Skip to main content
SpringerLink
Log in

Innate Immune Responses to Viruses Inducing Diabetes

  • Chapter
  • First Online:
Diabetes and Viruses

Abstract

Together with physical and chemical barriers, the innate immune system is the first line of defense against infecting pathogens. By responding rapidly to conserved structures expressed by pathogens, so-called pathogen-associated molecular patterns (PAMPs), the innate immune system prevents replication and spread of pathogens, and promotes the activation of specific immune responses. Many observations have indicated that certain virus infections may contribute to the development of type 1 diabetes. Although it has been difficult to establish firmly the role of viruses in the development of human type 1 diabetes, numerous animal models have provided proof-of-concept for their involvement in the pathogenesis of the disease. It is also becoming clear that the innate immune response to the infecting pathogens may contribute to disease development. Recent genome-wide studies have identified several type 1 diabetes susceptibility loci containing genes of direct or indirect importance for the functions of the innate immune system. Increased knowledge of host–pathogen interactions as well as the functional effects of the type 1 diabetes-associated gene polymorphisms may therefore contribute to a better understanding of the potential role of viruses in type 1 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Berhan Y, Waernbaum I, Lind T, Mollsten A, Dahlquist G (2011) Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden. Diabetes 60:577–581

    Article  PubMed  CAS  Google Scholar 

  • Brennan K, Bowie AG (2011) Activation of host pattern recognition receptors by viruses. Curr Opin Microbiol 13:503–507

    Article  Google Scholar 

  • Chung YH, Jun HS, Kang Y, Hirasawa K, Lee BR, Van Rooijen N, Yoon JW (1997) Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant BioBreeding rats. J Immunol 159:466–471

    PubMed  CAS  Google Scholar 

  • Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, Greissl C, Ramos-Lopez E, Hypponen E, Dunger DB, Spector TD, Ouwehand WH, Wang TJ, Badenhoop K, Todd JA (2011) Inherited variation in vitamin d genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60:1624–1631

    Article  PubMed  CAS  Google Scholar 

  • Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Prato SD, Elliott JF, Covacci A, Rappuoli R, Roep BO, Marchetti P (2007) Coxsackie B4 virus infection of beta-cells and NK cell insulitis in recent onset type 1 diabetic patients. Proc Natl Acad Sci USA 104:5115–5120

    Article  PubMed  CAS  Google Scholar 

  • Flodstrom M, Horwitz MS, Maday A, Balakrishna D, Rodriguez E, Sarvetnick N (2001) A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. Virology 281:205–215

    Article  PubMed  CAS  Google Scholar 

  • Flodstrom M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N (2002) Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 3:373–382

    Article  PubMed  CAS  Google Scholar 

  • Flodstrom-Tullberg M (2003) Viral infections: their elusive role in regulating susceptibility to autoimmune disease. Microbes Infect 5:911–921

    Article  PubMed  CAS  Google Scholar 

  • Flodstrom-Tullberg M, Hultcrantz M, Stotland A, Maday A, Tsai D, Fine C, Williams B, Silverman R, Sarvetnick N (2005) RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J Immunol 174:1171–1177

    PubMed  Google Scholar 

  • Fuse K, Chan G, Liu Y, Gudgeon P, Husain M, Chen M, Yeh WC, Akira S, Liu PP (2005) Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112:2276–2285

    Article  PubMed  CAS  Google Scholar 

  • Gale EA (2005) Spring harvest? Reflections on the rise of type 1 diabetes. Diabetologia 48:2445–2450

    Article  PubMed  CAS  Google Scholar 

  • Heinig M, Petretto E, Wallace C, Bottolo L, Rotival M, Lu H, Li Y, Sarwar R, Langley SR, Bauerfeind A, Hummel O, Lee YA, Paskas S, Rintisch C, Saar K, Cooper J, Buchan R, Gray EE, Cyster JG, Erdmann J, Hengstenberg C, Maouche S, Ouwehand WH, Rice CM, Samani NJ, Schunkert H, Goodall AH, Schulz H, Roider HG, Vingron M, Blankenberg S, Munzel T, Zeller T, Szymczak S, Ziegler A, Tiret L, Smyth DJ, Pravenec M, Aitman TJ, Cambien F, Clayton D, Todd JA, Hubner N, Cook SA (2011) A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467:460–464

