Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population

ABSTRACT More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or throu...

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Autores principales:	Lisa N. Akhtar, Christopher D. Bowen, Daniel W. Renner, Utsav Pandey, Ashley N. Della Fera, David W. Kimberlin, Mark N. Prichard, Richard J. Whitley, Matthew D. Weitzman, Moriah L. Szpara
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	comparative genomics herpes simplex virus human herpesvirus 2 minor variants neonatal viral spread Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/aa2c3b7fa3974724b3e58319699cd762
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spelling	oai:doaj.org-article:aa2c3b7fa3974724b3e58319699cd7622021-11-15T15:22:05ZGenotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population10.1128/mSphere.00590-182379-5042https://doaj.org/article/aa2c3b7fa3974724b3e58319699cd7622019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00590-18https://doaj.org/toc/2379-5042ABSTRACT More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or throughout the infected neonate (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but the viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated 10 HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independently of host immune factors, we measured viral growth characteristics in cultured cells and found diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger plaque size and enhanced spread, with the isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all 10 neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive interhost and intrahost genomic diversity throughout the viral genome, including amino acid differences in more than 90% of the viral proteome. The genes encoding glycoprotein G (gG; US4), glycoprotein I (gI; US7), and glycoprotein K (gK; UL53) and viral proteins UL8, UL20, UL24, and US2 contained variants that were found in association with CNS isolates. Many of these viral proteins are known to contribute to cell spread and neurovirulence in mouse models of CNS disease. This report represents the first application of comparative pathogen genomics to neonatal HSV disease. IMPORTANCE Herpes simplex virus (HSV) causes invasive disease in half of infected neonates, resulting in significant mortality and permanent cognitive morbidity. The factors that contribute to invasive disease are not understood. This study revealed diversity among HSV isolates from infected neonates and detected the first associations between viral genetic variations and clinical disease manifestations. We found that viruses isolated from newborns with encephalitis showed enhanced spread in culture. These viruses contained protein-coding variations not found in viruses causing noninvasive disease. Many of these variations were found in proteins known to impact neurovirulence and viral spread between cells. This work advances our understanding of HSV diversity in the neonatal population and how it may impact disease outcome. Podcast: A podcast concerning this article is available.Lisa N. AkhtarChristopher D. BowenDaniel W. RennerUtsav PandeyAshley N. Della FeraDavid W. KimberlinMark N. PrichardRichard J. WhitleyMatthew D. WeitzmanMoriah L. SzparaAmerican Society for Microbiologyarticlecomparative genomicsherpes simplex virushuman herpesvirus 2minor variantsneonatalviral spreadMicrobiologyQR1-502ENmSphere, Vol 4, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	comparative genomics herpes simplex virus human herpesvirus 2 minor variants neonatal viral spread Microbiology QR1-502
spellingShingle	comparative genomics herpes simplex virus human herpesvirus 2 minor variants neonatal viral spread Microbiology QR1-502 Lisa N. Akhtar Christopher D. Bowen Daniel W. Renner Utsav Pandey Ashley N. Della Fera David W. Kimberlin Mark N. Prichard Richard J. Whitley Matthew D. Weitzman Moriah L. Szpara Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
description	ABSTRACT More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or throughout the infected neonate (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but the viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated 10 HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independently of host immune factors, we measured viral growth characteristics in cultured cells and found diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger plaque size and enhanced spread, with the isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all 10 neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive interhost and intrahost genomic diversity throughout the viral genome, including amino acid differences in more than 90% of the viral proteome. The genes encoding glycoprotein G (gG; US4), glycoprotein I (gI; US7), and glycoprotein K (gK; UL53) and viral proteins UL8, UL20, UL24, and US2 contained variants that were found in association with CNS isolates. Many of these viral proteins are known to contribute to cell spread and neurovirulence in mouse models of CNS disease. This report represents the first application of comparative pathogen genomics to neonatal HSV disease. IMPORTANCE Herpes simplex virus (HSV) causes invasive disease in half of infected neonates, resulting in significant mortality and permanent cognitive morbidity. The factors that contribute to invasive disease are not understood. This study revealed diversity among HSV isolates from infected neonates and detected the first associations between viral genetic variations and clinical disease manifestations. We found that viruses isolated from newborns with encephalitis showed enhanced spread in culture. These viruses contained protein-coding variations not found in viruses causing noninvasive disease. Many of these variations were found in proteins known to impact neurovirulence and viral spread between cells. This work advances our understanding of HSV diversity in the neonatal population and how it may impact disease outcome. Podcast: A podcast concerning this article is available.
format	article
author	Lisa N. Akhtar Christopher D. Bowen Daniel W. Renner Utsav Pandey Ashley N. Della Fera David W. Kimberlin Mark N. Prichard Richard J. Whitley Matthew D. Weitzman Moriah L. Szpara
author_facet	Lisa N. Akhtar Christopher D. Bowen Daniel W. Renner Utsav Pandey Ashley N. Della Fera David W. Kimberlin Mark N. Prichard Richard J. Whitley Matthew D. Weitzman Moriah L. Szpara
author_sort	Lisa N. Akhtar
title	Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
title_short	Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
title_full	Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
title_fullStr	Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
title_full_unstemmed	Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population
title_sort	genotypic and phenotypic diversity of herpes simplex virus 2 within the infected neonatal population
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/aa2c3b7fa3974724b3e58319699cd762
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Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population

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