Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein

ABSTRACT Between 2015 and 2017, routine molecular surveillance in the United States detected multiple mumps viruses (MuVs) with mutations in the small hydrophobic (SH) gene compared to a reference virus of the same genotype. These mutations include an unusual pattern of uracil-to-cytosine hypermutat...

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Autores principales:	Rita Czakó Stinnett, Andrew S. Beck, Elena N. Lopareva, Rebecca J. McNall, Donald R. Latner, Carole J. Hickman, Paul A. Rota, Bettina Bankamp
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	SH protein genomics molecular epidemiology mumps virus next-generation sequencing paramyxovirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/78d8d502d69d41fe8f55f93131f94d32
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spelling	oai:doaj.org-article:78d8d502d69d41fe8f55f93131f94d322021-11-15T15:31:13ZFunctional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein10.1128/mSphere.00840-202379-5042https://doaj.org/article/78d8d502d69d41fe8f55f93131f94d322020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00840-20https://doaj.org/toc/2379-5042ABSTRACT Between 2015 and 2017, routine molecular surveillance in the United States detected multiple mumps viruses (MuVs) with mutations in the small hydrophobic (SH) gene compared to a reference virus of the same genotype. These mutations include an unusual pattern of uracil-to-cytosine hypermutations and other mutations resulting in the generation of premature stop codons or disruption of the canonical stop codon. The mumps virus SH protein may serve as a virulence factor, based on evidence that it inhibits apoptosis and innate immune signaling in vitro and that recombinant viruses that do not express the SH protein are attenuated in an animal model. In this study, mumps viruses bearing variant SH sequences were isolated from contemporary outbreak samples to evaluate the impact of the observed mutations on SH protein function. All isolates with variant SH sequences replicated in interferon-competent cells with no evidence of attenuation. Furthermore, all SH-variant viruses retained the ability to abrogate induction of NF-κB-mediated innate immune signaling in infected cells. Ectopic expression of variant mumps SH genes is consistent with findings from infection experiments, indicating that the observed abrogation of signaling was not mediated by other viral factors that may modulate innate immune signaling. Molecular surveillance is an important public health tool for monitoring the diversity of circulating mumps viruses and can provide insights into determinants of disease. These findings, in turn, will inform studies employing reverse genetics to elucidate the specific mechanisms of MuV pathogenesis and potential impacts of observed sequence variants on infectivity, fitness, and virulence. IMPORTANCE Mumps virus (MuV) outbreaks occur in the United States despite high coverage with measles, mumps, rubella (MMR) vaccine. Routine genotyping of laboratory-confirmed mumps cases has been practiced in the United States since 2006 to enhance mumps surveillance. This study reports the detection of unusual mutations in the small hydrophobic (SH) protein of contemporary laboratory-confirmed mumps cases and is the first to describe the impact of such mutations on SH protein function. These mutations are predicted to profoundly alter the amino acid sequence of the SH protein, which has been shown to antagonize host innate immune responses; however, they were neither associated with defects in virus replication nor attenuated protein function in vitro, consistent with detection in clinical specimens. A better understanding of the forces governing mumps virus sequence diversity and of the functional consequences of mutations in viral proteins is important for maintaining robust capacity for mumps detection and disease control.Rita Czakó StinnettAndrew S. BeckElena N. LoparevaRebecca J. McNallDonald R. LatnerCarole J. HickmanPaul A. RotaBettina BankampAmerican Society for MicrobiologyarticleSH proteingenomicsmolecular epidemiologymumps virusnext-generation sequencingparamyxovirusMicrobiologyQR1-502ENmSphere, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	SH protein genomics molecular epidemiology mumps virus next-generation sequencing paramyxovirus Microbiology QR1-502
spellingShingle	SH protein genomics molecular epidemiology mumps virus next-generation sequencing paramyxovirus Microbiology QR1-502 Rita Czakó Stinnett Andrew S. Beck Elena N. Lopareva Rebecca J. McNall Donald R. Latner Carole J. Hickman Paul A. Rota Bettina Bankamp Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
description	ABSTRACT Between 2015 and 2017, routine molecular surveillance in the United States detected multiple mumps viruses (MuVs) with mutations in the small hydrophobic (SH) gene compared to a reference virus of the same genotype. These mutations include an unusual pattern of uracil-to-cytosine hypermutations and other mutations resulting in the generation of premature stop codons or disruption of the canonical stop codon. The mumps virus SH protein may serve as a virulence factor, based on evidence that it inhibits apoptosis and innate immune signaling in vitro and that recombinant viruses that do not express the SH protein are attenuated in an animal model. In this study, mumps viruses bearing variant SH sequences were isolated from contemporary outbreak samples to evaluate the impact of the observed mutations on SH protein function. All isolates with variant SH sequences replicated in interferon-competent cells with no evidence of attenuation. Furthermore, all SH-variant viruses retained the ability to abrogate induction of NF-κB-mediated innate immune signaling in infected cells. Ectopic expression of variant mumps SH genes is consistent with findings from infection experiments, indicating that the observed abrogation of signaling was not mediated by other viral factors that may modulate innate immune signaling. Molecular surveillance is an important public health tool for monitoring the diversity of circulating mumps viruses and can provide insights into determinants of disease. These findings, in turn, will inform studies employing reverse genetics to elucidate the specific mechanisms of MuV pathogenesis and potential impacts of observed sequence variants on infectivity, fitness, and virulence. IMPORTANCE Mumps virus (MuV) outbreaks occur in the United States despite high coverage with measles, mumps, rubella (MMR) vaccine. Routine genotyping of laboratory-confirmed mumps cases has been practiced in the United States since 2006 to enhance mumps surveillance. This study reports the detection of unusual mutations in the small hydrophobic (SH) protein of contemporary laboratory-confirmed mumps cases and is the first to describe the impact of such mutations on SH protein function. These mutations are predicted to profoundly alter the amino acid sequence of the SH protein, which has been shown to antagonize host innate immune responses; however, they were neither associated with defects in virus replication nor attenuated protein function in vitro, consistent with detection in clinical specimens. A better understanding of the forces governing mumps virus sequence diversity and of the functional consequences of mutations in viral proteins is important for maintaining robust capacity for mumps detection and disease control.
format	article
author	Rita Czakó Stinnett Andrew S. Beck Elena N. Lopareva Rebecca J. McNall Donald R. Latner Carole J. Hickman Paul A. Rota Bettina Bankamp
author_facet	Rita Czakó Stinnett Andrew S. Beck Elena N. Lopareva Rebecca J. McNall Donald R. Latner Carole J. Hickman Paul A. Rota Bettina Bankamp
author_sort	Rita Czakó Stinnett
title	Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
title_short	Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
title_full	Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
title_fullStr	Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
title_full_unstemmed	Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein
title_sort	functional characterization of circulating mumps viruses with stop codon mutations in the small hydrophobic protein
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/78d8d502d69d41fe8f55f93131f94d32
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Functional Characterization of Circulating Mumps Viruses with Stop Codon Mutations in the Small Hydrophobic Protein

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