title: Acid sphingomyelinase deficiency increases susceptibility to fatal alphavirus encephalomyelitis.
abstract: 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-1beta 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.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Ching G
authors.initials: CG
authors.lastname: Ng
authors.forename: Diane E
authors.initials: DE
authors.lastname: Griffin
mesh_terms: D018354:Alphavirus Infections / Q000235:genetics* / Q000401:mortality; D000825:Animal Structures / Q000821:virology; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000821:virology; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004679:Encephalomyelitis / Q000235:genetics* / Q000821:virology*; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012367:RNA, Viral / Q000032:analysis; D012845:Sindbis Virus; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000032:analysis
chemical_list: D015850:Interleukin-6; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D013108:Sphingomyelin Phosphodiesterase