Selective vulnerability of dorsal root ganglia neurons in experimental rabies after peripheral inoculation of CVS-11 in adult mice

Rossiter, John P.; Hsu, Lena; Jackson, Alan C.

doi:10.1007/s00401-009-0503-6

Cited by 21 publications

(17 citation statements)

References 31 publications

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“…Axonal retraction was observed without neuronal cell death, there were reactive oxygen species produced in neuronal cell bodies, and the mitochondrial membrane potential was reduced, indicating mitochondrial dysfunction. However, the situation in DRG in vivo is quite different in rabies in both humans and animals, in which neuronal death is quite prominent without the typical features of necrosis or apoptosis (20); likely, this neuronal death is due to autophagy.…”

Section: Discussionmentioning

confidence: 99%

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Jackson

Kammouni

Zherebitskaya

et al. 2010

J Virol

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Rabies virus infection of dorsal root ganglia (DRG) was studied in vitro with cultured adult mouse DRG neurons. Recent in vivo studies of transgenic mice that express the yellow fluorescent protein indicate that neuronal process degeneration, involving both dendrites and axons, occurs in mice infected with the challenge virus standard (CVS) strain of rabies virus by footpad inoculation. Because of the similarities of the morphological changes in experimental rabies and in diabetic neuropathy and other diseases, we hypothesize that neuronal process degeneration occurs as a result of oxidative stress. DRG neurons were cultured from adult ICR mice. Two days after plating, they were infected with CVS. Immunostaining was evaluated with CVS-and mock-infected cultures for neuron specific ␤-tubulin, rabies virus antigen, and amino acid adducts of 4-hydroxy-2-nonenal (4-HNE) (marker of lipid peroxidation and hence oxidative stress). Neuronal viability (by trypan blue exclusion), terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and axonal growth were also assessed with the cultures. CVS infected 33 to 54% of cultured DRG neurons. Levels of neuronal viability and TUNEL staining were similar in CVS-and mock-infected DRG neurons. There were significantly more 4-HNE-labeled puncta at 2 and 3 days postinfection in CVS-infected cultures than in mock-infected cultures, and axonal outgrowth was reduced at these time points in CVS infection. Axonal swellings with 4-HNE-labeled puncta were also associated with aggregations of actively respiring mitochondria. We have found evidence that rabies virus infection in vitro causes axonal injury of DRG neurons through oxidative stress. Oxidative stress may be important in vivo in rabies and may explain previous observations of the degeneration of neuronal processes.Rabies is an acute viral infection of the central nervous system (CNS) that is usually fatal in humans and animals (10). Despite its lethality, under natural conditions only relatively mild histopathological lesions are typically found in association with a paucity of degenerative neuronal changes (9, 21). Li et al. (13) showed severe destruction and disorganization of axons and disruption of synaptic structures in silver-stained hippocampal sections from mice infected intracerebrally with the pathogenic N2C strain of rabies virus. Infection with the challenge virus standard (CVS) strain of rabies virus has recently been evaluated using hindlimb footpad inoculation in adult transgenic mice expressing yellow fluorescent protein (26). In this model, dendritic beading and axonal swellings were prominent, and neuronal process degeneration appeared to account for the severe clinical disease and fatal outcome. The axonal swellings exhibited striking morphological similarities to the neurodegenerative changes that occur in the axons of neurons in diabetic sensory and autonomic neuropathy and in human immunodeficiency virus (HIV) infection (4,12,24,35). Studies of cultured adult dorsal root ganglio...

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Section: Discussionmentioning

confidence: 99%

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Jackson

Kammouni

Zherebitskaya

et al. 2010

J Virol

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“…23 There is neuronal infection with inflammatory changes associated with degenerative neuronal changes in dorsal root ganglia in human rabies and in most experimental models of rabies. 48 The neuronal degeneration is much greater than what is seen in the central nervous system in the mouse model with footpad inoculation of challenge virus standard 48 and is highly inflammatory, which suggests the possibility of an immune-mediated process. The neuronal degeneration lacks morphologic features of necrosis or morphologic or biochemical features of apoptosis.…”

