title: An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets.
abstract: The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFNλ1 and IFNλ2, linking rs1990760 to the expression of type III IFNs. In the high-responding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positive-feedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.
authors.affiliation: The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital, Stockholm, 141 86, Sweden.
authors.forename: Erna
authors.initials: E
authors.lastname: Domsgen
authors.affiliation: The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital, Stockholm, 141 86, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lind
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, 205 20, Finland.
authors.forename: Lingjia
authors.initials: L
authors.lastname: Kong
authors.affiliation: The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital, Stockholm, 141 86, Sweden.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hühn
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, 205 20, Finland.
authors.forename: Omid
authors.initials: O
authors.lastname: Rasool
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: van Kuppeveld
authors.affiliation: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 751 05, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, 205 20, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.affiliation: The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital, Stockholm, 141 86, Sweden.|Institute of Biosciences and Medical Technologies, University of Tampere, Tampere, 33520, Finland.
authors.forename: Malin
authors.initials: M
authors.lastname: Flodström-Tullberg
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015551:Autoimmunity / Q000235:genetics*; D003384:Coxsackievirus Infections / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics*; D007372:Interferons / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk
chemical_list: D050856:Interferon Regulatory Factor-1; D007372:Interferons; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1