Features of Circulating Parainfluenza Virus Required for Growth in Human Airway

ABSTRACT Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted str...

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Autores principales:	Laura M. Palermo, Manik Uppal, Lucy Skrabanek, Paul Zumbo, Soren Germer, Nora C. Toussaint, Bert K. Rima, Devra Huey, Stefan Niewiesk, Matteo Porotto, Anne Moscona
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/52fe91ffaa564643a8215a7f41c6529f
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spelling	oai:doaj.org-article:52fe91ffaa564643a8215a7f41c6529f2021-11-15T15:41:41ZFeatures of Circulating Parainfluenza Virus Required for Growth in Human Airway10.1128/mBio.00235-162150-7511https://doaj.org/article/52fe91ffaa564643a8215a7f41c6529f2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00235-16https://doaj.org/toc/2150-7511ABSTRACT Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted strains of virus in immortalized cultured cell lines. We show that findings made in such systems about the receptor interaction and viral fusion requirements for entry and fitness—mediated by the receptor binding protein and the fusion protein—can be drastically different from the requirements for infection in vivo. Here we carried out whole-genome sequencing and genomic analysis of circulating human parainfluenza virus field strains to define functional and structural properties of proteins of circulating strains and to identify the genetic basis for properties that confer fitness in the field. The analysis of clinical strains suggests that the receptor binding-fusion molecule pairs of circulating viruses maintain a balance of properties that result in an inverse correlation between fusion in cultured cells and growth in vivo. Future analysis of entry mechanisms and inhibitory strategies for paramyxoviruses will benefit from considering the properties of viruses that are fit to infect humans, since a focus on viruses that have adapted to laboratory work provides a distinctly different picture of the requirements for the entry step of infection. IMPORTANCE Mechanistic information about viral infection—information that impacts antiviral and vaccine development—is generally derived from viral strains grown under laboratory conditions in immortalized cells. This study uses whole-genome sequencing of clinical strains of human parainfluenza virus 3—a globally important respiratory paramyxovirus—in cell systems that mimic the natural human host and in animal models. By examining the differences between clinical isolates and laboratory-adapted strains, the sequence differences are correlated to mechanistic differences in viral entry. For this ubiquitous and pathogenic respiratory virus to infect the human lung, modulation of the processes of receptor engagement and fusion activation occur in a manner quite different from that carried out by the entry glycoprotein-expressing pair of laboratory strains. These marked contrasts in the viral properties necessary for infection in cultured immortalized cells and in natural host tissues and animals will influence future basic and clinical studies.Laura M. PalermoManik UppalLucy SkrabanekPaul ZumboSoren GermerNora C. ToussaintBert K. RimaDevra HueyStefan NiewieskMatteo PorottoAnne MosconaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Laura M. Palermo Manik Uppal Lucy Skrabanek Paul Zumbo Soren Germer Nora C. Toussaint Bert K. Rima Devra Huey Stefan Niewiesk Matteo Porotto Anne Moscona Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
description	ABSTRACT Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted strains of virus in immortalized cultured cell lines. We show that findings made in such systems about the receptor interaction and viral fusion requirements for entry and fitness—mediated by the receptor binding protein and the fusion protein—can be drastically different from the requirements for infection in vivo. Here we carried out whole-genome sequencing and genomic analysis of circulating human parainfluenza virus field strains to define functional and structural properties of proteins of circulating strains and to identify the genetic basis for properties that confer fitness in the field. The analysis of clinical strains suggests that the receptor binding-fusion molecule pairs of circulating viruses maintain a balance of properties that result in an inverse correlation between fusion in cultured cells and growth in vivo. Future analysis of entry mechanisms and inhibitory strategies for paramyxoviruses will benefit from considering the properties of viruses that are fit to infect humans, since a focus on viruses that have adapted to laboratory work provides a distinctly different picture of the requirements for the entry step of infection. IMPORTANCE Mechanistic information about viral infection—information that impacts antiviral and vaccine development—is generally derived from viral strains grown under laboratory conditions in immortalized cells. This study uses whole-genome sequencing of clinical strains of human parainfluenza virus 3—a globally important respiratory paramyxovirus—in cell systems that mimic the natural human host and in animal models. By examining the differences between clinical isolates and laboratory-adapted strains, the sequence differences are correlated to mechanistic differences in viral entry. For this ubiquitous and pathogenic respiratory virus to infect the human lung, modulation of the processes of receptor engagement and fusion activation occur in a manner quite different from that carried out by the entry glycoprotein-expressing pair of laboratory strains. These marked contrasts in the viral properties necessary for infection in cultured immortalized cells and in natural host tissues and animals will influence future basic and clinical studies.
format	article
author	Laura M. Palermo Manik Uppal Lucy Skrabanek Paul Zumbo Soren Germer Nora C. Toussaint Bert K. Rima Devra Huey Stefan Niewiesk Matteo Porotto Anne Moscona
author_facet	Laura M. Palermo Manik Uppal Lucy Skrabanek Paul Zumbo Soren Germer Nora C. Toussaint Bert K. Rima Devra Huey Stefan Niewiesk Matteo Porotto Anne Moscona
author_sort	Laura M. Palermo
title	Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
title_short	Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
title_full	Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
title_fullStr	Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
title_full_unstemmed	Features of Circulating Parainfluenza Virus Required for Growth in Human Airway
title_sort	features of circulating parainfluenza virus required for growth in human airway
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/52fe91ffaa564643a8215a7f41c6529f
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Features of Circulating Parainfluenza Virus Required for Growth in Human Airway

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