    Article  Google Scholar 

  • Horwitz MS, Bradley LM, Harbertson J, Krahl T, Lee J, Sarvetnick N (1998) Diabetes induced by coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med 4:781–785

    Article  PubMed  CAS  Google Scholar 

  • Huhn MH, McCartney SA, Lind K, Svedin E, Colonna M, Flodstrom-Tullberg M (2010) Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after coxsackievirus infection. Virology 401:42–48

    Article  PubMed  Google Scholar 

  • Hyoty H (2004) Environmental causes: viral causes. Endocrinol Metab Clin North Am 33:27–44, viii

    Article  PubMed  Google Scholar 

  • Jeong E, Lee JY (2011) Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Med J 52:379–392

    Article  PubMed  CAS  Google Scholar 

  • Jun HS, Yoon JW (2001) The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia 44:271–285

    Article  PubMed  CAS  Google Scholar 

  • Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  PubMed  CAS  Google Scholar 

  • Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30:16–34

    Article  PubMed  CAS  Google Scholar 

  • McCartney SA, Vermi W, Lonardi S, Rossini C, Otero K, Calderon B, Gilfillan S, Diamond MS, Unanue ER, Colonna M (2011) RNA sensor-induced type I IFN prevents diabetes caused by a beta cell-tropic virus in mice. J Clin Invest 121:1497–1507

    Article  PubMed  CAS  Google Scholar 

  • Munz C, Lunemann JD, Getts MT, Miller SD (2009) Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 9:246–258

    Article  PubMed  Google Scholar 

  • Negishi H, Osawa T, Ogami K, Ouyang X, Sakaguchi S, Koshiba R, Yanai H, Seko Y, Shitara H, Bishop K, Yonekawa H, Tamura T, Kaisho T, Taya C, Taniguchi T, Honda K (2008) A critical link between toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc Natl Acad Sci USA 105:20446–20451

    Article  PubMed  CAS  Google Scholar 

  • Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324:387–389

    Article  PubMed  CAS  Google Scholar 

  • Redondo MJ, Jeffrey J, Fain PR, Eisenbarth GS, Orban T (2008) Concordance for islet autoimmunity among monozygotic twins. N Engl J Med 359:2849–2850

    Article  PubMed  CAS  Google Scholar 

  • Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG (2009) The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 52:1143–1151

    Article  PubMed  CAS  Google Scholar 

  • Roivainen M, Rasilainen S, Ylipaasto P, Nissinen R, Ustinov J, Bouwens L, Eizirik DL, Hovi T, Otonkoski T (2000) Mechanisms of coxsackievirus-induced damage to human pancreatic beta- cells. J Clin Endocrinol Metab 85:432–440

    Article  PubMed  CAS  Google Scholar 

  • Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14:778–809

    Article  PubMed  CAS  Google Scholar 

  • Seo YJ, Hahm B (2010) Type I interferon modulates the battle of host immune system against viruses. Adv Appl Microbiol 73:83–101

    Article  PubMed  CAS  Google Scholar 

  • Serreze DV, Ottendorfer EW, Ellis TM, Gauntt CJ, Atkinson MA (2000) Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. Diabetes 49:708–711

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Steck AK, Armstrong TK, Babu SR, Eisenbarth GS (2011) Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 60:1045–1049

    Article  PubMed  CAS  Google Scholar 

  • Szopa TM, Gamble DR, Taylor KW (1986) Coxsackie B4 virus induces short-term changes in the metabolic functions of mouse pancreatic islets in vitro. Cell Biochem Funct 4:181–187

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi O, Akira S (2011) Pattern recognition receptors and inflammation. Cell 140:805–820

    Article  Google Scholar 

  • Tauriainen S, Oikarinen S, Oikarinen M, Hyoty H (2011) Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol 33:45–55

    Article  PubMed  CAS  Google Scholar 

  • Triantafilou K, Triantafilou M (2004) Coxsackievirus B4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4. J Virol 78:11313–11320

    Article  PubMed  CAS  Google Scholar 

  • Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M (2005) Human cardiac inflammatory responses triggered by coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol 7:1117–1126

