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Cellular and Molecular Life Sciences :... Nov 2023Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately...
BACKGROUND
Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei. Foxp2 is a transcription factor involved in cell differentiation and reported low in patients with HD. However, the role of the Foxp2 in the thalamus in HD remains unexplored.
METHODS
We used two different mouse models of HD, the R6/1 and the HdhQ111 mice, to demonstrate a consistent thalamic Foxp2 reduction in the context of HD. We used in vivo electrophysiological recordings, microdialysis in behaving mice and rabies virus-based monosynaptic tracing to study thalamo-striatal and thalamo-cortical synaptic connectivity in R6/1 mice. Micro-structural synaptic plasticity was also evaluated in the striatum and cortex of R6/1 mice. We over-expressed Foxp2 in the thalamus of R6/1 mice or reduced Foxp2 in the thalamus of wild type mice to evaluate its role in sensory and motor skills deficiencies, as well as thalamo-striatal and thalamo-cortical connectivity in such mouse models.
RESULTS
Here, we demonstrate in a HD mouse model a clear and early thalamo-striatal aberrant connectivity associated with a reduction of thalamic Foxp2 levels. Recovering thalamic Foxp2 levels in the mouse rescued motor coordination and sensory skills concomitant with an amelioration of neuropathological features and with a repair of the structural and functional connectivity through a restoration of neurotransmitter release. In addition, reduction of thalamic Foxp2 levels in wild type mice induced HD-like phenotypes.
CONCLUSIONS
In conclusion, we show that a novel identified thalamic Foxp2 dysregulation alters basal ganglia circuits implicated in the pathophysiology of HD.
Topics: Humans; Animals; Mice; Huntington Disease; Motor Disorders; Thalamus; Corpus Striatum; Movement; Disease Models, Animal; Repressor Proteins; Forkhead Transcription Factors
PubMed: 37987826
DOI: 10.1007/s00018-023-05015-z -
Vaccines Jul 2023Novel lyssaviruses, the causative agents of rabies, continue to be described mostly due to increased surveillance in bat hosts. Biologicals for the prevention of rabies...
Novel lyssaviruses, the causative agents of rabies, continue to be described mostly due to increased surveillance in bat hosts. Biologicals for the prevention of rabies in humans have, however, remained largely unchanged for decades. This study aimed to determine if commercial rabies immunoglobulin (RIG) could neutralize diverse lyssaviruses. Two commercial preparations, of human or equine origin, were evaluated against a panel consisting of 13 lyssavirus species. Reduced neutralization was observed for the majority of lyssaviruses compared to rabies virus and was more evident for lyssaviruses outside of phylogroup I. Neutralization of more diverse lyssaviruses only occurred at very high doses, except for Ikoma lyssavirus, which could not be neutralized by the RIG evaluated in this study. The use of RIG is a crucial component of rabies post-exposure prophylaxis and the data generated here indicate that RIG, in its current form, will not protect against all lyssaviruses. In addition, higher doses of RIG may be required for neutralization as the genetic distance from vaccine strains increases. Given the limitations of current RIG preparations, alternative passive immunization options should be investigated.
PubMed: 37515070
DOI: 10.3390/vaccines11071255 -
Frontiers in Cellular and Infection... 2023Rabies is a highly fatal infectious disease that poses a significant threat to human health in developing countries. In vitro study-based understanding of pathogenesis...
BACKGROUND
Rabies is a highly fatal infectious disease that poses a significant threat to human health in developing countries. In vitro study-based understanding of pathogenesis and tropism of different strains of rabies virus (RABV) in the central nervous system (CNS) is limited due to the lack of suitable culture models that recapitulate the complex communication pathways among host cells, extracellular matrices, and viruses. Therefore, a three-dimensional (3D) cell culture that mimics cell-matrix interactions, resembling in vivo microenvironment, is necessary to discover relevant underlying mechanisms of RABV infection and host responses.
METHODS
The 3D collagen-Matrigel hydrogel encapsulating hiPSC-derived neurons for RABV infection was developed and characterized based on cell viability, morphology, and gene expression analysis of neuronal markers. The replication kinetics of two different strains of RABV [wild-type Thai (TH) and Challenge Virus Standard (CVS)-11 strains] in both 2D and 3D neuronal cultures were examined. Differential gene expression analysis (DEG) of the neuropathological pathway of RABV-infected 2D and 3D models was also investigated via NanoString analysis.
