title: Oligodendrocytes are a major target of the toxicity of spongiogenic murine retroviruses.
abstract: The neurovirulent retroviruses FrCasE and Moloney MLV-ts1 cause noninflammatory spongiform neurodegeneration in mice, manifested clinically by progressive spasticity and paralysis. Neurons have been thought to be the primary target of toxicity of these viruses. However the neurons themselves appear not to be infected, and the possible indirect mechanisms driving the neuronal toxicity have remained enigmatic. Here we have re-examined the cells that are damaged by these viruses, using lineage-specific markers. Surprisingly, these cells expressed the basic helix-loop-helix transcription factor Olig2, placing them in the oligodendrocyte lineage. Olig2+ cells were found to be infected, and many of these cells exhibited focal cytoplasmic vacuolation, suggesting that infection by spongiogenic retroviruses is directly toxic to these cells. As cytoplasmic vacuolation progressed, however, signs of viral protein expression appeared to wane, although residual viral RNA was detectable by in situ hybridization. Cells with the most advanced cytoplasmic effacement expressed the C/EBP-homologous protein (CHOP). This protein is up-regulated as a late event in a cellular response termed the integrated stress response. This observation may link the cellular pathology observed in the brain with cellular stress responses known to be induced by these viruses. The relevance of these observations to oligodendropathy in humans is discussed.
authors.affiliation: Laboratory of Persistent Viral Diseases, The Microscopy Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4th St., Hamilton, MT 59840, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Clase
authors.forename: Derek E
authors.initials: DE
authors.lastname: Dimcheff
authors.forename: Cynthia
authors.initials: C
authors.lastname: Favara
authors.forename: David
authors.initials: D
authors.lastname: Dorward
authors.forename: Frank J
authors.initials: FJ
authors.lastname: McAtee
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Parrie
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: John L
authors.initials: JL
authors.lastname: Portis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008979:Moloney murine leukemia virus; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D010243:Paralysis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012192:Retroviridae Infections / Q000378:metabolism* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051742:Transcription Factor CHOP; C405708:OLIG2 protein, human; C512773:Olig2 protein, mouse