An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

Domsgen, EKarolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden. (author)

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.

Lind, KKarolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden. (author)
Kong, LJUniv Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland. (author)
Huhn, MHKarolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Astra Zeneca AB R&D, Pepparedsleden 1, S-43150 Molndal, Sweden. (author)
Rasool, OUniv Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland. (author)
van Kuppeveld, FUniv Utrecht, Div Virol, Dept Infect Dis & Immunol, Fac Vet Med, NL-3584 Utrecht, Netherlands. (author)
Korsgren, OlleUppsala universitet,Klinisk immunologi(Swepub:uu)ollekors (author)
Lahesmaa, RUniv Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland. (author)
Flodstrom-Tullberg, MKarolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland. (author)
Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland. (creator_code:org_t)

In:Scientific reports: Springer Science and Business Media LLC6, s. 39378-2045-2322

By the author/editor: Domsgen, E; Lind, K; Kong, LJ; Huhn, MH; Rasool, O; van Kuppeveld, F; show more...; Korsgren, Olle; Lahesmaa, R; Flodstrom-Tullbe ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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