RESULTS
The 3D hiPSC-derived neurons revealed a more physiologically interconnected neuronal network as well as more robust and prolonged maturation and differentiation than the conventional 2D monolayer model. TH and CVS-11 exhibited distinct growth kinetics in 3D neuronal model. Additionally, gene expression analysis of the neuropathological pathway observed during RABV infection demonstrated a vast number of differentially expressed genes (DEGs) in 3D model. Unlike 2D neuronal model, 3D model displayed more pronounced cellular responses upon infection with CVS-11 when compared to the TH-infected group, highlighting the influence of the cell environment on RABV-host interactions. Gene ontology (GO) enrichment of DEGs in the infected 3D neuronal culture showed alterations of genes associated with the inflammatory response, apoptotic signaling pathway, glutamatergic synapse, and trans-synaptic signaling which did not significantly change in 2D culture.
CONCLUSION
We demonstrated the use of a hydrogel-based 3D hiPSC-derived neuronal model, a highly promising technology, to study RABV infection in a more physiological environment, which will broaden our understanding of RABV-host interactions in the CNS.
Topics: Humans; Rabies virus; Rabies; Induced Pluripotent Stem Cells; Hydrogels; Neurons
PubMed: 37692167
DOI: 10.3389/fcimb.2023.1215205 -
Biomedicine & Pharmacotherapy =... Mar 2024Interest in multifunctional polymer nanoparticles for targeted delivery of anti-cancer drugs has grown significantly in recent years. In this study, tumor-targeting...
Interest in multifunctional polymer nanoparticles for targeted delivery of anti-cancer drugs has grown significantly in recent years. In this study, tumor-targeting echogenic polymer micelles were prepared from poly(ethylene glycol) methyl ether-alkyl carbonate (mPEG-AC) derivatives, and their potential in cancer therapy was assessed. Various mPEG derivatives with carbonate linkages were synthesized via an alkyl halide reaction between mPEG and alkyl chloroformate. Micelle formation using polymer amphiphiles in aqueous media and the subsequent carbon dioxide (CO) gas generation from the micelles was confirmed. Their ability to target neuroblastoma was substantially enhanced by incorporating the rabies virus glycoprotein (RVG) peptide. RVG-modified gas-generating micelles significantly inhibited tumor growth in a tumor-bearing mouse model owing to CO gas generation within tumor cells and resultant cytolytic effects, showing minimal side effects. The development of multifunctional polymer micelles may offer a promising therapeutic approach for various diseases, including cancer.
Topics: Animals; Mice; Polymers; Micelles; Carbon Dioxide; Polyethylene Glycols; Neuroblastoma; Peptides; Carbonates; Formates
PubMed: 38354570
DOI: 10.1016/j.biopha.2024.116272 -
Scientific Reports Dec 2023The small Indian mongoose (Urva auropunctata) is the primary terrestrial wildlife rabies reservoir on at least four Caribbean islands, including Puerto Rico. In Puerto...
The small Indian mongoose (Urva auropunctata) is the primary terrestrial wildlife rabies reservoir on at least four Caribbean islands, including Puerto Rico. In Puerto Rico, mongooses represent a risk to public health, based on direct human exposure and indirectly through the transmission of rabies virus to domestic animals. To date, the fundamental ecological relationships of space use among mongooses and between mongooses and domestic animals remain poorly understood. This study is the first to report mongoose home range estimates based on GPS telemetry, as well as concurrent space use among mongooses and free roaming domestic dogs (FRDD; Canis lupus familiaris). Mean (± SE) home range estimates from 19 mongooses in this study (145 ± 21 ha and 60 ± 14 ha for males and females, respectively) were greater than those reported in prior radiotelemetry studies in Puerto Rico. At the scale of their home range, mongooses preferentially used dry forest and shrubland areas, but tended to avoid brackish water vegetation, salt marshes, barren lands and developed areas. Home ranges from five FRDDs were highly variable in size (range 13-285 ha) and may be influenced by availability of reliable anthropogenic resources. Mongooses displayed high home range overlap (general overlap index, GOI = 82%). Home range overlap among mongooses and FRDDs was intermediate (GOI = 50%) and greater than home range overlap by FRDDs (GOI = 10%). Our results provide evidence that space use by both species presents opportunities for interspecific interaction and contact and suggests that human provisioning of dogs may play a role in limiting interactions between stray dogs and mongooses.
Topics: Female; Male; Animals; Dogs; Humans; Rabies; Puerto Rico; Herpestidae; Homing Behavior; Animals, Domestic
PubMed: 38135706
DOI: 10.1038/s41598-023-50261-7 -
International Journal of Circumpolar... Dec 2024Rabies is often described as the quintessential One Health problem, linking especially animal health to human health. I examined how rabies is managed in the circumpolar...
