by using opto- and chemo-genetics, to real-time monitoring of neuronal dynamics shedding light on functional connectivity within the reconstructed circuits by using genetically encoded (calcium) indicators . Finally, structural reconstruction and mapping communication pathways between grafted and host neurons can be achieved by monosynaptic tracing with viral vectors. The cutting-edge toolbox presented here holds immense promise for elucidating the impact of cell therapy on neural circuitry and guiding the development of more effective treatments for neurological disorders.
PubMed: 38790353
DOI: 10.3390/bioengineering11050487 -
Journal of Nanobiotechnology May 2024Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and...
Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer's disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aβ, we developed an Aβ and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ misfolding, accelerating Aβ clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.
Topics: Alzheimer Disease; Animals; Reactive Oxygen Species; Amyloid beta-Peptides; Nanocomposites; Mice; Cerium; Mice, Transgenic; Silicon Dioxide; Peptide Fragments; Humans; Brain; Nanoparticles; Glycoproteins; Disease Models, Animal; Viral Proteins
PubMed: 38783363
DOI: 10.1186/s12951-024-02543-z -
BioRxiv : the Preprint Server For... May 2024The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and...
The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and cutaneous sensory signals. The lateral PB subpopulation expressing the gene which produces the neuropeptide calcitonin gene-related peptide (CGRP) relays signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet the afferents to these neurons are only partially understood. We mapped the afferent projections to the lateral part of the PB in mice using conventional cholera toxin B subunit (CTb) retrograde tracing, and then used conditional rabies virus retrograde tracing to map monosynaptic inputs specifically targeting the PB neurons. Using vesicular GABA (vGAT) and glutamate (vGLUT2) transporter reporter mice, we found that lateral PB neurons receive GABAergic afferents from regions such as the lateral part of the central nucleus of the amygdala, lateral dorsal subnucleus of the bed nucleus of the stria terminalis, substantia innominata, and the ventrolateral periaqueductal gray. Additionally, they receive glutamatergic afferents from the infralimbic and insular cortex, paraventricular nucleus, parasubthalamic nucleus, trigeminal complex, medullary reticular nucleus, and nucleus of the solitary tract. Using anterograde tracing and confocal microscopy, we then identified close axonal appositions between these afferents and PB neurons. Finally, we used channelrhodopsin-assisted circuit mapping to test whether some of these inputs directly synapse upon the PB neurons. These findings provide a comprehensive neuroanatomical framework for understanding the afferent projections regulating the PB neurons.
PubMed: 38766214
DOI: 10.1101/2024.05.07.593004 -
Clinical and Experimental Vaccine... Apr 2024Alopecia areata (AA) is an autoimmune-related disorder characterized by non-scarring hair loss in children. We report the case of a child who had AA after the fifth dose...
Alopecia areata (AA) is an autoimmune-related disorder characterized by non-scarring hair loss in children. We report the case of a child who had AA after the fifth dose of rabies vaccine and summarized various potential mechanisms of vaccination induced AA. This case indicates that rabies vaccine might be a predisposition of AA by causing immune dysregulation.
PubMed: 38752007
DOI: 10.7774/cevr.2024.13.2.171 -
EMBO Molecular Medicine Jun 2024Although protein subunit vaccines generally have acceptable safety profiles with precise antigenic content, limited immunogenicity can lead to unsatisfactory humoral and...
Although protein subunit vaccines generally have acceptable safety profiles with precise antigenic content, limited immunogenicity can lead to unsatisfactory humoral and cellular immunity and the need for vaccine adjuvants and delivery system. Herein, we assess a vaccine adjuvant system comprising Quillaja Saponaria-21(QS-21) and cobalt porphyrin polymeric micelles that enabling the display of His-tagged antigen on its surface. The nanoscale micelles promote antigen uptake and dendritic cell activation to induce robust cytotoxic T lymphocyte response and germinal center formation. Using the recombinant protein antigens from influenza A and rabies virus, the micelle adjuvant system elicited robust antiviral responses and protected mice from lethal challenge. In addition, this system could be combined with other antigens to induce high titers of neutralizing antibodies in models of three highly pathogenic viral pathogens: Ebola virus, Marburg virus, and Nipah virus. Collectively, our results demonstrate this polymeric micelle adjuvant system can be used as a potent nanoplatform for developing antiviral vaccine countermeasures that promote humoral and cellular immunity.
Topics: Animals; Mice; Viral Vaccines; Micelles; Adjuvants, Vaccine; Adjuvants, Immunologic; Antibodies, Viral; Rabies virus; Dendritic Cells; Polymers; Female; Mice, Inbred C57BL; Influenza A virus; Mice, Inbred BALB C
PubMed: 38750307
DOI: 10.1038/s44321-024-00076-4 -
International Journal of Molecular... Apr 2024Tripartite motif (TRIM) proteins are a multifunctional E3 ubiquitin ligase family that participates in various cellular processes. Recent studies have shown that TRIM...
Tripartite motif (TRIM) proteins are a multifunctional E3 ubiquitin ligase family that participates in various cellular processes. Recent studies have shown that TRIM proteins play important roles in regulating host-virus interactions through specific pathways, but their involvement in response to rabies virus (RABV) infection remains poorly understood. Here, we identified that several TRIM proteins are upregulated in mouse neuroblastoma cells (NA) after infection with the rabies virus using RNA-seq sequencing. Among them, TRIM44 was found to regulate RABV replication. This is supported by the observations that downregulation of TRIM44 inhibits RABV replication, while overexpression of TRIM44 promotes RABV replication. Mechanistically, TRIM44-induced RABV replication is brought about by activating autophagy, as inhibition of autophagy with 3-MA attenuates TRIM44-induced RABV replication. Additionally, we found that inhibition of autophagy with rapamycin reverses the TRIM44-knockdown-induced decrease in LC3B expression and autophagosome formation as well as RABV replication. The results suggest that TRIM44 promotes RABV replication by an autophagy-dependent mechanism. Our work identifies TRIM44 as a key host factor for RABV replication, and targeting TRIM44 expression may represent an effective therapeutic strategy.
