Viral load and its relationship to quinolinic acid, TNFα, and IL-6 levels in the CNS of retroviral infected mice

Nagra, Rashed M.; Heyes, Melvyn P.; Wiley, Clayton A.

doi:10.1007/bf03160102

Cited by 26 publications

(17 citation statements)

References 32 publications

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“…Magnification before enlargement, ϫ25. E is consistent with reports that increased expression of TNF is a correlate of the spongiform encephalopathies caused by the oncornaviruses CasBrE (38) and ts-1 Moloney MuLV (7), as well as the transmissible spongiform encephalopathy agents (6). Neither TNF-␣ nor TNF-␤ mRNA was found to be upregulated in the brains of mice inoculated with the neuroinvasive but avirulent virus F43.…”

Section: Fig 4 Photomicrographs Of Sections Of Various Areas Of Thesupporting

confidence: 92%

“…Tumor necrosis factor alpha (TNF-␣) mRNA and protein were found to be increased in the brains of mice with advanced neurologic disease caused by ts-1, a neuropathogenic variant of Moloney MuLV (7), and CasBrE (38), respectively. In the present study we have quantified the expression of a variety of inflammatory mediators at the mRNA level in the brains of mice infected with FrCas E both in advanced and in early stages of the disease.…”

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confidence: 99%

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Increased Expression of MIP-1α and MIP-1β mRNAs in the Brain Correlates Spatially and Temporally with the Spongiform Neurodegeneration Induced by a Murine Oncornavirus

Ašković

Favara

McAtee

et al. 2001

J Virol

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The chimeric murine oncornavirus FrCas E causes a rapidly progressive paralytic disease associated with spongiform neurodegeneration throughout the neuroaxis. Neurovirulence is determined by the sequence of the viral envelope gene and by the capacity of the virus to infect microglia. The neurocytopathic effect of this virus appears to be indirect, since the cells which degenerate are not infected. In the present study we have examined the possible role of inflammatory responses in this disease and have used as a control the virus F43. F43 is an highly neuroinvasive but avirulent virus which differs from FrCas E only in 3 pol and env sequences. Like FrCas E , F43 infects large numbers of microglial cells, but it does not induce spongiform neurodegeneration. RNAase protection assays were used to detect differential expression of genes encoding a variety of cytokines, chemokines, and inflammatory cell-specific markers. Tumor necrosis factor alpha (TNF-␣) and TNF-␤ mRNAs were upregulated in advanced stages of disease but not early, even in regions with prominent spongiosis. Surprisingly there was no evidence for upregulation of the cytokines interleukin-1␣ (IL-1␣), IL-1␤, and IL-6 or of the microglial marker F4/80 at any stage of this disease. In contrast, increased levels of the ␤-chemokines MIP-1␣ and -␤ were seen early in the disease and were concentrated in regions of the brain rich in spongiosis, and the magnitude of responses was similar to that observed in the brains of mice injected with the glutamatergic neurotoxin ibotenic acid. MIP-1␣ and MIP-1␤ mRNAs were also upregulated in F43-inoculated mice, but the responses were three-to fivefold lower and occurred later in the course of infection than was observed in FrCas E -inoculated mice. These results suggest that the robust increase in expression of MIP-1␣ and MIP-1␤ in the brain represents a correlate of neurovirulence in this disease, whereas the TNF responses are likely secondary events.

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Section: Fig 4 Photomicrographs Of Sections Of Various Areas Of Thesupporting

confidence: 92%

mentioning

confidence: 99%

Increased Expression of MIP-1α and MIP-1β mRNAs in the Brain Correlates Spatially and Temporally with the Spongiform Neurodegeneration Induced by a Murine Oncornavirus

Ašković

Favara

McAtee

et al. 2001

J Virol

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“…Overexpression of IL-6 in the CNS of Tg mice was also reported to induce severe neuropathological changes, such as neurodegeneration and astrocytosis and vacuolation (13). In addition, upregulation of IL-6 was found by some (78), but not by all (5,14,86), investigators in the CNS of mice developing spongiform disease following inoculation of the neurovirulent MuLVs. In view of this controversy, we used the IL-6-deficient mice to determine the role of this cytokine in the development of MuLV-induced spongiform lesions.…”

Section: Resultsmentioning

confidence: 96%

“…Neurotoxins produced by infected microglial cells have also been postulated to represent important mediators of neurovirulence. In particular, MIP-1␣, MIP-1␤ (5, 86), tumor ne-crosis factor alpha (TNF-␣) (5,14,78,86), interleukin-6 (IL-6) (78), Fas/Fas ligand (FasL) (14), and, to a lesser extent, IL-1␣ (86) and gamma interferon (86) have all been found to be upregulated in the CNS of mice infected with neurovirulent MuLV, although the upregulation of gamma interferon (5,14) and IL-6 (5, 14, 86) has not been confirmed by other studies. Whether these changes in gene expression are causal in disease development or whether they mainly represent the consequences of the disease process remains unknown.…”

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confidence: 99%

Protection against Murine Leukemia Virus-InducedSpongiform Myeloencephalopathy in Mice Overexpressing Bcl-2 butNot in Mice Deficient for Interleukin-6, Inducible NitricOxide Synthetase, ICE, Fas, Fas Ligand, or TNF-R1Genes

