RT Journal Article SR Electronic(1) A1 Lulla, Valeria A1 Dinan, Adam A1 Hosmillo, Myra A1 Chaudhry, Yasmin A1 Sherry, Lee A1 Irigoyen, Nerea A1 Nayak, Komal A1 Stonehouse, Nicola A1 Zilbauer, Matthias A1 Goodfellow, Ian A1 Firth, AndrewYR 2019 T1 A novel enterovirus protein modulates infection in gut epithelial cells JF Access Microbiology, VO 1 IS 1A OP SP 274 DO https://doi.org/10.1099/acmi.ac2019.po0129 PB Microbiology Society, SN 2516-8290, AB 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 the enteroviral proteins were thought to derive from proteolytic processing of a polyprotein encoded in a single open reading frame (ORF). We report that many enterovirus genomes also harbor an upstream ORF (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed expression of uORF protein (UP) in infected cells. Using ribosome profiling (a technique for 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, UP-knockout echoviruses are attenuated compared to wild-type virus at late stages of infection where membrane-associated UP 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 understanding enterovirus pathogenesis., UL https://www.microbiologyresearch.org/content/journal/acmi/10.1099/acmi.ac2019.po0129