Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner
Autor: | Sangar Srivaratharajan, Antonio Alcami, Abel Viejo-Borbolla, Katinka Döhner, Alberto Domingo López-Muñoz, Beate Sodeik, Birgit Ritter, Alberto Rastrojo, Akshay Dhingra, Claus-Henning Nagel, Kai A. Kropp, Rocío Martín, Julia S. Czechowicz |
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Přispěvatelé: | German Research Foundation, Free and Hanseatic City of Hamburg, Hannover Medical School, Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España) |
Rok vydání: | 2020 |
Předmět: |
Nervous system
Neurite viruses Herpesvirus 2 Human Immunology Herpes simplex virus medicine.disease_cause neurotrophins Neurotrophins Microbiology 03 medical and health sciences Mice 0302 clinical medicine Virology Cell Line Tumor Chlorocebus aethiops Nerve Growth Factor medicine Neurites Animals Humans Vero Cells glycoproteins Glycoproteins 030304 developmental biology 0303 health sciences Mice Inbred BALB C Herpes Genitalis biology axon guidance Axon guidance Neuron herpes simplex virus neuron Cell biology Virus-Cell Interactions Nerve growth factor medicine.anatomical_structure HEK293 Cells Insect Science Peripheral nervous system biology.protein 030217 neurology & neurosurgery Neurotrophin |
Zdroj: | Journal of Virology Digital.CSIC. Repositorio Institucional del CSIC instname |
ISSN: | 1098-5514 |
Popis: | Herpes simplex virus 2 (HSV-2) is a prevalent human pathogen that establishes lifelong latency in neurons of the peripheral nervous system. Colonization of neurons is required for HSV-2 persistence and pathogenesis. The viral and cellular factors required for efficient infection of neurons are not fully understood. We show here that nonneuronal cells repel neurite outgrowth of sensory neurons, while HSV-2 infection overcomes this inhibition and, rather, stimulates neurite outgrowth. HSV-2 glycoprotein G and nerve growth factor contribute to this phenotype, which may attract neurites to sites of infection and facilitate virus spread to neurons. Understanding the mechanisms that modulate neurite outgrowth and facilitate HSV-2 infection of neurons might foster the development of therapeutics to reduce HSV-2 colonization of the nervous system and provide insights on neurite outgrowth and regeneration. During primary infection, herpes simplex virus 2 (HSV-2) replicates in epithelial cells and enters neurites to infect neurons of the peripheral nervous system. Growth factors and attractive and repulsive directional cues influence neurite outgrowth and neuronal survival. We hypothesized that HSV-2 modulates the activity of such cues to increase neurite outgrowth. To test this hypothesis, we exposed sensory neurons to nerve growth factor (NGF) and mock- or HSV-2-infected HEK-293T cells, since they express repellents of neurite outgrowth. We show that HEK-293T cells secrete factors that inhibit neurite outgrowth, while infection with HSV-2 strains MS and 333 reduces this repelling phenotype, increasing neurite numbers. The HSV-2-mediated restoration of neurite outgrowth required the activity of NGF. In the absence of infection, however, NGF did not overcome the repulsion mediated by HEK-293T cells. We previously showed that recombinant, soluble glycoprotein G of HSV-2 (rSgG2) binds and enhances NGF activity, increasing neurite outgrowth. However, the effect of gG2 during infection has not been investigated. Therefore, we addressed whether gG2 contributes to overcoming neurite outgrowth repulsion. To do so, we generated viruses lacking gG2 expression and complemented them by exogenous expression of gG2. Overall, our results suggest that HSV-2 infection of nonneuronal cells reduces their repelling effect on neurite outgrowth in an NGF-dependent manner. gG2 contributed to this phenotype, but it was not the only factor. The enhanced neurite outgrowth may facilitate HSV-2 spread from epithelial cells into neurons expressing NGF receptors and increase HSV-2-mediated pathogenesis. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a prevalent human pathogen that establishes lifelong latency in neurons of the peripheral nervous system. Colonization of neurons is required for HSV-2 persistence and pathogenesis. The viral and cellular factors required for efficient infection of neurons are not fully understood. We show here that nonneuronal cells repel neurite outgrowth of sensory neurons, while HSV-2 infection overcomes this inhibition and, rather, stimulates neurite outgrowth. HSV-2 glycoprotein G and nerve growth factor contribute to this phenotype, which may attract neurites to sites of infection and facilitate virus spread to neurons. Understanding the mechanisms that modulate neurite outgrowth and facilitate HSV-2 infection of neurons might foster the development of therapeutics to reduce HSV-2 colonization of the nervous system and provide insights on neurite outgrowth and regeneration. |
Databáze: | OpenAIRE |
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