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dc.contributor.authorLulla, Valeria
dc.contributor.authorDinan, Adam M
dc.contributor.authorHosmillo, Myra
dc.contributor.authorChaudhry, Yasmin
dc.contributor.authorSherry, Lee
dc.contributor.authorIrigoyen, Nerea
dc.contributor.authorNayak, Komal M
dc.contributor.authorStonehouse, Nicola J
dc.contributor.authorZilbauer, Matthias
dc.contributor.authorGoodfellow, Ian
dc.contributor.authorFirth, Andrew E
dc.date.accessioned2018-12-12T00:30:58Z
dc.date.available2018-12-12T00:30:58Z
dc.date.issued2019-02
dc.identifier.issn2058-5276
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286699
dc.description.abstractEnteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all of the enteroviral proteins were thought to derive from the proteolytic processing of a polyprotein encoded in a single open reading frame. Here we report that many enterovirus genomes also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed the expression of uORF protein in infected cells. Through ribosome profiling (a technique for the global footprinting of translating ribosomes), we also demonstrated translation of the uORF in representative members of the predominant human enterovirus species, namely Enterovirus A, B and C. In differentiated human intestinal organoids, uORF protein-knockout echoviruses are attenuated compared to the wild-type at late stages of infection where membrane-associated uORF protein facilitates virus release. Thus, we have identified a previously unknown enterovirus protein that facilitates virus growth in gut epithelial cells-the site of initial viral invasion into susceptible hosts. These findings overturn the 50-year-old dogma that enteroviruses use a single-polyprotein gene expression strategy and have important implications for the understanding of enterovirus pathogenesis.
dc.description.sponsorshipThis work was supported by Wellcome Trust grant [106207] and European Research Council grant [646891] to A.E.F; and Wellcome Trust grants 097997/Z/11/Z and 207498/Z/17/Z to I.G.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectIntestinal Mucosa
dc.subjectOrganoids
dc.subjectCell Line
dc.subjectCell Membrane
dc.subjectHumans
dc.subjectEnterovirus
dc.subjectEnterovirus Infections
dc.subjectViral Proteins
dc.subjectRNA, Viral
dc.subjectPhylogeny
dc.subjectGene Expression
dc.subjectProtein Biosynthesis
dc.subjectMutation
dc.subjectGenome, Viral
dc.subjectOpen Reading Frames
dc.subjectGene Knockout Techniques
dc.subjectSelection, Genetic
dc.subjectVirus Release
dc.titleAn upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.
dc.typeArticle
prism.endingPage292
prism.issueIdentifier2
prism.publicationDate2019
prism.publicationNameNat Microbiol
prism.startingPage280
prism.volume4
dc.identifier.doi10.17863/CAM.34006
dcterms.dateAccepted2018-10-19
rioxxterms.versionofrecord10.1038/s41564-018-0297-1
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-02
dc.contributor.orcidLulla, Valeria [0000-0002-6605-0727]
dc.contributor.orcidDinan, Adam M [0000-0003-2812-1616]
dc.contributor.orcidHosmillo, Myra [0000-0002-3514-7681]
dc.contributor.orcidSherry, Lee [0000-0002-4367-772X]
dc.contributor.orcidIrigoyen, Nerea [0000-0001-6346-3369]
dc.contributor.orcidStonehouse, Nicola J [0000-0003-1146-5519]
dc.contributor.orcidZilbauer, Matthias [0000-0002-7272-0547]
dc.contributor.orcidGoodfellow, Ian [0000-0002-9483-510X]
dc.contributor.orcidFirth, Andrew E [0000-0002-7986-9520]
dc.identifier.eissn2058-5276
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (106207/Z/14/Z)
pubs.funder-project-idEuropean Research Council (646891)
pubs.funder-project-idWellcome Trust (207498/Z/17/Z)
pubs.funder-project-idWellcome Trust (207498/Z/17/Z)
pubs.funder-project-idWellcome Trust (097997/Z/11/Z)
cam.issuedOnline2018-11-26
rioxxterms.freetoread.startdate2019-05-26


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