Borna disease virus phosphoprotein impairs the developmental program controlling neurogenesis and reduces human GABAergic neurogenesis.
It is well established that persistent viral infection may impair cellular function of specialized cells without overt damage. This concept, when applied to neurotropic viruses, may help to understand certain neurologic and neuropsychiatric diseases. Borna disease virus (BDV) is an excellent example of a persistent virus that targets the brain, impairs neural functions without cell lysis, and ultimately results in neurobehavioral disturbances. Recently, we have shown that BDV infects human neural progenitor cells (hNPCs) and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function. Here, we sought to identify the viral proteins and molecular pathways that are involved. Using lentiviral vectors for expression of the bdv-p and bdv-x viral genes, we demonstrate that the phosphoprotein P, but not the X protein, diminishes human neurogenesis and, more particularly, GABAergic neurogenesis. We further reveal a decrease in pro-neuronal factors known to be involved in neuronal differentiation (ApoE, Noggin, TH and Scg10/Stathmin2), demonstrating that cellular dysfunction is associated with impairment of specific components of the molecular program that controls neurogenesis. Our findings thus provide the first evidence that a viral protein impairs GABAergic human neurogenesis, a process that is dysregulated in several neuropsychiatric disorders. They improve our understanding of the mechanisms by which a persistent virus may interfere with brain development and function in the adult.
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
Chloé
C
Scordel
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
Alexandra
A
Huttin
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
Marielle
M
Cochet-Bernoin
Institut National de la Santé et de la Recherche Médicale, UMR 1043, Toulouse, France; Centre National de la Recherche Scientifique, UMR 5282, Toulouse, France; Université Paul Sabatier, Toulouse 3, Toulouse, France.
Marion
M
Szelechowski
CECS, I-STEM, AFM, Evry, France.
Aurélie
A
Poulet
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
Jennifer
J
Richardson
CECS, I-STEM, AFM, Evry, France.
Alexandra
A
Benchoua
Institut National de la Santé et de la Recherche Médicale, UMR 1043, Toulouse, France; Centre National de la Recherche Scientifique, UMR 5282, Toulouse, France; Université Paul Sabatier, Toulouse 3, Toulouse, France.
Daniel
D
Gonzalez-Dunia
Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France; Pasteur Institute, Pathogen Discovery Laboratory, Biology of Infection Unit, INSERM U1117, Paris, France.
Marc
M
Eloit
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
Muriel
M
Coulpier
D021581:Active Transport, Cell Nucleus; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors / Q000378:metabolism; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D001890:Borna Disease / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001891:Borna disease virus / Q000502:physiology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005602:France; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055495:Neurogenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000633:toxicity; D050777:Stathmin; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D000099176:Noggin Protein
D001057:Apolipoproteins E; D015415:Biomarkers; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; D050777:Stathmin; D014446:Tyrosine 3-Monooxygenase; D015678:Viral Structural Proteins; D000099176:Noggin Protein; C496537:P protein, Borna disease virus; C063314:STMN2 protein, human