Rabies is often described as the quintessential One Health problem, linking especially animal health to human health. I examined how rabies is managed in the circumpolar North through semi-structured interviews of key informants in three cases: Alaska, Northwest Territories, and Svalbard. While rabies is controlled at the territorial or state level in the Northwest Territories and Alaska, respectively, the perception of where authority lies in rabies management is less evident in Norway concerning Svalbard than in the other two cases. Respondents generally characterised the working relationship between sectors and scales of governments as positive. However, coordination remains one of the main challenges to rabies management, with harsh environmental conditions and small remote communities adding additional challenges in all three cases. Rabies managers in Svalbard also face unique conditions, such as risks associated with hunting and the particular administrative structure of Svalbard. Due to limited veterinary services in dispersed small and remote communities, dogs present challenges to rabies management in Alaska and the Northwest Territories. Personal relationships are important in disease management across agencies, and the unique challenges in the far North will likely pose challenges in adopting approaches to disease management from temperate climates.
Topics: Animals; Humans; Dogs; Rabies; Rabies virus; One Health; Alaska; Norway
PubMed: 38369781
DOI: 10.1080/22423982.2024.2318059 -
Journal of Virology May 2024Rabies virus (RABV) is highly lethal and triggers severe neurological symptoms. The neuropathogenic mechanism remains poorly understood. Ras-related C3 botulinum toxin...
Rabies virus (RABV) is highly lethal and triggers severe neurological symptoms. The neuropathogenic mechanism remains poorly understood. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho-GTPase that is involved in actin remodeling and has been reported to be closely associated with neuronal dysfunction. In this study, by means of a combination of pharmacological inhibitors, small interfering RNA, and specific dominant-negatives, we characterize the crucial roles of dynamic actin and the regulatory function of Rac1 in RABV infection, dominantly in the viral entry phase. The data show that the RABV phosphoprotein interacts with Rac1. RABV phosphoprotein suppress Rac1 activity and impedes downstream Pak1-Limk1-Cofilin1 signaling, leading to the disruption of F-actin-based structure formation. In early viral infection, the EGFR-Rac1-signaling pathway undergoes a biphasic change, which is first upregulated and subsequently downregulated, corresponding to the RABV entry-induced remodeling pattern of F-actin. Taken together, our findings demonstrate for the first time the role played by the Rac1 signaling pathway in RABV infection and may provide a clue for an explanation for the etiology of rabies neurological pathogenesis.IMPORTANCEThough neuronal dysfunction is predominant in fatal rabies, the detailed mechanism by which rabies virus (RABV) infection causes neurological symptoms remains in question. The actin cytoskeleton is involved in numerous viruses infection and plays a crucial role in maintaining neurological function. The cytoskeletal disruption is closely associated with abnormal nervous symptoms and induces neurogenic diseases. In this study, we show that RABV infection led to the rearrangement of the cytoskeleton as well as the biphasic kinetics of the Rac1 signal transduction. These results help elucidate the mechanism that causes the aberrant neuronal processes by RABV infection and may shed light on therapeutic development aimed at ameliorating neurological disorders.
PubMed: 38809020
DOI: 10.1128/jvi.00606-24 -
Journal of Global Infectious Diseases 2023Encephalitis is a major public health problem worldwide that causes huge emotional and economic loss to humanity. Encephalitis, being a serious illness, affects people...
INTRODUCTION
Encephalitis is a major public health problem worldwide that causes huge emotional and economic loss to humanity. Encephalitis, being a serious illness, affects people of all ages. The aim is to describe the sociodemographic, clinical, etiological, and neuroimaging profile among 101 acute encephalitis syndrome (AES) patients visiting a tertiary neuro-specialty care hospital in India.
METHODS
Record review of medical records of all patients attending neurology emergency and outpatient services at NIMHANS Hospital, diagnosed with AES in 2019, was conducted. Data were collected using standardized data collection forms for all cases in the study. Descriptive analyses (mean and standard deviation for continuous variables and proportions for categorical variables) were conducted. The Chi-square test/Fisher's exact test was used for the comparison of independent groups for categorical variables, and -test for comparing means for continuous variables.
