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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-02-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00590-18 |
| _version_ | 1818567608009490432 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T06:25:33Z |
| format | Article |
| id | doaj.art-aa2c3b7fa3974724b3e58319699cd762 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-14T06:25:33Z |
| publishDate | 2019-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-aa2c3b7fa3974724b3e58319699cd7622022-12-21T23:13:41ZengAmerican Society for MicrobiologymSphere2379-50422019-02-014110.1128/mSphere.00590-18Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal PopulationLisa N. Akhtar0Christopher D. Bowen1Daniel W. Renner2Utsav Pandey3Ashley N. Della Fera4David W. Kimberlin5Mark N. Prichard6Richard J. Whitley7Matthew D. Weitzman8Moriah L. Szpara9Department of Pediatrics, Division of Infectious Diseases, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartment of Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania, USADepartment of Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania, USADepartment of Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania, USADepartment of Pathology and Laboratory Medicine, Division of Protective Immunity and Division of Cancer Pathobiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartment of Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USADepartment of Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USADepartment of Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USADepartment of Pathology and Laboratory Medicine, Division of Protective Immunity and Division of Cancer Pathobiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartment of Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mSphere.00590-18comparative genomicsherpes simplex virushuman herpesvirus 2minor variantsneonatalviral spread |
| spellingShingle | 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 mSphere comparative genomics herpes simplex virus human herpesvirus 2 minor variants neonatal viral spread |
| title | 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_short | 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 |
| topic | comparative genomics herpes simplex virus human herpesvirus 2 minor variants neonatal viral spread |
| url | https://journals.asm.org/doi/10.1128/mSphere.00590-18 |
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