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Appearance of RNA virus-induced lesions in the CNS of weanling mice. a, Neuronal vacuolar degeneration (v) and debris-laden macrophages (arrow) in the ventral horn of the spinal cord of an SJL mouse, 9 days after intracerebral infection with the BeAn strain of Theiler's virus. b. Myelin vacuolation (v), loss of niyelinated fibres, naked and remyelinated axons. and leptomeningeal leucocytic infiltration (left) in the spinal cord of an SJL mouse. 7 3 days after intracerebral infection with the BeAn strain of Theiler's virus. c. Myelin vacuolation and putative necrotic oligodendrocytes (arrows) in the spinal cord of a BALB/c mouse. 5 days after intraperitoneal infection with the M9 mutant of Semliki Forest virus. d. Myelin vacuolation (v). numerous naked axons and macrophages laden with myelin debris (arrows) in the medulla oblongata of a BAL13/c mouse. 21 days after intraperitoneal infection with the M9 mutant of Semliki Forest virus. Toluidine blue stained 1 pm resin sections. x 511.
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RNA viruses with segmented genomes were the first model used for molecular analysis of viral neuropathogenesis, since they could be analysed genetically by reassortment. Four viruses with non-segmented genomes have been used as models of neurovirulence and demyelinating disease: JHM coronavirus, Theiler's virus, Sindbis virus and Semliki Forest vir...
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Context 1
... amount of damage is small, and most mice survive: however, in the second phase of the disease virus is found in glial cells of the white matter, and virus persists in these cells. This persistence is associated with immune-mediated demyelination (Figure 1), so Theiler's virus has been used as a model for human multiple sclerosis (MS) [89]. ...
Context 2
... naturally occurring strains of SFV are virulent for adult mice when given peripherally. and avirulent strains or mutants often induce demyelination in the CNS which is immune-mediated (Figure 1). Avirulent strains or mutants also may infect the developing fetus and induce fetal death or teratogenesis [ 31. Figure 2 summarizes the relationships between strains and mutants of SFV. ...
Context 3
... amount of damage is small, and most mice survive: however, in the second phase of the disease virus is found in glial cells of the white matter, and virus persists in these cells. This persistence is associated with immune-mediated demyelination (Figure 1), so Theiler's virus has been used as a model for human multiple sclerosis (MS) [89]. ...
Context 4
... naturally occurring strains of SFV are virulent for adult mice when given peripherally. and avirulent strains or mutants often induce demyelination in the CNS which is immune-mediated (Figure 1). Avirulent strains or mutants also may infect the developing fetus and induce fetal death or teratogenesis [ 31. Figure 2 summarizes the relationships between strains and mutants of SFV. ...
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Citations
... In these cases, fertilized chicken embryos or experimental animals are used for virus cultivation. [22][23][24] More recent techniques, such as polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), can directly detect pathogen-specific DNA/RNA or proteins. When we compared these techniques, PCR is more sensitive than ELISA. ...
Since the beginning of the new millennium, viruses have shown huge epidemiological and pandemic potential: severe acute respiratory syndrome (SARS) in 2002, pandemic swine flu in 2009, and last but not least the West African Ebola outbreak in 2014. The occurrence and spread of the new virus in pandemic dimension poses a threat to the health and lives of 7 billion people worldwide. There is a growing urgency for highly sensitive and selective detection techniques, usable for a wide number of applications, including disease diagnosis, pharmaceutical research, agriculture, as well as preventive measures. Nanobiosensors represent a new promising tool for virus detection. This review gives a brief survey of the issue of viral detection, comprising diagnostics of target structure of viruses such as nucleic acids or proteins. This review covers different detection principles, methods of fabrication, and applications of virus biosensors.
... The resulting infection, albeit subclinical, may interfere with key neurogenetic processes and lead to insidious, potentially ingravescent functional impairments. Specifically, this neuropathic process has been shown to reflect the combination of the insults mediated by the cytopathic and mutagenic effects of the virus [6], as well as the immune response [7] [8] [9] [10]. Furthermore, the chronic enactment of compensatory, neuroprotective responses may also contribute to the pathogenesis of these disorders. ...
