title: A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection.
abstract: The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNA-sequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre- and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Kapil
authors.initials: K
authors.lastname: Saxena
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Lukas M
authors.initials: LM
authors.lastname: Simon
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Xi-Lei
authors.initials: XL
authors.lastname: Zeng
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Blutt
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Narayan P
authors.initials: NP
authors.lastname: Sastri
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Umesh C
authors.initials: UC
authors.lastname: Karandikar
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Ajami
authors.affiliation: Department of Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Zachos
authors.affiliation: Department of Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Olga
authors.initials: O
authors.lastname: Kovbasnjuk
authors.affiliation: Department of Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Conner
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030; mestes@bcm.tmc.edu.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Estes
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000235:genetics* / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology*; D012401:Rotavirus / Q000502:physiology; D012400:Rotavirus Infections / Q000235:genetics* / Q000276:immunology; D017423:Sequence Analysis, RNA; D014779:Virus Replication
chemical_list: D007372:Interferons
keywords: enteric virus; human enteroids; human rotavirus; interferon