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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00505

HERPES SIMPLEX VIRUS TYPE 1 ENHANCES EXPRESSION OF THE SYNAPTIC PROTEIN ARC FOR ITS OWN BENEFIT

 Francisca D. Acuña Hinrichsen1, Mariela Muñoz1, 2, Melissa Hott1,  Carolina Martin1,  Evelyn K. Mancilla Sierpe1, Paula Salazar1,  Luis Leyton1, Angara Zambrano1, Margarita I. Concha1,  Patricia V. Burgos1, 3, 4 and  Carola Otth1, 5*
  • 1Institute of clinical Microbiology, Faculty of Medicine, Southern University of Chile, Chile
  • 2Centro de Excelencia en Estudios Morfológicos y Quirúrgicos (CEMyQ),, Universidad de La Frontera, Chile
  • 3Centro de Biología Celular y Biomedicina, Facultad de Ciencia y Facultad de Medicina, Universidad San Sebastián, Chile
  • 4Center for Aging and Regeneration (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
  • 5Centro Interdisciplinario de Estudios del Sistema Nervioso, Universidad Austral de Chile, Chile

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to reach the central nervous system (CNS) after primary infection in oronasal mucosa. HSV-1 establishes latency inside neurons due the repression of its gene expression process that is related with periodic reactivations in response to cellular stress conditions constituting a risk factor for neurodegenerative diseases, including Alzheimer’s Disease. The immediate-early gene Arc plays an essential role in neuronal morphology, synaptic plasticity and memory formation. Arc acts as a hub protein interacting with components of the endocytic machinery required for AMPA receptor recycling as well as with proteins of the post-synaptic density and actin cytoskeleton. However, to date, no studies have evaluated whether persistent neurotropic HSV-1 infection modulates expression and function of Arc protein in brain tissue. Here we report that neuronal in vivo and in vitro infection of HSV-1 significantly increases Arc protein levels showing a robust perinuclear distribution in neuronal cell lines, a process that is dependent on active HSV-1 replicative cycle. Finally, we found that silencing of Arc protein caused a decrease in HSV-1 total proteins and viral progeny suggests that Arc is involved in HSV-1 life cycle. Our studies strongly suggest that pathogenicity of HSV-1 neuronal reactivations in humans could be mediated in part by Arc neuronal up-regulation and its potential role in endocytic trafficking and AMPA-neuronal function impairment. Further studies are necessary to define whether this phenomenon could have repercussions in cognition and learning processes in infected individuals.

Keywords: herpes, Arc protein, Neuronal dysfunction, Neuronal infection, neurotropic virus, Neurode generation, Alzheiemr's disease

Received: 24 Aug 2018; Accepted: 06 Dec 2018.

Edited by:

Sara Salinas, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Jason D. Shepherd, University of Utah, United States
Claudio Grassi, Catholic University of Sacred Heart, Italy  

Copyright: © 2018 Acuña Hinrichsen, Muñoz, Hott, Martin, Mancilla Sierpe, Salazar, Leyton, Zambrano, Concha, Burgos and Otth. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Carola Otth, Southern University of Chile, Institute of clinical Microbiology, Faculty of Medicine, Valdivia, Chile, cotth@uach.cl