Jolicoeur

Mak

et al. 2003

J Virol

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Some murine leukemia viruses (MuLVs), among them Cas-Br-E and ts-1 MuLVs, are neurovirulent, inducing spongiform myeloencephalopathy and hind limb paralysis in susceptible mice. It has been shown that the env gene of these viruses harbors the determinant of neurovirulence. It appears that neuronal loss occurs by an indirect mechanism, since the target motor neurons have not been found to be infected. However, the pathogenesis of the disease remains unclear. Several lymphokines, cytokines, and other cellular effectors have been found to be aberrantly expressed in the brains of infected mice, but whether these are required for the development of the neurodegenerative lesions is not known. In an effort to identify the specific effectors which are indeed required for the initiation and/or development of spongiform myeloencephalopathy, we inoculated gene-deficient (knockout [KO]) mice with ts-1 MuLV. We show here that interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), ICE, Fas, Fas ligand (FasL), and TNF-R1 KO mice still develop signs of disease. However, transgenic mice overexpressing Bcl-2 in neurons (NSE/Bcl-2) were largely protected from hind limb paralysis and had less-severe spongiform lesions. These results indicate that motor neuron death occurs in this disease at least in part by a Bcl-2-inhibitable pathway not requiring the ICE, iNOS, Fas/FasL, TNF-R1, and IL-6 gene products.A few murine leukemia viruses (MuLVs) (e.g., Cas-Br-E and ts-1) are neurovirulent and induce spongiform myeloencephalopathy, leading to hind limb paralysis in susceptible mice (32-34, 91, 106, 109). Results with chimeric MuLV constructed with genes from parental virulent and avirulent MuLVs have established that the envelope (env) gene of these viruses harbors the major determinant of neurovirulence (23,39,75,77,85,89,90,92,98) (reviewed in reference 91). In the case of ts-1 MuLV, a single point mutation (Val 3 Ile) at amino acid position 25 of the coding sequence of the env gene distinguishes it from the parental Moloney MuLV strain from which this ts mutant was derived (98). The important role of the env gene in inducing this disease was also confirmed by expressing the env gene of Cas-Br-E (59) and subsequently of ts-1 (110) MuLV in transgenic (Tg) mice. These env Tg mice developed typical spongiform lesions. ts-1 and Cas-Br-E MuLVs replicate preferentially in microglial cells and to a certain extent in endothelial cells (8,9,18,36,58,72,73,93), while a third neurovirulent MuLV, PVC-211, replicates mainly in the brain capillary endothelial cells (42,75). Although replication has been reported by one study to occur in motor neurons (95), this observation has not been confirmed by other studies (36,58,72). Therefore, the motor neurons which degenerate in these diseases do not appear to be infected by the virus and are most likely affected indirectly (43,49,50,52,55).The spongiform myeloencephalopathy induced by these viruses is most evident in the brain stem and in the lumbar spinal cord. The lesions are characterized by v...

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“…Activation of NO synthesis appears to require very specific stimuli in human monocyte-derived macrophages (Dumarey et al, 1994). By contrast, human macrophages activated with interferon-y synthesize much higher concentrations of the neurotoxin quinolinic acid (Heyes et al, 1992a,b) than similarly activated rat macrophages (Nagra et al, 1994;Saito et al, 1993). It has been suggested in a recent report that NO directly inhibits indoleamine 2,3-dioxygenase-a key enzyme in the kynurenine pathway leading to quinolinate production (Thomas et al, 1994).…”

Section: Discussionmentioning

confidence: 92%

Intrathecal Infusion of the Nitric Oxide Synthase InhibitorN-Methyll-Arginine after Experimental Spinal Cord Injury in Guinea Pigs

Cohen¹,

Weinberg²,

Blight³

1996

Journal of Neurotrauma

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The potential role of nitric oxide (NO) production in secondary pathologic processes that follow spinal cord injury was examined in a guinea pig model that shows secondary loss of function for at least 3 days after trauma. Lateral compression injury of the lower thoracic cord was performed under ketamine/xylazine/acepromazine anesthesia. A fine polyethylene cannula was inserted through an incision in the dura rostral to the injury and run along the dorsal subdural space to the lesion level. The tube was connected to an osmotic pump delivering 1 microL/h of a 10 mM solution of either N-methyl-L-arginine or N-methyl-D-arginine in normal saline (pH 7.2). N-Methyl-L-arginine blocks both constitutive and inducible forms of NO synthase (NOS), present in neurons and inflammatory cells, respectively: N-methyl-D-arginine is the inactive stereoisomer. Two groups of 10 animals were used. Behavioral analysis and somatosensory evoked potential measurements were performed daily for 3 days, then the animals were fixed and survival of white matter at the center of the injury was evaluated, using toluidine-blue stained, 1 microns plastic sections. No significant difference was found between treated and control groups in degree or rate of secondary loss of spinal cord function or in the cross-sectional area of surviving white matter. These data do not support the hypothesis that local NO production by phagocytes, neurons, or other cells plays a significant role in secondary pathology of injury in this model.

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Viral load and its relationship to quinolinic acid, TNFα, and IL-6 levels in the CNS of retroviral infected mice

Cited by 26 publications

References 32 publications

Increased Expression of MIP-1α and MIP-1β mRNAs in the Brain Correlates Spatially and Temporally with the Spongiform Neurodegeneration Induced by a Murine Oncornavirus

Increased Expression of MIP-1α and MIP-1β mRNAs in the Brain Correlates Spatially and Temporally with the Spongiform Neurodegeneration Induced by a Murine Oncornavirus

Protection against Murine Leukemia Virus-InducedSpongiform Myeloencephalopathy in Mice Overexpressing Bcl-2 butNot in Mice Deficient for Interleukin-6, Inducible NitricOxide Synthetase, ICE, Fas, Fas Ligand, or TNF-R1Genes

Intrathecal Infusion of the Nitric Oxide Synthase InhibitorN-Methyll-Arginine after Experimental Spinal Cord Injury in Guinea Pigs

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