Murine Leukemia Virus-Induced Neurodegeneration of Rats: Enhancement of Neuropathogenicity Correlates with Enhanced Viral Tropism for Macrophages, Microglia, and Brain Vascular Cells

Czub, Markus; Czub, Stefanie; Rappold, M.; Mazgareanu, Stefan; Schwender, S.; Demuth, M.; Hein, Andreas; Dörries, Rüdiger

doi:10.1006/viro.1995.0027

Cited by 27 publications

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“…In rodents, some of the murine leukemia viruses (MuLV) cause a nonin¯ammatory neurodegeneration, restricted to selective areas of the central nervous system (CNS) and the spinal cord (Baszler and Zachary, 1990;Czub et al, 1994Czub et al, , 1995Kay et al, 1991). Most neurovirulent MuLV as well as certain lentiviruses including the human, simian, and feline immunode®ciency viruses (HIV, SIV, FIV) exhibit a strong af®nity for cells of the monocytic lineage, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Most neurovirulent MuLV as well as certain lentiviruses including the human, simian, and feline immunode®ciency viruses (HIV, SIV, FIV) exhibit a strong af®nity for cells of the monocytic lineage, i.e. in the CNS these viruses infect primarily microglia cells (Brinkmann et al, 1992;Czub et al, 1995Czub et al, , 1996Lynch et al, 1991). However, while infected microglia cells appear not to be morphologically altered, degenerating neurons do not express retroviral gene products (Baszler and Zachary, 1990;Czub et al, 1994Czub et al, , 1995Kay et al, 1991;Koenig et al, 1986;Lynch et al, 1991;Wiley et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Czub¹,

Czub²,

Gosztonyi³

et al. 1999

J Neurovirol

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Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-in¯ammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which ± under different conditions ± exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) signi®cantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Czub¹,

Czub²,

Gosztonyi³

et al. 1999

J Neurovirol

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“…Since the discovery of CasBrE MLV 20 years ago, other neuropathogenic murine retroviruses have been found. In the ecotropic host range group, variants of Friend MLV, including PVC211 [10], NT40 [4], A8 [25], and PVC441 [27] , and temperature sensitive-mutants of Moloney MLV, including ts1 [30,31] and ts-BA1 [2], cause neurodegenerative disease in mice and/or rats. The neuropathology of these viruses is characterized by spongiform neurodegeneration without inflammatory infiltrates, primarily involving the motor system of the brain and spinal cord, and is associated with widespread astrogliosis and neuropil vacuolation [1,3,17,24].…”

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“…As shown in Fig. 1, after administration of [1-13 C] glucose into the animals, the [1-13 C] glucose incorporated into brain cells is converted to [3][4][5][6][7][8][9][10][11][12][13] C] pyruvate and non-labeled pyruvate by glycolysis. This pyruvate is converted to acetylCoA through the pyruvate dehydrogenase complex and then enters the citric acid cycle.…”

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confidence: 99%

Cerebral Metabolism in Brains of Rats Infected with Neuropathogenic Murine Leukemia Viruses

Kanamatsu

Watanabe

Takase‐Yoden

2006

The Journal of Veterinary Medical Science

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ABSTRACT. Friend murine leukemia virus A8 and PVC211 cause spongiform neurodegeneration in rat brains. Glutamate is an important neurotransmitter synthesized from α-ketoglutaric acid, an intermediate product of the citric acid cycle, and glutamine is synthesized from glutamate. To examine the brain metabolism of rats infected with neuropathogenic viruses, the amount of glutamate and glutamine in the brains of rats infected with A8, PVC211, and non-neuropathogenic 57 was measured using high performance liquid chromatography, and the 13 C-label incorporation into the C4 position of glutamate and glutamine from [1-13 C] glucose was measured with 13 C nuclear magnetic resonance. In the cerebral hemisphere and region containing the brain stem and basal ganglia of rats infected with A8 and PVC211 at 8-9 weeks post-infection (wpi), the amount of glutamine was decreased compared with the 57-infected rats. The amount of glutamate was decreased in the cerebral hemisphere of the A8-infected rats and the region containing the brain stem and basal ganglia of PVC211-infected rats at 8-9 wpi. The amount of [4-13 C] glutamine and [4-13 C] glutamate in the cerebral hemisphere and region containing the brain stem and basal ganglia of rats infected with A8 and PVC211 at 8-9 wpi was equivalent to that of the 57-infected rats. These results suggest that in the brains of rats infected with neuropathogenic viruses, de novo synthesis of glutamate and glutamine is not decreased, but the ability to maintain quantitative levels of glutamate and glutamine is decreased compared with the brains of rats infected with non-neuropathogenic virus. KEY WORDS: cerebral metabolism, 13 C, mouse retrovirus, neuropathogenicity.J. Vet. Med. Sci. 68(3): 259-265, 2006 Murine leukemia viruses (MLVs) cause neurodegenerative diseases without inflammatory infiltrates. The first case that showed that murine retroviruses could induce neurological disorders was found in wild mice, which developed hind limb paralysis accompanied with replication-competent ecotropic MLVs, from the Lake Casitas region of California [9,16]. Ecotropic CasBrE MLV isolated from these mice caused a similar disease in the central nervous system (CNS) in laboratory mice [7]. Since the discovery of CasBrE MLV 20 years ago, other neuropathogenic murine retroviruses have been found. , cause neurodegenerative disease in mice and/or rats. The neuropathology of these viruses is characterized by spongiform neurodegeneration without inflammatory infiltrates, primarily involving the motor system of the brain and spinal cord, and is associated with widespread astrogliosis and neuropil vacuolation [1,3,17,24]. One common feature of these viruses, including A8 and PVC211, is that the primary determinant for induction of neurodegenerative disease is the env gene, although other viral genes also have an effect on neuropathogenicity [5,6,15,20,21,26,28]. Some uninfected neurons may exhibit cytopathogenicity, indicating an indirect mechanism of MLV-induced neuropathogenicity [8,19]. However, the patho...

