Abstract
Understanding the pathogenesis of infection by neurotropic viruses represents a major challenge and may improve our knowledge of many human neurological diseases for which viruses are thought to play a role. Borna disease virus (BDV) represents an attractive model system to analyze the molecular mechanisms whereby a virus can persist in the central nervous system (CNS) and lead to altered brain function, in the absence of overt cytolysis or inflammation. Recently, we showed that BDV selectively impairs neuronal plasticity through interfering with protein kinase C (PKC)–dependent signaling in neurons. Here, we tested the hypothesis that BDV phosphoprotein (P) may serve as a PKC decoy substrate when expressed in neurons, resulting in an interference with PKC-dependent signaling and impaired neuronal activity. By using a recombinant BDV with mutated PKC phosphorylation site on P, we demonstrate the central role of this protein in BDV pathogenesis. We first showed that the kinetics of dissemination of this recombinant virus was strongly delayed, suggesting that phosphorylation of P by PKC is required for optimal viral spread in neurons. Moreover, neurons infected with this mutant virus exhibited a normal pattern of phosphorylation of the PKC endogenous substrates MARCKS and SNAP-25. Finally, activity-dependent modulation of synaptic activity was restored, as assessed by measuring calcium dynamics in response to depolarization and the electrical properties of neuronal networks grown on microelectrode arrays. Therefore, preventing P phosphorylation by PKC abolishes viral interference with neuronal activity in response to stimulation. Our findings illustrate a novel example of viral interference with a differentiated neuronal function, mainly through competition with the PKC signaling pathway. In addition, we provide the first evidence that a viral protein can specifically interfere with stimulus-induced synaptic plasticity in neurons.
Highlights
The finding that persistent viruses could selectively affect differentiated functions of their target cell without causing cell lysis or widespread inflammation was first demonstrated more than 25 years ago [1]
We have examined the mechanisms whereby the neurotropic Borna disease virus (BDV) can selectively interfere with synaptic plasticity upon infection of neurons
Using genetically engineered recombinant viruses, we show that the phosphorylation of BDV phosphoprotein (P) by the cellular protein kinase C (PKC) is the main determinant for this interference, mainly by competing with the phosphorylation of the natural PKC substrates in neurons
Summary
The finding that persistent viruses could selectively affect differentiated functions of their target cell without causing cell lysis or widespread inflammation was first demonstrated more than 25 years ago [1]. This type of viral persistence, characterized by minimal cell damage, seems well suited for the central nervous system (CNS) given the limited capacity of renewal of CNS resident cells, in particular of neurons. The mechanisms whereby viruses can interfere with brain function are not well understood and are strongly dependent on the strategy that a given virus has developed to persist in the CNS [5,6]. It is clear that much is needed for a better understanding of the pathogenesis of persistent viral infections of the CNS and for the identification of the viral determinants responsible for the associated diseases
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