Gammaherpesvirus Infection of Human Neuronal Cells

ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically ass...

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Autores principales:	Hem Chandra Jha, Devan Mehta, Jie Lu, Darine El-Naccache, Sanket K. Shukla, Colleen Kovacsics, Dennis Kolson, Erle S. Robertson
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e3f9723521d04fdcb341dd126965f784
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spelling	oai:doaj.org-article:e3f9723521d04fdcb341dd126965f7842021-11-15T15:41:23ZGammaherpesvirus Infection of Human Neuronal Cells10.1128/mBio.01844-152150-7511https://doaj.org/article/e3f9723521d04fdcb341dd126965f7842015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01844-15https://doaj.org/toc/2150-7511ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer's disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis. IMPORTANCE To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer's disease. In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.Hem Chandra JhaDevan MehtaJie LuDarine El-NaccacheSanket K. ShuklaColleen KovacsicsDennis KolsonErle S. RobertsonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Hem Chandra Jha Devan Mehta Jie Lu Darine El-Naccache Sanket K. Shukla Colleen Kovacsics Dennis Kolson Erle S. Robertson Gammaherpesvirus Infection of Human Neuronal Cells
description	ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer's disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis. IMPORTANCE To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer's disease. In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.
format	article
author	Hem Chandra Jha Devan Mehta Jie Lu Darine El-Naccache Sanket K. Shukla Colleen Kovacsics Dennis Kolson Erle S. Robertson
author_facet	Hem Chandra Jha Devan Mehta Jie Lu Darine El-Naccache Sanket K. Shukla Colleen Kovacsics Dennis Kolson Erle S. Robertson
author_sort	Hem Chandra Jha
title	Gammaherpesvirus Infection of Human Neuronal Cells
title_short	Gammaherpesvirus Infection of Human Neuronal Cells
title_full	Gammaherpesvirus Infection of Human Neuronal Cells
title_fullStr	Gammaherpesvirus Infection of Human Neuronal Cells
title_full_unstemmed	Gammaherpesvirus Infection of Human Neuronal Cells
title_sort	gammaherpesvirus infection of human neuronal cells
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/e3f9723521d04fdcb341dd126965f784
work_keys_str_mv	AT hemchandrajha gammaherpesvirusinfectionofhumanneuronalcells AT devanmehta gammaherpesvirusinfectionofhumanneuronalcells AT jielu gammaherpesvirusinfectionofhumanneuronalcells AT darineelnaccache gammaherpesvirusinfectionofhumanneuronalcells AT sanketkshukla gammaherpesvirusinfectionofhumanneuronalcells AT colleenkovacsics gammaherpesvirusinfectionofhumanneuronalcells AT denniskolson gammaherpesvirusinfectionofhumanneuronalcells AT erlesrobertson gammaherpesvirusinfectionofhumanneuronalcells
_version_	1718427736129667072

Gammaherpesvirus Infection of Human Neuronal Cells

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