Converging lines of clinical and epidemiological evidence suggest that viral infections in early developmental stages may be a causal factor in neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism-spectrum disorders. This etiological link, however, remains controversial in view of the lack of consistent and reproducible associations between viruses and mental illness. Animal models of virus-induced neurobehavioral disturbances afford powerful tools to test etiological hypotheses and explore pathophysiological mechanisms. Prenatal or neonatal inoculations of neurotropic agents (such as herpes-, influenza-, and retroviruses) in rodents result in a broad spectrum of long-term alterations reminiscent of psychiatric abnormalities. Nevertheless, the complexity of these sequelae often poses methodological and interpretational challenges and thwarts their characterization. The recent conceptual advancements in psychiatric nosology and behavioral science may help determine new heuristic criteria to enhance the translational value of these models. A particularly critical issue is the identification of intermediate phenotypes, defined as quantifiable factors representing single neurochemical, neuropsychological, or neuroanatomical aspects of a diagnostic category. In this paper, we examine how the employment of these novel concepts may lead to new methodological refinements in the study of virus-induced neurobehavioral sequelae through animal models.
... The SFV4 strain of SFV, derived from an infectious clone, induces lethal encephalitis when given intranasally (i.n.) to adult mice. Avirulent strains such as A7 do not kill infected mice older than 14 days, but induce central nervous system (CNS) demyelination [3,4]. Experiments with both virulent and avirulent strains of SFV have shown that SFV can utilize olfactory pathways as a route of entry into the brain and have indicated that axonal transport and macrophages play a role in the transport of virus from nerve endings in the olfactory mucosa [5,6]. ...
... To confirm this, we immunolabeled olfactory bulb sections for axons as well as oligodendrocytes. Within the olfactory bulbs, we found no oligodendrocytes to be expressing EGFP (wild-type SFV infects neurons and oligodendrocytes, but not astrocytes [1,3,4]). Nerve fibers in periglomerular areas that were expressing EGFP were also positively labeled with the MAP1 antibody (not shown). ...
... Control mice infected with SFV4 and sampled at 3 dpi showed perivascular cuffing and mild neuronal degeneration. Extensive laminar and focal areas of necrosis were present in SFV4infected mice sampled at 5 dpi, which was consistent with previous findings [1,3,4]. ...
We have initiated studies to determine the feasibility of employing the Semliki Forest virus (SFV) expression system as a central nervous system (CNS) vector. We investigated the effects of infecting Balb/c mice intranasally (i.n.) with recombinant SFV particles expressing the enhanced green fluorescent protein (EGFP) reporter gene. EGFP expression was detected by fluorescence microscopy in the olfactory bulb as early as 1 day postinfection. No pathological changes were associated with infection. Viral RNA could be detected in the olfactory mucosa only, whereas fluorescence was detected in axons in the olfactory bulb, indicating that only the expressed protein was present. A vector expressing interleukin 10 (IL-10) was constructed and shown to induce good cytokine expression in cultured cells. IL-10 expression in the nasal passage and olfactory bulb of infected mice was enhanced following i.n. administration of such particles. Mice induced for experimental autoimmune encephalomyelitis (EAE) were treated i.n. with vectors expressing EGFP and IL-10 and with empty vector. The EGFP-expressing and empty vectors were found to exacerbate EAE, whereas that expressing IL-10 ameliorated EAE. It is concluded that the mice showed a significant biological response when treated i.n. with recombinant SFV particles and that such particles administered by the i.n. route have potential as a noninvasive vector for protein delivery to the CNS.
... The SFV4 strain of SFV, derived from an infectious clone, induces lethal encephalitis when given intranasally (i.n.) to adult mice. Avirulent strains such as A7 do not kill infected mice older than 14 days, but induce central nervous system (CNS) demyelination [3,4]. Experiments with both virulent and avirulent strains of SFV have shown that SFV can utilize olfactory pathways as a route of entry into the brain and have indicated that axonal transport and macrophages play a role in the transport of virus from nerve endings in the olfactory mucosa [5,6]. ...
... To confirm this, we immunolabeled olfactory bulb sections for axons as well as oligodendrocytes. Within the olfactory bulbs, we found no oligodendrocytes to be expressing EGFP (wild-type SFV infects neurons and oligodendrocytes, but not astrocytes [1,3,4]). Nerve fibers in periglomerular areas that were expressing EGFP were also positively labeled with the MAP1 antibody (not shown). ...
... Control mice infected with SFV4 and sampled at 3 dpi showed perivascular cuffing and mild neuronal degeneration. Extensive laminar and focal areas of necrosis were present in SFV4infected mice sampled at 5 dpi, which was consistent with previous findings [1,3,4]. ...
