Differentiation of an adult neuron cell line increases susceptibility to rabies infection (original) (raw)
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International Journal of Morphology, 2016
Rabies is a lethal disease caused by a neurotropic virus that produces inconspicuous morphological changes hardly observable with conventional histopathology. The fatal outcome caused by rabies could be attributed to specific biochemical changes that severely impact neuronal function. The neuronal nuclear protein (NeuN) has become a widely used neuronal marker for the research and the histopathological diagnosis of nervous system diseases. To evaluate the distribution of the protein NeuN in the motor cortex of normal and rabies-infected mice adult ICR mice were inoculated with rabies virus either intramuscularly or intracerebrally. Rabies-infected mice were sacrificed at the terminal stage of the disease. Control mice were also euthanized at the same age. The brains were removed and cut into coronal sections on a vibratome. Immunohistochemistry was used to study the expression of NeuN in the motor area of the cerebral cortex. Neuronal counts, cellular optical densitometry and neuronal diameter measurements were performed to analyze the immunoreactivity of the protein. All parameters revealed decreased immunoreactivity for NeuN in cortical neurons of mice intracerebrally infected with rabies. In contrast, the changes were not statistically significant in mice inoculated intramuscularly. Either the immunoreactivity of NeuN or its expression is affected by the presence of rabies virus in the cerebral cortex depending on the inoculation route. These results contribute to the knowledge of the dynamics of cellular infection on rabies pathogenesis.
The CVS strain of fixed rabies virus causes acute, fatal encephalomyelitis in young adult ICR mice. Variant RV194-2, which was selected from CVS virus in cell culture with a neutralizing antiglycoprotein monoclonal antibody, has a single amino acid change in the glycoprotein. The infections caused by CVS virus and RV194-2 virus were compared in mice for 14 days postinoculation of 5 x 107 PFU into the right masseter muscle. All CVS virus-infected mice died (mean time to death, 7.9 days), compared with a mortality rate of 8.5% for RV194-2 virus-infected mice. RV194-2 virus spread to the ipsilateral trigeminal ganglion during the first 2 days postinoculation, and both viruses spread to the ipsilateral motor nucleus of the trigeminal nerve in the pons. Both viruses spread centrifugally and caused infection of bilateral trigeminal ganglia on day 3. The viruses spread throughout the central nervous system (CNS) at similar rates, but CVS virus infected many more neurons than did RV194-2 virus. Rabies virus antigen was observed in only occasional CNS neurons after day 6 of RV194-2 virus infection. By this time, CVS virus had caused severe widespread infection. In this model, virulence depends on improved efficiency of viral spread between CNS neurons rather than the rate of spread or topographical distribution of the infection.
Neuropathogenesis of Human Rabies
KESANS : International Journal of Health and Science
Rabies is an acute infection that occurs in the central nervous system caused by a virus from the Rhabdoviridae family and the Lyssavirus genus that can be transmitted by dogs, cats, monkeys, bats, civets, and wolves. The purpose of writing this literature review is to determine the definition, epidemiology, neuropathogenesis and the role of neurotransmitters, clinical features, diagnosis, and management of rabies. The method used in writing this journal is a literature review, using literature searching. Search the library using website-based search tools, namely Google and Google Scholar using the keywords Rabies, Human Rabies, and Neuropathogenesis of Human Rabies. Free full text English and Indonesian publications. The journals selected in this literature review are 12 journals published between 2015-2021. Rabies infection begins with the transfer of viral microorganisms into the bite wound through the saliva of an infected animal. Rabies virus receptors consist of nicotinic ace...
2009
The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV.
Iranian Journal of Basic Medical Sciences, 2021
Objective(s): The mechanisms of rabies evasion and immunological interactions with the host defense have not been completely elucidated. Here, we evaluated the dynamic changes in the number of astrocytes, microglial and neuronal cells in the brain following intramuscular (IM) and intracerebral (IC) inoculations of street rabies virus (SRV). Materials and Methods: The SRV isolated from a jackal and CVS-11 were used to establish infection in NMRI-female mice. The number of astrocytes (by expression of GFAP), microglial (by Iba1), and neuronal cells (by MAP-2) in the brain following IM and IC inoculations of SRV were evaluated by immunohistochemistry and H & E staining 7 to 30 days post-infection. Results: Increased numbers of astrocytes and microglial cells in dead mice infected by SRV via both IC and IM routes were recorded. The number of neuronal cells in surviving mice was decreased only in IC-infected mice, while in the dead group, this number was decreased by both routes. The ris...
