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An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.

Accepted version
Peer-reviewed

Type

Article

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Abstract

Enteroviruses 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.

Description

Keywords

Cell Line, Cell Membrane, Enterovirus, Enterovirus Infections, Gene Expression, Gene Knockout Techniques, Genome, Viral, Humans, Intestinal Mucosa, Mutation, Open Reading Frames, Organoids, Phylogeny, Protein Biosynthesis, RNA, Viral, Selection, Genetic, Viral Proteins, Virus Release

Journal Title

Nat Microbiol

Conference Name

Journal ISSN

2058-5276
2058-5276

Volume Title

4

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (106207/Z/14/Z)
European Research Council (646891)
Wellcome Trust (207498/Z/17/Z)
Wellcome Trust (207498/Z/17/Z)
Wellcome Trust (097997/Z/11/Z)
This 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.