    Article  PubMed  CAS  Google Scholar 

  • van der Werf N, Kroese FG, Rozing J, Hillebrands JL (2007) Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 23:169–183

    Article  PubMed  Google Scholar 

  • Vehik K, Dabelea D (2011) The changing epidemiology of type 1 diabetes: why is it going through the roof? Diabetes Metab Res Rev 27:3–13

    Article  PubMed  Google Scholar 

  • Wang JP, Cerny A, Asher DR, Kurt-Jones EA, Bronson RT, Finberg RW (2010) MDA5 and MAVS mediate type I interferon responses to coxsackie B virus. J Virol 84:254–260

    Article  PubMed  CAS  Google Scholar 

  • Whitton JL, Cornell CT, Feuer R (2005) Host and virus determinants of picornavirus pathogenesis and tropism. Nat Rev Microbiol 3:765–776

    Article  PubMed  CAS  Google Scholar 

  • Wolter TR, Wong R, Sarkar SA, Zipris D (2009) DNA microarray analysis for the identification of innate immune pathways implicated in virus-induced autoimmune diabetes. Clin Immunol 132:103–115

    Article  PubMed  CAS  Google Scholar 

  • Yeung WC, Rawlinson WD, Craig ME (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35

    Article  PubMed  Google Scholar 

  • Ylipaasto P, Klingel K, Lindberg AM, Otonkoski T, Kandolf R, Hovi T, Roivainen M (2004) Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47:225–239

    Article  PubMed  CAS  Google Scholar 

  • Yoon JW, Jun HS (2006) Viruses cause type 1 diabetes in animals. Ann N Y Acad Sci 1079:138–146

    Article  PubMed  Google Scholar 

  • Yoon JW, Austin M, Onodera T, Notkins AL (1979) Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300:1173–1179

    Article  PubMed  CAS  Google Scholar 

  • Zaragoza C, Ocampo CJ, Saura M, Bao C, Leppo M, Lafond-Walker A, Thiemann DR, Hruban R, Lowenstein CJ (1999) Inducible nitric oxide synthase protection against coxsackievirus pancreatitis. J Immunol 163:5497–5504

    PubMed  CAS  Google Scholar 

  • Zipris D (2009) Epidemiology of type 1 diabetes and what animal models teach us about the role of viruses in disease mechanisms. Clin Immunol 131:11–23

    Article  PubMed  CAS  Google Scholar 

  • Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA (2005) TLR activation syjournaltitlenergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol 174:131–142

    PubMed  CAS  Google Scholar 

  • Zipris D, Lien E, Nair A, Xie JX, Greiner DL, Mordes JP, Rossini AA (2007) TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol 178:693–701

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Work in the M.F-T. group is supported by the European Foundation for the Study of Diabetes, the European Union, the Swedish Child Diabetes Foundation, The Swedish Diabetes Association Research Foundation, and the Swedish Research Council.

Author information

Authors and Affiliations

  1. Department of Medicine HS, The Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge F59, 14186, Stockholm, Sweden

    Katharina Lind B.Sc. & Malin Flodström Tullberg Ph.D.

Authors
  1. Katharina Lind B.Sc.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malin Flodström Tullberg Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Malin Flodström Tullberg Ph.D. .

Editor information

Editors and Affiliations

  1. Queen Mary's School of Medicine and Dent, Centre for Diabetes & Metabolic Medicine, Institute of Cell & Molecular Science, n/a, London, E1 2AT, United Kingdom

    Keith Taylor

  2. Tampere University Hospital, Department of Virology, University of Tampere, n/a, Tampere, 33520, Finland

    Heikki Hyöty

  3. University of Insubria & Ospedale di Cir, Varese, Italy

    Antonio Toniolo

  4. University College London Medical School, n/a, London, NW3 2PF, United Kingdom

    Arie J. Zuckerman

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lind, K., Tullberg, M.F. (2013). Innate Immune Responses to Viruses Inducing Diabetes. In: Taylor, K., Hyöty, H., Toniolo, A., Zuckerman, A. (eds) Diabetes and Viruses. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4051-2_27

Download citation

Publish with us

Policies and ethics

Search

Navigation