Neuronal Cytoskeletal Dynamic Modification and Neurodegeneration Induced by Infection with Herpes Simplex Virus Type 1

Abstract

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) belong to the family Herpesviridae, the subfamily Alphaherpesvirinae, and the genus Simplexvirus. They are ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 has been suggested as an environmental risk factor for Alzheimer's disease. However, the mechanisms involved in HSV-1 infection that may trigger the neurodegenerative process are still unknown. In general, HSV-1 induced cytoskeletal alterations reported to date involve the overall disruption of one or more elements of the cytoskeleton in cell lines. Axonal injury has recently attracted attention as a key predictor for the outcome of a number of brain disorders. Here we show that infection of mice neuronal cultures with HSV-1 result in marked neurite damage and neuronal death. Furthermore, in this in vitro model of infection, neurons manifested considerable alterations in microtubule dynamics and tau hyperphosphorylation. These results suggest a possible link between HSV-1 infection and neuronal cytoskeletal disruption.

Cofilin 1-Mediated Biphasic F-Actin Dynamics of Neuronal Cells Affect Herpes Simplex Virus 1 Infection and Replication

“…The invasion of the nervous system by HSV-1 results in the acute brain disease HSE and related neurological dysfunctions. As a consequence, affected patients face high mortality rates and severe comorbidity, which may be related to virus-induced cytoskeleton alterations (11,46). Our results further suggest the possibility that HSV-1 may cause dysfunction of the nervous system by its ability to remodel F-actin dynamics.…”

“…Among these changes, herpes simplex encephalitis (HSE) is considered to be the most common sporadic but fatal encephalitis, over 90% of the cases of which are caused by HSV-1; if left untreated, HSE results in the death of 70% of affected patients (20,43). The neuronal infection can result in marked neurite damage, neuronal-cell death, and a disruption of cytoskeleton dynamics, which may contribute to virus-induced neurodegenerative processes (11,46). As an essential facet of virus-cell interactions, HSV interacts with the host cytoskeleton at various stages of the viral life cycle (12,28,35,39).…”

Mortalin – a multipotent chaperone regulating cellular processes ranging from viral infection to neurodegeneration

“…Itzhaki and coworkers suggest that HSV-1 in the brain and the presence of the apolipoprotein E allele 4 (the recognized risk factor for AD) together confer high risk for AD (Lin et al, 2002). Studies on neuropathological features of HSV-1 demonstrated that the viral infection of human neuronal cells in culture causes an increase in intracellular levels of both Aβ (Piacentini et al, 2011;Santana et al, 2012;Wozniak et al, 2007) and phosphorylated tau (Lerchundi et al, 2011;Wozniak et al, 2009;Zambrano et al, 2008). Furthermore, HSV-1 triggers AD-like cas pase-3 activation and tau cleavage (Lerchundi et al, 2011).…”

Herpes simplex virus tipo 1 como factor de riesgo asociado con la enfermedad de Alzheimer

“…Estos eventos de hiperfosforilación son previos a la formación de estructuras anómalas generadas por la autoagregación de las formas hiperfosforiladas de tau, que forman una red fi lamentosa y compacta. Se ha descrito la hiperfosforilación de tau por acción de diversos estímulos neurotóxicos que, además, inducen apoptosis, como por ejemplo lo que ocurre en animales sometidos a isquemia transciente 46 o por alteración del metabolismo de la glucosa 47 ; en cultivos neuronales tratados con radicales libres 48 , en neuroblastomas tratados con plaquitaxel y doxorubicina (compuestos anticancerígenos) 49 , en neuroblastomas sometidos a estrés hiperosmótico 50 e incluso tratados con inhibidores de la quinasa de supervivencia PI3K 51 . Todos estos hallazgos indican que los eventos de hiperfosforilación de tau, ocurren en la vía de activación del proceso apoptótico, quizás como requerimiento para todos los cambios que ocurren a nivel celular que fi nalizan con la generación de los cuerpos apoptóticos.…”