We have initiated studies to determine the feasibility of employing the Semliki Forest virus (SFV) expression system as a central nervous system (CNS) vector. We investigated the effects of infecting Balb/c mice intranasally (i.n.) with recombinant SFV particles expressing the enhanced green fluorescent protein (EGFP) reporter gene. EGFP expression was detected by fluorescence microscopy in the olfactory bulb as early as 1 day postinfection. No pathological changes were associated with infection. Viral RNA could be detected in the olfactory mucosa only, whereas fluorescence was detected in axons in the olfactory bulb, indicating that only the expressed protein was present. A vector expressing interleukin 10 (IL-10) was constructed and shown to induce good cytokine expression in cultured cells. IL-10 expression in the nasal passage and olfactory bulb of infected mice was enhanced following i.n. administration of such particles. Mice induced for experimental autoimmune encephalomyelitis (EAE) were treated i.n. with vectors expressing EGFP and IL-10 and with empty vector. The EGFP-expressing and empty vectors were found to exacerbate EAE, whereas that expressing IL-10 ameliorated EAE. It is concluded that the mice showed a significant biological response when treated i.n. with recombinant SFV particles and that such particles administered by the i.n. route have potential as a noninvasive vector for protein delivery to the CNS.
... On the other hand, exacerbations of MS have been correlated with viral infections (30)(31)(32)(33). Several animal models of MS are based on viral infections; for example, canine distemper virus infection of dogs, visna virus infection of sheep, and murine coronavirus and Theiler's murine encephalomyelitis virus infection of mice (11,29,(34)(35)(36)(37). The presence of persistent virus infection in these animals results in demyelination with characteristic features similar to MS in humans. ...
Viruses have been implicated in the initiation, progression, and exacerbation of several human autoimmune diseases, including multiple sclerosis. However, no single virus has been demonstrated as the etiologic agent. Multiple different infections may be involved, first in priming the immune system for autoimmunity and then in triggering the actual disease. A model based on experimental allergic encephalomyelitis, an animal model of multiple sclerosis, has been developed, which shows that an initial early infection with a virus having molecular mimicry to self-epitopes can prime for disease that occurs after a subsequent non-specific immunologic stimulus, such as a different infection. The role of multiple infections in the development of autoimmune disease may explain why no one virus has been implicated.
... The A7 and M9 strains remain at the site of CNS entry and induce a long-term CNS demyelination by infecting oligodendrocytes and not neurons (Atkins et al., 1985(Atkins et al., , 1994Fazakerley et al., 1993). The demyelination caused by SFV-A7 and SFV-M9 infection is dependent upon a bystander effect mediated by CD8+ T-cells (Subak-Sharpe et al., 1993). ...
Thesis (Ph. D.)--Texas A & M University, 2001. Includes bibliographical references (leaves 156-191). Vita. "Major Subject: Veterinary Anatomy." In title symbols are used.
... Laboratory virus infections of mice and rats have also been used as models to understand the processes of virus-induced demyelination. These experimental models include murine coronavirus, where persistent virus infection induces an EAE-like disease [22,34]. Myelin reactive T cells are also observed following experimental infection of rats with measles virus and some of these T cell lines are encephalitogenic, supporting the hypothesis that a virus trigger can lead to autoimmunity and myelin damage [35±37]. ...
... Another virus model of MS is Theiler's murine encephalomyelitis virus (TMEV) infection of mice, which produces a chronic demyelinating disease associated with virus persistence [10,11,22,23,38]. ...
Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS in which autoimmunity to myelin plays a role in pathogenesis. The epidemiology of MS indicates that it may be triggered by a virus infection before the age of adolescence, but attempts to associate a specific virus with MS have produced equivocal results. Many studies of the aetiology of MS have postulated that a persistent virus infection is involved, but transient virus infection may provide a plausible alternative mechanism that could explain many of the inconsistencies in MS research. The most studied animal model of MS is chronic relapsing experimental autoimmune encephalomyelitis (CREAE), which is induced in susceptible animals following injection of myelin components. While CREAE cannot provide information on the initiating factor for MS, it may mimic disease processes occurring after an initial trigger that may involve transient virus infection. The disease process may comprise separate triggering and relapse phases. The triggering phase may involve sensitisation to myelin antigens as a result of damage to oligodendrocytes or molecular mimicry. The relapse phase could be similar to CREAE, or alternatively relapses may be induced by further transient virus infections which may not involve infection of the CNS, but which may involve the recrudescence of anti-myelin autoimmunity. Although current vaccines have a high degree of biosafety, it is suggested that the measles-mumps-rubella vaccine in particular could be modified to obviate any possibility of triggering anti-myelin autoimmunity.
... Among these are early studies with reovirus (Spriggs et al., 1983;Tyler et al., 1986), lymphocytic choriomeningitis virus (Ahmed et al., 1984;Ahmed and Oldstone, 1988), bunyaviruses (Endres et al., 1991), and Sindbis virus (Davis et al., 1986). With the advent of molecular clones of poliovirus (Racaniello and Baltimore, 1981) and alphaviruses (Rice et al., 1987;Davis et al., 1989;Liljeström et al., 1991;Kuhn et al., 1991), it became possible to unequivocally assign pathogenesis functions to particular nucleotide substitutions by comparing otherwise isogenic virus clones (e.g., Polo et al., 1988;Lustig et al., 1988;Westrop et al., 1989;Tucker and Griffin, 1991;Davis et al., 1991;Atkins et al., 1994). We have continued the evolution of this genetic approach in these studies of Venezuelan equine encephalitis virus (VEE). ...