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Identification of Genetic Determinants That Regulate Tumorigenicity of Friend Murine Leukemia Virus in Rats

Takase‐Yoden

Watanabe

2002

Microbiology and Immunology

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Friend murine leukemia virus (FrMLV) clone A8 causes a progressive neurodegenerative disease when the virus is inoculated into newborn rats in addition to the related clones PVC211 and FB29, and of a variant, NT40, derived from FB29 (5,16,24). It has been reported that PVC211, FB29 and NT40 do not induce leukemia in rats, as they do in mice (16,17,23,25). However, clone A8 has high leukemogenic potential against both mice and rats (25). When the A8 virus was inoculated into newborn mice, all of the mice exhibited splenomegaly at 2 3 months post-infection to the same extent as FrMLV clone 57. In the case of inoculation into newborn rats, the A8 virus induced thymoma and leukemic cell infiltration to organs at 7 8 weeks postinfection, but the onset of the disease by 57-virus infection was observed at 20 weeks post-infection (25). The previous studies of chimeric viruses between A8 and 57 revealed that the ClaI-AatII fragment containing the LTR and the 5' half of the 5' leader sequence of A8 is crucial for the induction of aggressive leukemia in rats (25). The LTR of MLV contains enhancer motifs, which are important determinants of leukemogenicity, tissue tropism, and disease specificity (3, 7, 10 13). The 5' leader sequence of MLV, which extends from the 3' end of a primer-binding site to the initiation codon for gag (4, 9), also plays an important role in virus replication. This region contains a donor site for the generation of spliced subgenomic mRNA (4, 22), the packaging signal for the incorporation of genome RNA into virions (1,8), and the internal ribosomal entry mechanism that promotes the translation of gag polyprotein precursors (2). In this study, we restricted the genetic determinants responsible for the induction of thymoma and leukemic infiltration to organs with rapid progression caused by A8 virus in rats. Materials and MethodsViruses and cells. Chimeric viruses combining the high-tumorigenic A8 and the low-tumorigenic 57 (18) were prepared as described previously (24) (Fig. 2). Briefly, to construct R7a, the AatII-HindIII fragment Abstract: A neuropathogenic variant of Friend murine leukemia virus (FrMLV), clone A8, has been shown to cause thymoma and infiltration of leukemic cells to organs at 7 8 weeks post-infection in rats with a more rapid progression than clone 57. We have previously reported that the determinant for induction of aggressive leukemia in rats is located in the ClaI-AatII fragment containing the long terminal repeat (LTR) and the 5' half of the 5' leader sequence of A8 virus. Further studies of chimeric viruses restricted the determinant for the induction of thymoma to only the 0.6-kb ClaI-KpnI fragment of A8. This fragment contains a 0.1 kb region of the 3' terminus of the env gene, the intergenic region, the U3, and the 5' half of the R region in the LTR. Major differences in the fragment between A8 and 57 viruses were found in the U3 region, especially in the enhancer motifs. These results indicate that the enhancer region of A8-LTR contributes to the manifestation of thymom...

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Murine Leukemia Virus-Induced Neurodegeneration of Rats: Enhancement of Neuropathogenicity Correlates with Enhanced Viral Tropism for Macrophages, Microglia, and Brain Vascular Cells

Cited by 27 publications

References 0 publications

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Cerebral Metabolism in Brains of Rats Infected with Neuropathogenic Murine Leukemia Viruses

Identification of Genetic Determinants That Regulate Tumorigenicity of Friend Murine Leukemia Virus in Rats

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