Abstract
Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that establishes a latent persistent neuronal infection in humans. The pathogenic effects of repeated viral reactivation in infected neurons are still unknown. Several studies have reported that during HSV-1 epithelial infection, the virus could modulate diverse cell signaling pathways remodeling the Golgi apparatus (GA) membranes, but the molecular mechanisms implicated, and the functional consequences to neurons is currently unknown. Here we report that infection of primary neuronal cultures with HSV-1 triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 GTPase, two players with a role in GA integrity maintenance. Immunofluorescence analyses showed that HSV-1 productive neuronal infection caused a scattered and fragmented distribution of the GA through the cytoplasm, contrasting with the uniform perinuclear distribution pattern observed in control cells. In addition, transmission electron microscopy revealed swollen cisternae and disorganized stacks in HSV-1 infected neurons compared to control cells. Interestingly, PP2, a selective inhibitor for Src-family kinases markedly reduced these morphological alterations of the GA induced by HSV-1 infection strongly supporting the possible involvement of Src tyrosine kinase. Finally, we showed that HSV-1 tegument protein VP11/12 is necessary but not sufficient to induce Dyn2 phosphorylation. Altogether, these results show that HSV-1 neuronal infection triggers activation of Src tyrosine kinase, phosphorylation of Dynamin 2 GTPase, and perturbation of GA integrity. These findings suggest a possible neuropathogenic mechanism triggered by HSV-1 infection, which could involve dysfunction of the secretory system in neurons and central nervous system.
Highlights
Herpes simplex virus type 1 (HSV-1) is a DNA enveloped virus, ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans (Whitley, 2006; Steiner, 2011)
Consistent with these findings, we show that HSV-1 neuronal infection activates Src tyrosine kinase and Dynamin 2 (Dyn2) GTPase, two players functionally implicated in the maintenance of the Golgi apparatus (GA) integrity
In the present study we evaluated if HSV-1 could activate Src tyrosine kinase in cortical primary neurons to this end, we studied the relative levels of phosphorylated Src-Tyr424, a highly conserved phosphorylation site among all SFKs members, crucial modification for Src kinase activation (Roskoski, 2005; Ingley, 2008)
Summary
Herpes simplex virus type 1 (HSV-1) is a DNA enveloped virus, ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans (Whitley, 2006; Steiner, 2011). HSV-1 DNA has been detected in the brain of normal aged individuals as well as in AD patients (Itzhaki et al, 2004; Wozniak et al, 2005). The fact that the virus is present in the CNS of 70% of the population over 50 years old (Wozniak et al, 2005) suggests that recurrent reactivations in infected individuals could lead to neuronal alterations (for review see Itzhaki et al, 2004, 2016). The pathogenic mechanism of HSV-1 at the central nervous system (CNS), and the possibility of neuronal dysfunction are yet unknown (Mori, 2010; Roizman et al, 2013)
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