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confidence: 99%

Update on rabies

Jackson¹

2011

RRTM

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Human rabies is almost invariably fatal, and globally it remains an important public health problem. Our knowledge of rabies pathogenesis has been learned mainly from studies performed in experimental animal models, and a number of unresolved issues remain. In contrast with the neural pathway of spread, there is still no credible evidence that hematogenous spread of rabies virus to the central nervous system plays a significant role in rabies pathogenesis. Although neuronal dysfunction has been thought to explain the neurological disease in rabies, recent evidence indicates that structural changes involving neuronal processes may explain the severe clinical disease and fatal outcome. Endemic dog rabies results in an ongoing risk to humans in many resource-limited and resource-poor countries, whereas rabies in wildlife is important in North America and Europe. In human cases in North America, transmission from bats is most common, but there is usually no history of a bat bite and there may be no history of contact with bats. Physicians may not recognize typical features of rabies in North America and Europe. Laboratory diagnostic evaluation for rabies includes rabies serology plus skin biopsy, cerebrospinal fluid, and saliva specimens for rabies virus antigen and/or RNA detection. Methods of postexposure rabies prophylaxis, including wound cleansing and administration of rabies vaccine and human rabies immune globulin, are highly effective after recognized exposure. Although there have been rare survivors of human rabies, no effective therapy is presently available. Therapeutic coma (midazolam and phenobarbital), ketamine, and antiviral therapies (known as the "Milwaukee protocol") were given to a rabies survivor, but this therapy was likely not directly responsible for the favorable outcome. New therapeutic approaches for human rabies need to be developed. A better understanding of basic mechanisms involved in rabies pathogenesis may be helpful in the development of potential new therapies for the future.

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“…CVS strain of fixed RABV in suckling, neonatal and adult mice produces encephalitis with marked neuronal apoptosis in various regions of brain when inoculated intracerebrally [15,16]. In contrast, peripheral routes of inoculation of CVS in adult mice showed severe and fatal encephalitis without prominent neuronal apoptosis [3,13,[17][18][19].…”

Section: Discussionmentioning

confidence: 99%

“…However, in rabies the T cell response was found inefficient being inactivated by the virus [2,12]. Further, cells undergoing death were leukocytes and not neurons, which were confirmed by immunohistochemical studies [2,3,[12][13][14]. The CVS strain of RABV by intracerebral route in mice produces encephalitis with marked neuronal apoptosis [15,16], whereas peripheral routes of inoculation produces severe and fatal encephalitis without prominent neuronal apoptosis [3,13,[17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Role of nitric oxide in the regulation of immune responses during rabies virus infection in mice

et al. 2016

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Rabies virus (RABV) stimulates nitric oxide (NO) production, which either triggers T cell differentiation or suppresses T cell function depending on its concentration. Herein, we assessed the potential role of NO in regulation of immune responses during RABV infection in mice model. The experimental animals were divided into four groups and 100LD 50 of challenge virus standard (CVS) strain of RABV was inoculated intracerebrally on day 0 and subsequently aminoguanidine (AG; inducible nitric oxide synthase inhibitor) was injected intraperitoneally twice a day, up to 6 days. The samples were collected at 2, 4, 6, 8, 9, 10 and 12 days post infection (DPI). The immune cells including CD4? , CD8 ? T lymphocytes and natural killer (NK) cells were estimated from peripheral blood mononuclear cells (PBMCs) and splenocytes. Serum total NO concentration, histopathology, immunohistochemistry, direct fluorescent antibody technique and TUNEL assay was performed. Infection with CVS resulted in significant early increase in CD4? , CD8?and NK cells in blood and spleen until 2 DPI. From 4 DPI onwards significant reduction was noticed in these parameters which coincided with increased NO on 4 DPI, rising to maximum on 8 DPI, until their death on 10 DPI. Conversely, the CVS-AG treated group showed lower levels of NO and increased number of CD4 ? , CD8 ? and NK cells. Increased number of cells in blood and spleen coincided with increased survival time, delayed development of clinical signs, reduced viral load and less apoptotic cells. NO played important role in regulation of immune responses during RABV infection. The findings of present study confirmed the role of NO and/or iNOS using iNOS inhibitor (aminoguanidine) in immune response during RABV infection, which would further help in understanding the virus immunopathogenesis with adoption of newer antiviral strategies to counter the progression of disease.

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Selective vulnerability of dorsal root ganglia neurons in experimental rabies after peripheral inoculation of CVS-11 in adult mice

Cited by 21 publications

References 31 publications

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Update on rabies

Role of nitric oxide in the regulation of immune responses during rabies virus infection in mice

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