title: Modeling rotavirus infection and antiviral therapy using primary intestinal organoids.
abstract: Despite the introduction of oral vaccines, rotavirus still kills over 450,000 children under five years of age annually. The absence of specific treatment prompts research aiming at further understanding of pathogenesis and the development of effective antiviral therapy, which in turn requires advanced experimental models. Given the intrinsic limitations of the classical rotavirus models using immortalized cell lines infected with laboratory-adapted strains in two dimensional cultures, our study aimed to model infection and antiviral therapy of both experimental and patient-derived rotavirus strains using three dimensional cultures of primary intestinal organoids. Intestinal epithelial organoids were successfully cultured from mouse or human gut tissues. These organoids recapitulate essential features of the in vivo tissue architecture, and are susceptible to rotavirus. Human organoids are more permissive to rotavirus infection, displaying an over 10,000-fold increase in genomic RNA following 24h of viral replication. Furthermore, infected organoids are capable of producing infectious rotavirus particles. Treatment of interferon-alpha or ribavirin inhibited viral replication in organoids of both species. Importantly, human organoids efficiently support the infection of patient-derived rotavirus strains and can be potentially harnessed for personalized evaluation of the efficacy of antiviral medications. Therefore, organoids provide a robust model system for studying rotavirus-host interactions and assessing antiviral medications.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bijvelds
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wen
authors.initials: W
authors.lastname: Dang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Viroscience, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Annemiek A
authors.initials: AA
authors.lastname: van der Eijk
authors.affiliation: Nutricia Research, Utrecht, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Knipping
authors.affiliation: Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Tuysuz
authors.affiliation: Department of Pediatric Pulmonology/Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Pediatric Pulmonology/Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.affiliation: Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Derk
authors.initials: D
authors.lastname: Ten Berge
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: de Jonge
authors.affiliation: Department of Viroscience, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marion P G
authors.initials: MP
authors.lastname: Koopmans
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands. Electronic address: q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D016898:Interferon-alpha / Q000494:pharmacology; D007422:Intestines / Q000473:pathology* / Q000821:virology*; D008297:Male; D051379:Mice; D008954:Models, Biological; D009940:Organoids / Q000473:pathology* / Q000821:virology*; D012254:Ribavirin / Q000494:pharmacology; D012401:Rotavirus / Q000187:drug effects / Q000502:physiology; D012400:Rotavirus Infections / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin
keywords: Interferon; Intestinal organoids; Ribavirin; Rotavirus