The early stages of Venezuelan equine encephalitis virus (VEE) pathogenesis in the mouse model have been examined using a genetic approach. Disease progression of a molecularly cloned single-site mutant was compared with that of the parental virus to determine the step in the VEE pathogenetic sequence at which the mutant was blocked. Assuming that such a block constitutes a genetic screen, isolates from different tissues thought to be distal to the block in the VEE pathogenetic sequence were analyzed to determine the pathogenetic step at which revertants of the mutant were selected. Directed mutation and analysis of reversion in vivo provide two powerful genetic tools for the dissection of the wild-type VEE pathogenetic sequence. Virus from the parental virulent clone, V3000, first replicated in the draining lymph node after subcutaneous inoculation in the left rear footpad. Movement of a cloned avirulent mutant, V3010 (E2 76 Glu to Lys), to the draining lymph node was impaired, replication in the node was delayed, and spread beyond the draining lymph node was sporadic. Serum, contralateral lymph node, spleen, and brain isolates from V3010 inoculated animals were invariably revertant with respect to sequence at E2 76 and/or virulence in mice. Revertants isolated from serum and contralateral lymph node retained the V3010 E2 Lys 76 mutation but also contained a second-site mutation, Glu to Lys at E2 116. Modification of the V3010 clone by addition of the second-site mutation at E2 116 produced a virus that bypassed the V3010 block at the draining lymph node but that did not possess full wild-type capacity for replication in the central nervous system or for induction of mortality. A control construct containing only the E2 116 reverting mutation on the V3000 background was identical to V3000 in terms of early pathogenetic steps and virulence. Therefore, analysis of mutant replication and reversion in vivo suggested (1) that the earliest steps in VEE pathogenesis are transit to the draining lymph node and replication at that site, (2) that the mutation in V3010 impairs transit to the draining lymph node and blocks dissemination to other tissues, and (3) that reversion can overcome the block without restoring full virulence.
... SFV has been exploited for many years as a model of viral neuropathogenesis (13,14). Virulent strains of SFV such as L10 (derived from the original isolate) kill adult mice through a lethal encephalitis when given intraperitoneally (i.p.), subcutaneously, or intranasally (i.n.). ...
The Semliki Forest virus (SFV) expression vector consists of a plasmid based on the SFV infectious clone. Foreign genes may be inserted into the structural coding region, transcribed as RNA, and expressed in cell culture after transfection. RNA containing inserted sequences may be packaged into virions using a helper systems. This allows efficient infection and expression without chemical transfection, but only one round of multiplication is possible. The biosafety of the system has been increased by the introduction of multiple mutations, specifying a maturation defect, into the helper. Potential vaccines can be constructed by insertion of genes coding for antigenic proteins into the vector. Following insertion of the influenza virus nucleoprotein (NP) into the SFV vector, immunity was induced following injection of packaged or naked RNA into mice. The SFV vector is a "suicide" expression vector that has great potential for the construction of vaccines for both human and veterinary use.
Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS in which autoimmunity to myelin plays a role in pathogenesis. The epidemiology of MS indicates that it may be triggered by a virus infection before the age of adolescence, but attempts to associate a specific virus with MS have produced equivocal results. Many studies of the aetiology of MS have postulated that a persistent virus infection is involved, but transient virus infection may provide a plausible alternative mechanism that could explain many of the inconsistencies in MS research. The most studied animal model of MS is chronic relapsing experimental autoimmune encephalomyelitis (CREAE), which is induced in susceptible animals following injection of myelin components. While CREAE cannot provide information on the initiating factor for MS, it may mimic disease processes occurring after an initial trigger that may involve transient virus infection. The disease process may comprise separate triggering and relapse phases. The triggering phase may involve sensitisation to myelin antigens as a result of damage to oligodendrocytes or molecular mimicry. The relapse phase could be similar to CREAE, or alternatively relapses may be induced by further transient virus infections which may not involve infection of the CNS, but which may involve the recrudescence of anti-myelin autoimmunity. Although current vaccines have a high degree of biosafety, it is suggested that the measles-mumps-rubella vaccine in particular could be modified to obviate any possibility of triggering anti-myelin autoimmunity. Copyright © 2000 John Wiley & Sons, Ltd.
