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Viruses Jan 2024Rabies encephalitis has plagued humankind for thousands of years. In developed countries, access to preventive care, both pre-exposure and post-exposure, has... (Review)
Review
Rabies encephalitis has plagued humankind for thousands of years. In developed countries, access to preventive care, both pre-exposure and post-exposure, has significantly reduced the burden of suffering and disease. However, around the world, rabies remains a neglected tropical disease, largely due to uncontrolled dog rabies, and tens of thousands perish each year. Currently, the standard of care for management of rabies encephalitis is palliation. Heroic attempts to treat human rabies patients over the last few decades have yielded glimpses into our understanding of pathophysiology, opening the door to the development of new antiviral therapies and modalities of treatment. Researchers continue to investigate new compounds and approaches to therapy, yet there remain real challenges given the complexity of the disease. We explore and review some of the promising therapies on the horizon in pursuit of a salvage treatment for rabies.
Topics: Humans; Animals; Dogs; Rabies; Zoonoses; Rabies virus; Encephalitis; Rabies Vaccines
PubMed: 38275970
DOI: 10.3390/v16010160 -
Cells Jan 2024Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the family and genus, which is highly neurotropic and can infect almost all warm-blooded... (Review)
Review
Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the family and genus, which is highly neurotropic and can infect almost all warm-blooded animals, including humans. Autophagy and apoptosis are two evolutionarily conserved and genetically regulated processes that maintain cellular and organismal homeostasis, respectively. Autophagy recycles unnecessary or dysfunctional intracellular organelles and molecules in a cell, whereas apoptosis eliminates damaged or unwanted cells in an organism. Studies have shown that RABV can induce both autophagy and apoptosis in target cells. To advance our understanding of pathogenesis of rabies, this paper reviews the molecular mechanisms of autophagy and apoptosis induced by RABV and the effects of the two cellular events on RABV replication.
Topics: Animals; Humans; Rabies virus; Rabies; Apoptosis; Autophagy; Virus Replication
PubMed: 38247875
DOI: 10.3390/cells13020183 -
Redox Biology Aug 2023Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has...
Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has been well-studied in several neuro-associated diseases in recent years. In the present study, we found that CH24H expression can be induced by several neuroinvasive viruses, including vesicular stomatitis virus (VSV), rabies virus (RABV), Semliki Forest virus (SFV) and murine hepatitis virus (MHV). The CH24H metabolite, 24-hydroxycholesterol (24HC), also shows competence in inhibiting the replication of multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 24HC can increase the cholesterol concentration in multivesicular body (MVB)/late endosome (LE) by disrupting the interaction between OSBP and VAPA, resulting in viral particles being trapped in MVB/LE, ultimately compromising VSV and RABV entry into host cells. These findings provide the first evidence that brain cholesterol oxidation products may play a critical role in viral infection.
Topics: Animals; Mice; Cholesterol; COVID-19; Homeostasis; SARS-CoV-2; Virus Internalization; Cholesterol 24-Hydroxylase
PubMed: 37285742
DOI: 10.1016/j.redox.2023.102769 -
Viruses Jul 2023This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics... (Review)
Review
This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics and vaccines, plasma immunoglobulin therapy from whole blood donation can still play a key role. These treatments provide passive transfer of high-titer antibodies that either reduces the risk or the severity of the infection and offer immediate but short-term protection against specific diseases. Antibody preparations derived from immunized human donors are commonly used for the prophylaxis and treatment of rabies, hepatitis A and B viruses, varicella-zoster virus, and pneumonia caused by respiratory syncytial virus, , . The use of hyperimmune globulin therapy is a promising challenge, especially for the treatment of emerging viral infections for which there are no specific therapies or licensed vaccines.
Topics: Humans; Immunoglobulins; Globulins; Immunization, Passive; Vaccines; Communicable Diseases; Antibodies, Viral
PubMed: 37515229
DOI: 10.3390/v15071543 -
CNS Neuroscience & Therapeutics Dec 2023The lateral periaqueductal gray (LPAG), which mainly contains glutamatergic neurons, plays an important role in social responses, pain, and offensive and defensive...
OBJECTIVE
The lateral periaqueductal gray (LPAG), which mainly contains glutamatergic neurons, plays an important role in social responses, pain, and offensive and defensive behaviors. Currently, the whole-brain monosynaptic inputs to LPAG glutamatergic neurons are unknown. This study aims to explore the structural framework of the underlying neural mechanisms of LPAG glutamatergic neurons.
METHODS
This study used retrograde tracing systems based on the rabies virus, Cre-LoxP technology, and immunofluorescence analysis.
RESULTS
We found that 59 nuclei projected monosynaptic inputs to the LPAG glutamatergic neurons. In addition, seven hypothalamic nuclei, namely the lateral hypothalamic area (LH), lateral preoptic area (LPO), substantia innominata (SI), medial preoptic area, ventral pallidum, posterior hypothalamic area, and lateral globus pallidus, projected most densely to the LPAG glutamatergic neurons. Notably, we discovered through further immunofluorescence analysis that the inputs to the LPAG glutamatergic neurons were colocalized with several markers related to important neurological functions associated with physiological behaviors.
CONCLUSION
The LPAG glutamatergic neurons received dense projections from the hypothalamus, especially nuclei such as LH, LPO, and SI. The input neurons were colocalized with several markers of physiological behaviors, which show the pivotal role of glutamatergic neurons in the physiological behaviors regulation by LPAG.
Topics: Mice; Animals; Periaqueductal Gray; Brain; Neurons; Hypothalamus; Preoptic Area
PubMed: 37424163
DOI: 10.1111/cns.14338 -
Open Veterinary Journal Nov 2023An infectious disease known as rabies (family Rhabdoviridae, genus ) causes severe damage to mammals' central nervous systems (CNS). This illness has been around for a... (Review)
Review
An infectious disease known as rabies (family Rhabdoviridae, genus ) causes severe damage to mammals' central nervous systems (CNS). This illness has been around for a very long time. The majority of human cases of rabies take place in underdeveloped regions of Africa and Asia. Following viral transmission, the Rhabdovirus enters the peripheral nervous system and proceeds to the CNS, where it targets the encephalon and produces encephalomyelitis. Postbite prophylaxis requires laboratory confirmation of rabies in both people and animals. All warm-blooded animals can transmit the infection, while the virus can also develop in the cells of cold-blooded animals. In the 21st century, more than 3 billion people are in danger of contracting the rabies virus in more than 100 different nations, resulting in an annual death toll of 50,000-59,000. There are three important elements in handling rabies disease in post exposure prophylaxis (PEP), namely wound care, administration of anti-rabies serum, and anti-rabies vaccine. Social costs include death, lost productivity as a result of early death, illness as a result of vaccination side effects, and the psychological toll that exposure to these deadly diseases has on people. Humans are most frequently exposed to canine rabies, especially youngsters and the poor, and there are few resources available to treat or prevent exposure, making prevention of human rabies challenging.
Topics: Animals; Humans; Dogs; Rabies; Rabies Vaccines; Rabies virus; Animals, Domestic; Vaccination; Mammals; Dog Diseases
PubMed: 38107233
DOI: 10.5455/OVJ.2023.v13.i11.1 -
Bioinformation 2024Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin...
Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin receptor, CD71. Because of its structure, CD71 facilitates the binding and penetration of a large variety of viruses into the host. Among which the hemorrhagic fever-causing New World mammarena viruses (family of single stranded ambisense segmented RNA Arenaviridae), the single stranded positive sense RNA hepatitis C virus, the single stranded negative sense segmented influenza A virus, the single stranded negative sense RNA rabies virus, the single stranded positive sense SARS-CoV2 and possibly many others. In this process, CD71 is associated with the target of the anti-proliferative antibody-1 (CD81) viral co-receptor. In light of the plethora of novel and ancient viruses and microbes emerging from melting eternal glacier ice and permafrost, it is timely and critical to define and characterize interventions, besides the soluble form of CD71 (sCD71), that can abrogate or minimize this novice non-canonical function of CD71.
PubMed: 38711995
DOI: 10.6026/973206300200208 -
ELife Nov 2023Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit...
Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, allows the long term genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that "revertant" mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments.
Topics: Humans; Rabies; Rabies virus; Mutation; Cell Line; Genomic Instability
PubMed: 37921437
DOI: 10.7554/eLife.83459 -
International Journal of Medical... 2023Rabies continues to be a huge threat to public health. The rabies virus envelope glycoprotein (RABV G) is a major rabies virus antigen and contains neutralizing...
Rabies continues to be a huge threat to public health. The rabies virus envelope glycoprotein (RABV G) is a major rabies virus antigen and contains neutralizing epitopes, which are primary candidates for subunit vaccines and diagnostic antigens. However, the production and purification of rRABV G while retaining its antigenic and immunogenic remains to be a challenge. Here, we aimed to establish a platform for rRABV G production and purification, and determine the immunogenicity and antigenicity of rRABV G. The cDNA fragment encoding the soluble form of RABV G was synthesized and cloned into a lentiviral expressing vector. Recombinant lentiviral vector LV-CMV-RABV G-eGFP was packaged, titered, and then transduced into HEK 293T cells. The cell culture supernatant was purified using nickel affinity chromatography and subsequently confirmed through Western Blot analysis and indirect enzyme-linked immunosorbent assay (ELISA). The ELISA utilized human sera obtained from individuals who had been vaccinated with the human commercial Purified Vero Cells Rabies Vaccine (PVRV). Notably, we observed a neutralizing antibody response in immunized pigs rather than in mice. This discrepancy could potentially be attributed to factors such as the instability of the rRABV G protein, variations in host responses, and variances in the adjuvant used. Taking all these findings into account, the rRABV G protein generated in this study exhibits promise as a potential vaccine candidate for the prevention of rabies.
Topics: Chlorocebus aethiops; Humans; Animals; Mice; Swine; Rabies virus; Rabies; HEK293 Cells; Vero Cells; Antibodies, Viral; Glycoproteins; Rabies Vaccines; Viral Envelope Proteins; Recombinant Proteins
PubMed: 37786447
DOI: 10.7150/ijms.87134 -
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