Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner

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 m...

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Autores: Kropp, Kai A., López-Muñoz, Alberto Domingo, Ritter, Birgit, Martín, Rocío, Rastrojo, Alberto, Srivaratharajan, Sangar, Döhner, Katinka, Dhingra, Akshay, Czechowicz, Julia S., Nagel, Claus-Henning, Sodeik, Beate, Alcamí, Antonio, Viejo-Borbolla, Abel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/236673
Acceso en línea:http://hdl.handle.net/10261/236673
Access Level:acceso abierto
Palabra clave:Axon guidance
Glycoproteins
Herpes simplex virus
Neuron
Neurotrophins
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spelling Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent mannerKropp, Kai A.López-Muñoz, Alberto DomingoRitter, BirgitMartín, RocíoRastrojo, AlbertoSrivaratharajan, SangarDöhner, KatinkaDhingra, AkshayCzechowicz, Julia S.Nagel, Claus-HenningSodeik, BeateAlcamí, AntonioViejo-Borbolla, AbelAxon guidanceGlycoproteinsHerpes simplex virusNeuronNeurotrophinsDuring 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.Deutsche Forschungsgemeinschaft (DFG [German Research Foundation]) grant SFB 900/3-158989968 to A.V.-B. (TPB9) and B.S. (TPC2) (https://www.mh-hannover.de/sfb900.html) and by the DFG under Germany’s Excellence Strategy (grant EXC 2155, project number 390874280, to B.S. and A.V.-B. and Cluster of Excellence REBIRTH to B.S. [Unit 8.1]). A.V.-B. received a Marie Curie Career Integration Grant fellowship (European Union Horizon 2020 program FP7-PEOPLE-2013-CIG [INMA] project number 631792), and K.A.K. was funded by grant SFB 900/3 from the DFG. S.S. was funded by the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony (to B.S. and A.V.-B.; http://www.tiho-hannover.de/forschung/n-rennt/). J.S.C. was funded by the Free and Hanseatic City of Hamburg, Germany (grant Graduiertenkolleg DELIGRAH LFFGK06). A.D. was funded by core funding from the Hannover Medical School. The laboratory of A.A. was funded by the Spanish Ministry of Economy and Competitiveness and the European Union (European Regional Development Funds [FEDER] grant SAF2015-67485-R), and A.D.L.-M. was funded by a Ph.D. fellowship from the Ministerio de Educacion, Cultura y DeporteAmerican Society for MicrobiologyGerman Research FoundationFree and Hanseatic City of HamburgHannover Medical SchoolMinisterio de Economía y Competitividad (España)Ministerio de Educación, Cultura y Deporte (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120202021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/236673reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1128/JVI.01370-20Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2366732026-05-22T06:33:51Z
dc.title.none.fl_str_mv Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
title Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
spellingShingle Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
Kropp, Kai A.
Axon guidance
Glycoproteins
Herpes simplex virus
Neuron
Neurotrophins
title_short Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
title_full Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
title_fullStr Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
title_full_unstemmed Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
title_sort Herpes simplex virus 2 counteracts neurite outgrowth repulsion during infection in a nerve growth factor-dependent manner
dc.creator.none.fl_str_mv Kropp, Kai A.
López-Muñoz, Alberto Domingo
Ritter, Birgit
Martín, Rocío
Rastrojo, Alberto
Srivaratharajan, Sangar
Döhner, Katinka
Dhingra, Akshay
Czechowicz, Julia S.
Nagel, Claus-Henning
Sodeik, Beate
Alcamí, Antonio
Viejo-Borbolla, Abel
author Kropp, Kai A.
author_facet Kropp, Kai A.
López-Muñoz, Alberto Domingo
Ritter, Birgit
Martín, Rocío
Rastrojo, Alberto
Srivaratharajan, Sangar
Döhner, Katinka
Dhingra, Akshay
Czechowicz, Julia S.
Nagel, Claus-Henning
Sodeik, Beate
Alcamí, Antonio
Viejo-Borbolla, Abel
author_role author
author2 López-Muñoz, Alberto Domingo
Ritter, Birgit
Martín, Rocío
Rastrojo, Alberto
Srivaratharajan, Sangar
Döhner, Katinka
Dhingra, Akshay
Czechowicz, Julia S.
Nagel, Claus-Henning
Sodeik, Beate
Alcamí, Antonio
Viejo-Borbolla, Abel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv 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)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Axon guidance
Glycoproteins
Herpes simplex virus
Neuron
Neurotrophins
topic Axon guidance
Glycoproteins
Herpes simplex virus
Neuron
Neurotrophins
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/236673
url http://hdl.handle.net/10261/236673
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1128/JVI.01370-20
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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