title: Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone.
abstract: Lymphocytic choriomeningitis virus (LCMV) can be transmitted through congenital infection, leading to persistent infection of numerous organ systems including the central nervous system (CNS). Adult mice persistently infected with LCMV (LCMV-cgPi mice) exhibit learning deficits, such as poor performance in spatial discrimination tests. Given that deficits in spatial learning have been linked to defects in adult neurogenesis, we investigated the impact of congenital LCMV infection on generation of neuroblasts from neural progenitor cells within neurogenic zones of adult mice. In LCMV-cgPi mice, QPCR and immunohistochemistry detected presence of LCMV glycoprotein-coding RNA and nucleoprotein in the hippocampal dentate gyrus and subventricular zone (SVZ), sites of neurogenesis that harbor populations of neuroblasts. Numbers of neuroblasts were reduced in LCMV-cgPi mice, as determined by IHC quantification, and analysis of BrdU incorporation by flow cytometry revealed lower numbers of BrdU-labeled neuroblasts. Additionally, TUNEL assays performed in situ showed increased numbers of apoptotic cells in the two neurogenic regions. Next, neurosphere cultures were infected in vitro with LCMV and differentiated to create a population of cells that consisted of both transit amplifying cells and neuroblasts. Immunocytochemical and TUNEL assays revealed increased numbers of TUNEL-positive cells that express nestin, suggesting that the drop in numbers of neuroblasts was due to a combination of impaired proliferation and apoptosis of progenitor cells. LCMV-cgPi mice exhibited transcriptional up-regulation several cytokines and chemokines, including gamma-interferon inducible chemokines CXCL9 and CXCL10. Chronic up-regulation of these chemokines can facilitate a pro-inflammatory niche that may contribute to defects in neurogenesis.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Tony
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Vasek
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism / Q000821:virology*; D007371:Interferon-gamma / Q000378:metabolism; D020547:Lateral Ventricles / Q000378:metabolism / Q000821:virology*; D008216:Lymphocytic Choriomeningitis / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D007371:Interferon-gamma