Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.

Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 codi...

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Autores principales:	Nora McFadden, Dalan Bailey, Guia Carrara, Alicia Benson, Yasmin Chaudhry, Amita Shortland, Jonathan Heeney, Felix Yarovinsky, Peter Simmonds, Andrew Macdonald, Ian Goodfellow
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/65297a467a524f179dd09dd470377627
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spelling	oai:doaj.org-article:65297a467a524f179dd09dd4703776272021-11-18T06:05:00ZNorovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.1553-73661553-737410.1371/journal.ppat.1002413https://doaj.org/article/65297a467a524f179dd09dd4703776272011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22174679/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is translated during virus infection and the resultant protein localizes predominantly to the mitochondria. Using reverse genetics we demonstrated that expression of ORF4 is not required for virus replication in tissue culture but its loss results in a fitness cost since viruses lacking the ability to express ORF4 restore expression upon repeated passage in tissue culture. Functional analysis indicated that the protein produced from ORF4 antagonizes the innate immune response to infection by delaying the upregulation of a number of cellular genes activated by the innate pathway, including IFN-Beta. Apoptosis in the RAW264.7 macrophage cell line was also increased during virus infection in the absence of ORF4 expression. In vivo analysis of the WT and mutant virus lacking the ability to express ORF4 demonstrated an important role for ORF4 expression in infection and virulence. STAT1-/- mice infected with a virus lacking the ability to express ORF4 showed a delay in the onset of clinical signs when compared to mice infected with WT virus. Quantitative PCR and histopathological analysis of samples from these infected mice demonstrated that infection with a virus not expressing ORF4 results in a delayed infection in this system. In light of these findings we propose the name virulence factor 1, VF1 for this protein. The identification of VF1 represents the first characterization of an alternative open reading frame protein for the calicivirus family. The immune regulatory function of the MNV VF1 protein provide important perspectives for future research into norovirus biology and pathogenesis.Nora McFaddenDalan BaileyGuia CarraraAlicia BensonYasmin ChaudhryAmita ShortlandJonathan HeeneyFelix YarovinskyPeter SimmondsAndrew MacdonaldIan GoodfellowPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 12, p e1002413 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Nora McFadden Dalan Bailey Guia Carrara Alicia Benson Yasmin Chaudhry Amita Shortland Jonathan Heeney Felix Yarovinsky Peter Simmonds Andrew Macdonald Ian Goodfellow Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
description	Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is translated during virus infection and the resultant protein localizes predominantly to the mitochondria. Using reverse genetics we demonstrated that expression of ORF4 is not required for virus replication in tissue culture but its loss results in a fitness cost since viruses lacking the ability to express ORF4 restore expression upon repeated passage in tissue culture. Functional analysis indicated that the protein produced from ORF4 antagonizes the innate immune response to infection by delaying the upregulation of a number of cellular genes activated by the innate pathway, including IFN-Beta. Apoptosis in the RAW264.7 macrophage cell line was also increased during virus infection in the absence of ORF4 expression. In vivo analysis of the WT and mutant virus lacking the ability to express ORF4 demonstrated an important role for ORF4 expression in infection and virulence. STAT1-/- mice infected with a virus lacking the ability to express ORF4 showed a delay in the onset of clinical signs when compared to mice infected with WT virus. Quantitative PCR and histopathological analysis of samples from these infected mice demonstrated that infection with a virus not expressing ORF4 results in a delayed infection in this system. In light of these findings we propose the name virulence factor 1, VF1 for this protein. The identification of VF1 represents the first characterization of an alternative open reading frame protein for the calicivirus family. The immune regulatory function of the MNV VF1 protein provide important perspectives for future research into norovirus biology and pathogenesis.
format	article
author	Nora McFadden Dalan Bailey Guia Carrara Alicia Benson Yasmin Chaudhry Amita Shortland Jonathan Heeney Felix Yarovinsky Peter Simmonds Andrew Macdonald Ian Goodfellow
author_facet	Nora McFadden Dalan Bailey Guia Carrara Alicia Benson Yasmin Chaudhry Amita Shortland Jonathan Heeney Felix Yarovinsky Peter Simmonds Andrew Macdonald Ian Goodfellow
author_sort	Nora McFadden
title	Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
title_short	Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
title_full	Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
title_fullStr	Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
title_full_unstemmed	Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
title_sort	norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/65297a467a524f179dd09dd470377627
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Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.

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