Topics: Animals; Humans; Mice; Autophagy; Cell Line, Tumor; Host-Pathogen Interactions; Intracellular Signaling Peptides and Proteins; Rabies; Rabies virus; Tripartite Motif Proteins; Virus Replication
PubMed: 38731834
DOI: 10.3390/ijms25094616 -
PloS One 2024Rabies virus (RABV; species Lyssavirus rabies) is causing one of the oldest zoonotic diseases known to mankind, leading to fatal encephalomyelitis in animals and humans....
BACKGROUND
Rabies virus (RABV; species Lyssavirus rabies) is causing one of the oldest zoonotic diseases known to mankind, leading to fatal encephalomyelitis in animals and humans. Despite the existence of safe and effective vaccines to prevent the disease, an estimated 99% of human rabies deaths worldwide are caused by dog-mediated rabies with children at the highest risk of infection. Rabies has been endemic in Madagascar for over a century, yet there has been little research evaluating local knowledge and practices impacting on the rabies control and prevention. Thus, this study was undertaken to better understand the dog ecology including canine vaccine coverage and to assess knowledge and practices of dog owners and veterinarians.
METHODOLOGY
A cross-sectional study was conducted among 123 dog-owning households in thirteen fokontanys in Mahajanga from July 4 to September 13, 2016. Single and multi-member dog-owning households in the study area on the day of the interview were eligible for inclusion and purposively selected with the support of a local guide. The survey included a household questionnaire capturing information on the dog's demographics, husbandry practices, knowledge and practices towards rabies and its control measures; the dog ecology questionnaire collected dog characteristics, vaccination status and husbandry practices. All households that reported a dog bite incident, were invited to participate in a dog bite questionnaire. In addition, direct observations of roaming dogs were conducted to assess dog population demographics and to document behavioural characteristics. Two veterinarians were purposively selected and took part in an interview during the survey period, providing information on rabies control activities, including dog-care practices in the area. Descriptive and inferential data analyses were performed using Epi Info version 7.1.5.0 (CDC Atlanta, USA).
RESULTS
We recorded a total of 400 dogs, of which 338 (84.5%) were owned amongst 123 households. More than half (67.8%) of owned dogs were between 1 to 5 years old and 95.6% were kept for guarding purposes. 45% of the surveyed dogs had free access to roam outside the premises. The majority (85.4%) of dog owners were knowledgeable that a dog bite could potentially transmit RABV to humans. 19 dog bites were reported and of these 73.6% were caused by the owner's or a neighbour's dog. In 6 of the 19 cases, children between 7 and 15 years of age were the victims. Dog vaccination coverage against rabies was 34% among owned dogs. Of the participants aware of a veterinarian, the majority (55/82) indicated that they accessed veterinarian services at irregular intervals. The main obstacles to vaccinations cited by dog owners were limited financial resources and difficulty accessing veterinary care.
CONCLUSION
This study contributes to enhanced understanding of the dog ecology including canine vaccine coverage as well as knowledge and practices of dog owners in Madagascar. Most dogs in the study area were accessible for preventive vaccination through their owners, however only one third of the investigated canine population was vaccinated against rabies. Concerted national efforts towards rabies prevention and control should aim to address financial challenges and access to veterinary services.
Topics: Dogs; Animals; Rabies; Madagascar; Dog Diseases; Humans; Rabies Vaccines; Cross-Sectional Studies; Male; Female; Health Knowledge, Attitudes, Practice; Surveys and Questionnaires; Adult; Vaccination Coverage; Middle Aged; Ecology; Rabies virus
PubMed: 38722982
DOI: 10.1371/journal.pone.0302690 -
PLoS Neglected Tropical Diseases May 2024
PubMed: 38722845
DOI: 10.1371/journal.pntd.0012171 -
IDCases 2024Rabies is a zoonosis caused by viruses of the family Rhabdoviridae. Prophylaxis with the rabies vaccine and immunoglobulins, depending on the severity of the case, is...
INTRODUCTION
Rabies is a zoonosis caused by viruses of the family Rhabdoviridae. Prophylaxis with the rabies vaccine and immunoglobulins, depending on the severity of the case, is recommended. After vaccination, mild, moderate, or severe adverse events (AE) are described. Although rare, severe skin reactions may occur, increasing the risk of anaphylaxis.
CASE REPORT
An 84-year-old woman was attacked by a stray unknown cat, leaving her with bites and scratches in the neck region and multiple injuries. The case was classified as severe. About 3 h after the first dose of the rabies vaccine, disseminated purplish spots appeared on her lower limbs, worsening significantly after the second dose, requiring hospitalization for the application of the third dose under observation, dermatology evaluation, and collection of skin tissue for biopsy. She was discharged 24 h after the third vaccination, and the purple spots cleared gradually. The biopsy suggested an adverse reaction to the vaccine components. Immunohistochemistry of the rabies virus antigen in dermal nerve fillets was negative. The seroconversion post rabies vaccine showed IgG antibody values below the reference levels.
CONCLUSION
Vaccination against rabies is extremely important; however, AEs may occur. Our patient developed an important AE and required hospitalization. After complete vaccination, the serum was not converted. A similar case was not previously described, and the case report is important for the creation of jurisprudence on rabies vaccination in elderly patients in Brazil.
PubMed: 38721055
DOI: 10.1016/j.idcr.2024.e01974