RESULTS
About 42.6% of AES patients had viral etiology, while in 57.4%, etiology was not ascertained. Common presenting symptoms were fever (96%), altered sensorium (64.4%), seizures (70.3%), headache (42.6%), and vomiting (27.7%). Herpes simplex was the most common (21.8%) identified viral encephalitis, followed by chikungunya (5%), arboviruses (chikungunya and dengue) (4%), Japanese encephalitis (4%), rabies (3%), dengue (1%), and varicella virus (1%). About 40% of AES patients showed cerebrospinal fluid pleocytosis (44%), increased protein (39.6%), abnormal computed tomography brain (44.6%), and magnetic resonance imaging abnormalities (41.6%).
CONCLUSION
The study highlights the need to ascertain etiology and importance of evidence-based management of AES patients. A better understanding of opportunities and limitations in the management and implementation of standard laboratory and diagnostic algorithms can favor better diagnosis and management of AES.
PubMed: 38292694
DOI: 10.4103/jgid.jgid_19_23 -
International Journal of Molecular... Sep 2023Inoculation routes may significantly affect vaccine performance due to the local microenvironment, antigen localization and presentation, and, therefore, final immune...
Immune Response of Inactivated Rabies Vaccine Inoculated via Intraperitoneal, Intramuscular, Subcutaneous and Needle-Free Injection Technology-Based Intradermal Routes in Mice.
Inoculation routes may significantly affect vaccine performance due to the local microenvironment, antigen localization and presentation, and, therefore, final immune responses. In this study, we conducted a head-to-head comparison of immune response and safety of inactivated rabies vaccine inoculated via intraperitoneal (IP), intramuscular (IM), subcutaneous (SC) and needle-free injection technology-based intradermal (ID) routes in ICR mice. Immune response was assessed in terms of antigen-specific antibodies, antibody subtypes and neutralizing antibodies for up to 28 weeks. A live rabies virus challenge was also carried out to evaluate vaccine potency. The dynamics of inflammatory cell infiltration at the skin and muscle levels were determined via histopathological examination. The kinetics and distribution of a model antigen were also determined by using in vivo fluorescence imaging. Evidence is presented that the vaccine inoculated via the ID route resulted in the highest antigen-specific antibody and neutralizing antibody titers among all administration routes, while IP and IM routes were comparable, followed by the SC route. Antibody subtype analysis shows that the IP route elicited a Th1-biased immune response, while SC and IM administration elicited a prominent Th2-type immune response. Unexpectedly, the ID route leads to a balanced Th1 and Th2 immune response. In addition, the ID route conferred effective protection against lethal challenge with 40 LD50 of the rabies CVS strain, which was followed by IP and IM routes. Moreover, a one-third dose of the vaccine inoculated via the ID route provided comparable or higher efficacy to a full dose of the vaccine via the other three routes. The superior performance of ID inoculation over other routes is related to longer local retention at injection sites and higher lymphatic drainage. Histopathology examination reveals a transient inflammatory cell infiltration at ID and IM injection sites which peaked at 48 h and 24 h, respectively, after immunization, with all side effects disappearing within one week. These results suggest that needle-free injection technology-based ID inoculation is a promising strategy for rabies vaccination in regard to safety and efficacy.
Topics: Animals; Mice; Mice, Inbred ICR; Rabies Vaccines; Rabies; Injections, Intramuscular; Antibodies, Neutralizing; Immunity
PubMed: 37686393
DOI: 10.3390/ijms241713587 -
Viruses Jun 2024A proteomics analysis of purified rabies virus (RABV) revealed 47 entrapped host proteins within the viral particles. Out of these, 11 proteins were highly disordered....
A proteomics analysis of purified rabies virus (RABV) revealed 47 entrapped host proteins within the viral particles. Out of these, 11 proteins were highly disordered. Our study was particularly focused on five of the RABV-entrapped mouse proteins with the highest levels of disorder: Neuromodulin, Chmp4b, DnaJB6, Vps37B, and Wasl. We extensively utilized bioinformatics tools, such as FuzDrop, DP, UniProt, RIDAO, STRING, AlphaFold, and ELM, for a comprehensive analysis of the intrinsic disorder propensity of these proteins. Our analysis suggested that these disordered host proteins might play a significant role in facilitating the rabies virus pathogenicity, immune system evasion, and the development of antiviral drug resistance. Our study highlighted the complex interaction of the virus with its host, with a focus on how the intrinsic disorder can play a crucial role in virus pathogenic processes, and suggested that these intrinsically disordered proteins (IDPs) and disorder-related host interactions can also be a potential target for therapeutic strategies.
Topics: Rabies virus; Animals; Mice; Intrinsically Disordered Proteins; Virion; Proteomics; Host-Pathogen Interactions; Rabies; Computational Biology; Viral Proteins
PubMed: 38932209
DOI: 10.3390/v16060916