Nerve growth factor and Neurotrophin-3 modulate the rabies infection of adult sensory neurons in primary cultures

Castellanos, Jaime E.; Martínez, M.; Acosta, Orlando; Hurtado, Hernán

doi:10.1016/s0006-8993(00)02408-2

Cited by 17 publications

(16 citation statements)

References 20 publications

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“…While there is some understanding of the roles of viral proteins in rabies pathogenesis, the contribution of host factors to RV transcription͞replication and axonal͞trans-synaptic spread remain unknown. Various technologies are now available to identify host genes that might be essential for the life cycle of RV, important in antiviral defense, or activated nonspecifically in RV infection (2)(3)(4). Because each technology is suited for the detection of different classes of genes and different levels of gene expression, we used a variety of assays, including differential display (DD), cDNA array hybridization, subtraction hybridization (SH), and restriction fragment differential display (RFDD), to assess gene expression in rabies-infected mouse brain.…”

Section: T He Outcome Of Rabies Virus (Rv) Infection Is Determined Bymentioning

confidence: 99%

Effect of rabies virus infection on gene expression in mouse brain

Prosniak

Hooper

Dietzschold

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

103

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A variety of molecular genetic approaches were used to study the effect of rabies virus (RV) infection on host gene expression in mouse brain. The down-regulation of gene expression was found to be a major effect of RV infection by using subtraction hybridization. However, a combination of techniques identified approximately 39 genes activated by infection. These included genes involved in regulation of cell metabolism, protein synthesis, synaptic activity, and cell growth and differentiation. Northern blot analysis to monitor temporal activation of several of these genes following infection revealed essentially two patterns of activation: (i) an early response with up-regulation beginning within 3 days after infection and correlating with transcription of RV nuclear protein; and (ii) a late response with enhanced expression occurring at days 6 -7 after infection and associated with peak RV replication. The gene activation patterns and the known functions of their products suggest that a number of host genes may be involved in the replication and spread of RV in the brain.T he outcome of rabies virus (RV) infection is determined by the convergence of several different virus-host interactions, including those that contribute to virus replication and spread, pathogenic effects on cells, and antiviral responses. RV is particularly suitable for the study of virus-host interactions because of the small size of its genome and its high specificity for infection of neurons. Nevertheless, the mechanisms involved in the disease process are undoubtedly complex. For example, the virus, which uses the neuronal network to spread within the host, must initially replicate in neurons without causing significant functional impairment that would compromise the infection cycle (1). While there is some understanding of the roles of viral proteins in rabies pathogenesis, the contribution of host factors to RV transcription͞replication and axonal͞trans-synaptic spread remain unknown. Various technologies are now available to identify host genes that might be essential for the life cycle of RV, important in antiviral defense, or activated nonspecifically in RV infection (2-4). Because each technology is suited for the detection of different classes of genes and different levels of gene expression, we used a variety of assays, including differential display (DD), cDNA array hybridization, subtraction hybridization (SH), and restriction fragment differential display (RFDD), to assess gene expression in rabies-infected mouse brain. With these approaches, we have revealed the effects of rabies infection on select gene expression patterns in the brain. Based on known functional properties of several gene products as well as the timing of their up-regulation after infection, we discuss possible contributions of host genes to the pathogenesis of rabies. Materials and MethodsVirus Infection of Mice. Female, 6-to 8-week-old Swiss Webster mice were purchased from Taconic Farms. Mice were maintained under pathogen-free conditions and used to 10 w...

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Section: T He Outcome Of Rabies Virus (Rv) Infection Is Determined Bymentioning

confidence: 99%

Effect of rabies virus infection on gene expression in mouse brain

Prosniak

Hooper

Dietzschold

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

103

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“…In order to evaluate this hypothesis, we have studied CVS versus mock infection of cultured adult mouse DRG neurons in order to determine the role of oxidative stress on rabies virus-infected DRG neurons and their neurites (axons). We have used cultured DRG neurons because these neurons are known to be relatively permissive to rabies virus infection (2,14,(27)(28)(29), which facilitates evaluation of processes involving axons. …”

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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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“…RV infection of the central nervous system in vivo occurs primarily through axonal transport of peripheral neurons, and we used cultured sensory neurons from the dorsal root ganglia (DRG) of adult mice as a model system. RV can infect subpopulations of DRG neurons in vivo (13) or in vitro (6,7,38).…”

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confidence: 99%

The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

Tuffereau

Schmidt

Langevin

et al. 2007

J Virol

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Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75 NTR ), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75 NTR in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75 NTR positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75 NTRexpressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75 NTR is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75 NTRExonIV؊/؊ mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75 NTR binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75 NTR interaction. We conclude that although p75 NTR is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75 NTR interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.Rabies causes severe progressive encephalitis, myelitis, and paralysis and affects more than 50,000 people worldwide each year (59). After onset of symptoms, the infection progresses relentlessly, and there is only one documented case of a nonvaccinated human patient who survived the disease (56). Rabies virus (RV) belongs to the genus Lyssavirus in the family Rhabdoviridae and is a simple, enveloped, nonsegmented, negative-strand RNA virus that encodes only five proteins (44). The glycoprotein (G) is known to be the only protein component of the viral envelope that mediates viral entry into host cells (44).RV is highly neurotropic, and after inoculation it is retrogradely transported by peripheral neurons before being passed on to second and higher-order neurons without being taken up by glia. It is this unique property of the virus that makes it a useful transsynaptic neuronal tracer over many synapses (28,52), which is dependent on RVG (17).Although several receptors have been suggested to be responsible for RV infection, none has been conclusively identified. In previous studies we adopted an expression cloning strategy using a soluble form of RVG as a ligand. That work identified the neurotrophin receptor p75 NTR as a unique interacting receptor (50). We have also shown that the glycoprotein from another lyssavirus genotype (EBL2) is also able to interact with p75 NTR (51). p75 NTR belongs to the tumor necrosis factor receptor family (11,14) and is the common receptor for all known mature neurotrophins as well immature proneurotrophins (35). In addition, several other ligands implicated in the patholo...

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Nerve growth factor and Neurotrophin-3 modulate the rabies infection of adult sensory neurons in primary cultures

Cited by 17 publications

References 20 publications

Effect of rabies virus infection on gene expression in mouse brain

Effect of rabies virus infection on gene expression in mouse brain

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

The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

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Nerve growth factor and Neurotrophin-3 modulate the rabies infection of adult sensory neurons in primary cultures

Cited by 17 publications

References 20 publications

Effect of rabies virus infection on gene expression in mouse brain

Effect of rabies virus infection on gene expression in mouse brain

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

The Rabies Virus Glycoprotein Receptor p75 NTR Is Not Essential for Rabies Virus Infection

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The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection