Induction of membrane proliferation in mouse CNS by gold sodium thiomalate with reference to increased virulence of the avirulent Semliki Forest virus

Mehta, S.; Pathak, S.; Webb, H. E.

doi:10.1007/bf01117243

Cited by 11 publications

(4 citation statements)

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“…Electron microscopic analysis of ASM-KO mice has shown that the accumulation of SM results in formation of numerous multilamellar, cytoplasmic inclusions, particularly in the brain (17). Proliferation of intracellular smooth membranes in the brain induced by gold sodium thiomalate is associated with enhanced replication of avirulent strains of Semliki Forest virus, another alphavirus, in the brains of mature mice (37,44). This pool of lipids in neurons of ASM-KO mice may increase availability of the intracellular membranes needed for efficient SV replication, thereby increasing viral spread.…”

Section: Discussionmentioning

confidence: 99%

Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

Griffin

2006

J Virol

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Sindbis virus (SV), an enveloped virus with a single-stranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family. In mice, SV infects neurons and can cause apoptosis of immature neurons. Sphingomyelin (SM) is the most prevalent cellular sphingolipid, is particularly abundant in the nervous systems of mammals, and is required for alphavirus fusion and entry. The level of SM is tightly regulated by sphingomyelinases. A defect in acid sphingomyelinase (ASMase) results in SM storage and subsequent intracellular accumulation of SM. To better understand the role of the SM pathway in SV pathogenesis, we have characterized SV infection of transgenic mice deficient in the ASMase gene. ASMase knockout (ASM-KO) mice were more susceptible to SV infection than wild-type (WT) or heterozygous (Het) animals. Titers of SV were higher in the brains of ASM-KO mice than in the brains of WT mice. More SV RNA was detected by in situ hybridization, more SV protein was detected by immunohistochemistry, and more terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were present in the cortex and hippocampus of ASM-KO mice than in those of WT or Het mice. Interleukin-6 (IL-6), but not IL-1␤ or tumor necrosis factor alpha, was elevated in infected ASM-KO mice compared to levels in WT or Het mice, but studies with IL-6-KO mice and recombinant SV expressing IL-6 showed no role for IL-6 in fatal disease. Together these data indicate that the increase in susceptibility of ASM-KO mice to SV infection was the result of more-rapid replication and spread of SV in the nervous system and increased neuronal death.Sindbis virus (SV), an enveloped virus with a singlestranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family (60). In nature, SV cycles between mosquito and avian vertebrate hosts, producing a lifelong infection in mosquitoes and transient infection in vertebrates. In humans, SV infection can cause fever, rash, and arthritis. In mice, SV causes encephalomyelitis, and neurons in the brain and spinal cord are the primary target cells. The severity of infection in mammals depends on both virus and host factors (20, 32) and makes SV an excellent model to study the pathogenesis of virus-induced encephalomyelitis.Cellular lipids play an important role in several aspects of alphavirus replication, but the roles of specific lipids and their interactions with cellular proteins are not clear (22,53,56). The plasma membranes of eukaryotic cells consist primarily of sphingolipids, glycerophospholipids, and cholesterol (16). Sphingomyelin (SM), comprised of a highly hydrophobic ceramide moiety and a hydrophilic phosphorylcholine head group, is the most prevalent cellular sphingolipid, is particularly abundant in the nervous system, and is often associated with cholesterol (16, 50). Hydrogen bonds and hydrophobic interactions mediate tight interactions between the cholesterol sterol ring system and the ceramide moiety of SM (16,50,54). The lateral association of...

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Section: Discussionmentioning

confidence: 99%

Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

Griffin

2006

J Virol

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“…RNA replication is JK Fazakerley associated with smooth membrane structures termed cytopathic vacuoles (CPVs), types I and II (Grimley et al, 1968;Grimley and Friedman, 1970;Kujala et al, 2001). These structures can be separated from other subcellular structures on sucrose gradients, and biochemical markers indicate they are derived from late endosomes and lysosomes (Friedman et al, 1972;Froshauer et al, 1988;Mehta et al, 1990;Kujala et al, 2001). Confocal microscopy and electronmicroscopy (EM) studies reveal that the surfaces of CPV-I are covered by small invaginations termed spherules, which contain the viral nsP's and are the likely sites of viral RNA replication (Grimley et al, 1968;Kujala et al, 2001).…”

Section: Sfv Replicationmentioning

confidence: 96%

Pathogenesis of Semliki Forest Virus Encephalitis

Fazakerley¹

2002

J. of Neurovirology

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This article provides a review of the pathogenesis of Semliki Forest virus (SFV) encephalitis. In mice, outcome of infection varies according to age of the mouse and strain of the virus and can include acute encephalitis, subacute demyelinating meningoencephalomyelitis, and persistent subclinical central nervous system (CNS) infection. All strains of virus are virulent in mice infected <12 days of age. The L10 strain is also virulent in mice >14 days age, whereas the A7(74) strain is avirulent. The genetic difference between these strains maps to the nsp3 gene. For A7(74) virus, age-related virulence correlates with ability of CNS neurons to replicate virus and undergo apoptotic cell death. Immature developing neurons support complete virus replication but as neuronal populations and circuits mature in the postnatal brain, virus infection becomes progressively restricted and nonproductive. This restricted replication can be overcome by gold I compounds, which may function by inducing neuronal dedifferentiation to a state permissive for virus replication. Biochemical pathways associated with membrane biogenesis may be an important determinant of this effect. Infection of some developing neuronal populations results in apoptosis, whereas infection of mature neurons results in persistent infection. An active type-I interferon system prevents virus spread in extraneural tissues. An initial high-titer plasma viremia is controlled by immunoglobulin M (IgM) antibodies. Virus enters the brain across cerebral endothelial cells and initiates scattered foci of perivascular infection. The blood-brain barrier is disrupted. Neurons and oligodendrocytes are the cell types most frequently infected. Infectivity in the brain can be eliminated by IgG antibodies, though an active T-cell response is required for virus elimination. Lesions of inflammatory demyelination require the presence of CD8(+) T lymphocytes and probably result from destruction by these cells of virally infected oligodendrocytes.

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“…Infection of mice with the virus causes an acute inflammatory reaction in the central nervous system, which leads to demyelination; demyelination can be prevented by depletion of CD8+ T cells (534). Treatment of mice with gold sodium thiomalate results in the proliferation of membranes in the mouse central nervous system and leads to increased growth and increased virulence of A7 (74), suggesting that the restriction in A7(74) growth in the brain is due at least in part to an inability of the virus to induce sufficient proliferation of membranes required for virus growth (343). Perhaps related to the hypothesis that membrane proliferation is required for SF growth in neurons is the report that synthesis of SF RNA requires continuous lipid synthesis (400).…”

Section: Pathogenesis and Immunitymentioning

confidence: 99%