Journal of General Virology, 1992
Av01 is a variant of the challenge virus standard strain of fixed rabies virus that was selected with a neutralizing anti-glycoprotein monoclonal antibody, and has a single amino acid change in the glycoprotein. It is avirulent after both intracerebral and peripheral routes of inoculation in adult mice. In this study, Av01 was found to be neurovirulent with stereotaxic brain inoculation in either the striatum or cerebellum of adult mice. Mice that had been inoculated simultaneously with Av01 by the intracerebral and intrastriatal routes recovered. More infectious virus was present in the brains of mice inoculated intrastriatally than intracerebrally, and more neurons contained rabies virus antigen. However, the topographical distribution of infected neurons was similar with both routes. Serum neutralizing antibodies against rabies virus were produced later and in smaller quantities after intrastriatal inoculation. Av01 is probably neurovirulent after stereotaxic brain inoculation because this route produces both a direct site of viral entry into the central nervous system and a low level of immune stimulation.
Microbes and infection, 2017
In the field of live viral vaccines production, there is an unmet need for in vitro tests complying a 3R approach (Refine, Replace and Reduce the use of animal experimentation) to replace the post-licensing safety tests currently assayed in animals. Here, we performed a pilot study evaluating whether virulence of rabies virus, RABV, can be forecast by an in vitro test of neurite outgrowth. The rationale to use neurite outgrowth as a read-out for this test is based on the salient property of the cytoplasmic domain of the G-protein (Cyto-G) of virulent RABV strains - not of attenuated RABV strains - to stimulate neurite outgrowth in vitro. We observed that neurite elongation triggered by the Cyto-Gs encoded by different RABV field isolates correlate with the distinct virulence scores obtained in a mouse model of experimental rabies. Our results cast the idea that it could be feasible to predict RABV virulence by testing the in vitro property of a RABV strain to promote neurite outgrow...
Journal of Virology, 1989
The penetration of the CVS strain of rabies virus and its avirulent derivative AvO1 into peripheral neurons was investigated after intramuscular inoculation into the forelimbs of adult mice. It was found that CVS directly penetrates both the sensitive and motor routes with equal efficiency, without prior multiplication in muscle cells. Infected neurons became detectable 18 h after infection. The second cycle of infection occurred within 2 days, and at day 3 there was a massive invasion of the spinal cord and sensory ganglia. In sensory ganglia, where it was possible to identify cell outlines, it was evident that the infection did not proceed directly from cell body to cell body. The avirulent strain AvO1 penetrated motor and sensory neurons with the same efficiency as CVS. Restriction of viral propagation was observed from the second and third cycles onwards. No further development of the infection could be seen after day 3, and by that time the lysis of primarily infected neurons s...
Acta Neuropathologica, 2007
This work was aimed at the morphological and biochemical characterisation of the most susceptible neuronal subpopulation to rabies virus (RABV) infection. Adult mouse DRG cultures were infected with RABV and double-processed for viral antigen detection and neuropeptides: calcitonine gene-related peptide (CGRP), galanin (GAL), substance P (SP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). It was found that 56% of the neurons in culture were small (diameter <20 m) but, in spite of this, 69% of the infected neurons had intermediate and large diameters (ΒΈ20 m). More than 50% of infected neurons expressed NPY, VIP or SP, whereas no association was found between infected neurons and the presence of CGRP or GAL. Despite SP having been shown to be a small neuron marker, it was found that RABV infects medium and large-sized SP positive cells. RABV preference for larger neurons could explain part of the neuropathogenesis since it can be suggested that, following a rabid accident, the virus uses large neurons (mainly inner-vating muscle and joints) in vivo to be transported later on to the central nervous system.