Abstract
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.
Highlights
Upon entrance in the brain, viruses most often induce inflammation, fever, and brain injury, all signs symptomatic of acute encephalitis
We have shown that Borna disease virus (BDV) infects human neural progenitor cells and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function
We identify that a singled-out BDV protein called P causes similar impairment of human neurogenesis, and further show that it leads to diminution in the genesis of a particular neuronal subtype, the GABAergic neurons
Summary
Upon entrance in the brain, viruses most often induce inflammation, fever, and brain injury, all signs symptomatic of acute encephalitis. Continuous viral replication may interfere with cellular functions, and while not causing overt tissue damage may lead to disease This was first recognized in the early 80s when the lymphocytic choriomeningitis virus (LCMV) was shown to disrupt homeostatic and cognitive functions without obvious tissue injury in its natural murine host [1,2,3,4]. Rabies is another well-known virus that disrupts brain function in the absence of cell lysis and causes dramatic alteration in behavior in both animals and humans [5]. Understanding the mechanisms by which persistent viruses impair brain function and how this may be related to neurological and neuropsychiatric diseases has become a major challenge in neuro-virology
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