title: Cytomegalovirus induces T-cell independent apoptosis in brain during immunodeficiency.
abstract: BACKGROUND
  Cytomegalovirus (CMV) is the most common opportunistic viral pathogen associated with HIV/AIDS or immunosuppressive therapy. Systemic pathology may be caused either through direct virus-mediated infection or by indirect mechanisms such as 'by-stander' apoptosis. CMV infection of the central nervous system (CNS) occurs late in disease progression and understanding of pathology in the brain is fundamental for selection of appropriate therapies.
  
  
  OBJECTIVE
  Using a model of disseminated neurotropic CMV disease, these experiments are designed to identify cellular predilection of murine CMV (MCMV) within mature brain and to determine, if CMV induces apoptosis within CNS cells.
  
  
  METHODS
  Adult immunodeficient (SCID) and normal BALB/c mice were infected via the tail vein with 4.5 x 10(5)pfu recombinant MCMV expressing a green fluorescent protein reporter. Animals were perfused at various time periods from 3 to 35 days post inoculation and tissues were stained for MCMV, GFAP, NEU-N, MBP, TUNEL, and caspase-3.
  
  
  RESULTS
  CMV infection within brain was observed in multiple, independent foci affecting several different cell types, including neurons, glial cells, meninges, ependymal cells, and cerebral vessels. Cellular changes included nuclear karyopyknosis and karyorrhexis, and associated meningitis, choroiditis, encephalitis, vasculitis, and necrosis. TUNEL and caspase-3 staining of brain-demonstrated apoptosis of nearby 'by-stander' meningial, glial, and neuronal cells, but only in immunodeficient mice lacking T- and B-lymphocytes. Generally, only large CMV infection foci were associated with apoptosis of non-infected adjacent cells.
  
  
  CONCLUSIONS
  These results indicate that MCMV may cause both direct and indirect pathology to brain and that T-cell independent apoptosis of surrounding cells of the CNS may be an important mechanism of disease in the pathogenesis of neurotropic CMV.
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, P.O. Box 208016, New Haven, CT 06520-8016, USA. jon.reuter@yale.edu
authors.forename: Jon D
authors.initials: JD
authors.lastname: Reuter
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology* / Q000821:virology; D001927:Brain Diseases / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D003587:Cytomegalovirus / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D016867:Immunocompromised Host; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D004676:Myelin Basic Protein / Q000032:analysis; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases