Journal of Medical Virology 83:1674 (2011) IFIH1/MDA5 in the Innate Immune Response to Coxsackievirus Infection Malin Flodstrom-Tullberg* Karolinska Instituet, Stockholm, Sweden Genome-wide association studies identified recently a type 1 diabetes locus in the gene melanoma differentiation-associated protein-5 (mda5, also denoted ifih1), coding for the viral RNA sensor MDA5. Variants of mda5 modify the risk for disease development [Smyth et al., 2006; Nejentsev et al., 2009]. Enteroviruses, such as Coxsackie B viruses (CVB), have been implicated in the aetiology of type 1 diabetes. A recent study was undertaken to determine whether MDA5 is important in the host response to CVB infection [Hu ¨ hn et al., 2010]. C57BL/6 and 129/SvJ mice lacking mda5 were infected with CVB serotype 3 (CVB3). Mice deficient in MDA5 showed a dramatically increased susceptibility to CVB3 infection. The loss of MDA5 allowed the virus to replicate more rapidly, resulting in increased damage of the pancreas and the liver. The pancreatic islet cells were spared from damage, and none of the infected animals developed diabetes or hyperglycemia. It was also found that MDA5 is not absolutely necessary for the induction of type 1 interferons (IFNs), but is required for the production of maximal levels of systemic IFN-a early after infection. In conclusion, MDA5 plays an important role in the host immune response to CVB3. By restricting virus replication it protects the host from tissue damage and inflammation. These results encourage further studies on the possible role of mda5 in regulating susceptibility to virus-induced diabetes. J. Med. Virol. 83:1674, 2011. ß 2011 Wiley-Liss, Inc. REFERENCES Huhn MH, McCartney SA, Lind K, Svedin E, Colonna M, Flod- strom-Tullberg M. 2010. Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essen- tial for the induction of type 1 interferons after Coxsackievirus infection. Virology 401:42–48. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. 2009. Rare variants of IFIH1, a gene implicated in antiviral responses, pro- tect against type 1 diabetes. Science 324:387–389. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, Guja C, Ionescu-Tirgoviste C, Widmer B, Dunger DB, Savage DA, Walker NM, Clayton DG, Todd JA. 2006. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619. *Correspondence to: Dr. Malin Flodstrom-Tullberg, Center for Infectious Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, F59, S-141 86 Stockholm, Sweden. E-mail: malin.flodstrom-tullberg@ki.se Accepted 19 January 2011 DOI 10.1002/jmv.22061 Published online in Wiley Online Library (wileyonlinelibrary.com). ß 2011 WILEY-LISS, INC.

IFIH1/MDA5 in the innate immune response to coxsackievirus infection

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Journal of Medical Virology 83:1674 (2011)

IFIH1/MDA5 in the Innate Immune Response toCoxsackievirus Infection

Malin Flodstrom-Tullberg*

Karolinska Instituet, Stockholm, Sweden

Genome-wide association studies identifiedrecently a type 1 diabetes locus in the genemelanoma differentiation-associated protein-5(mda5, also denoted ifih1), coding for the viralRNA sensor MDA5. Variants of mda5 modifythe risk for disease development [Smyth et al.,2006; Nejentsev et al., 2009]. Enteroviruses,such as Coxsackie B viruses (CVB), have beenimplicated in the aetiology of type 1 diabetes.A recent study was undertaken to determinewhether MDA5 is important in the hostresponse to CVB infection [Huhn et al., 2010].C57BL/6 and 129/SvJ mice lacking mda5 wereinfected with CVB serotype 3 (CVB3). Micedeficient in MDA5 showed a dramaticallyincreased susceptibility to CVB3 infection. Theloss of MDA5 allowed the virus to replicatemore rapidly, resulting in increased damage ofthe pancreas and the liver. The pancreatic isletcells were spared from damage, and none ofthe infected animals developed diabetes orhyperglycemia. It was also found that MDA5 isnot absolutely necessary for the induction oftype 1 interferons (IFNs), but is required for the

production of maximal levels of systemicIFN-a early after infection. In conclusion, MDA5plays an important role in the host immuneresponse to CVB3. By restricting virus replica-tion it protects the host from tissue damageand inflammation. These results encouragefurther studies on the possible role of mda5in regulating susceptibility to virus-induceddiabetes. J. Med. Virol. 83:1674, 2011.� 2011 Wiley-Liss, Inc.

REFERENCES

Huhn MH, McCartney SA, Lind K, Svedin E, Colonna M, Flod-strom-Tullberg M. 2010. Melanoma differentiation-associatedprotein-5 (MDA-5) limits early viral replication but is not essen-tial for the induction of type 1 interferons after Coxsackievirusinfection. Virology 401:42–48.

Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. 2009. Rarevariants of IFIH1, a gene implicated in antiviral responses, pro-tect against type 1 diabetes. Science 324:387–389.

Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, GujaC, Ionescu-Tirgoviste C, Widmer B, Dunger DB, Savage DA,Walker NM, Clayton DG, Todd JA. 2006. A genome-wide associ-ation study of nonsynonymous SNPs identifies a type 1 diabeteslocus in the interferon-induced helicase (IFIH1) region. NatGenet 38:617–619.

*Correspondence to: Dr. Malin Flodstrom-Tullberg, Center forInfectious Medicine, Karolinska Institute, Karolinska UniversityHospital Huddinge, F59, S-141 86 Stockholm, Sweden.E-mail: [email protected]

Accepted 19 January 2011

DOI 10.1002/jmv.22061Published online in Wiley Online Library(wileyonlinelibrary.com).

� 2011 WILEY-LISS, INC.