1932

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin deficiency and resultant hyperglycemia. Complex interactions of genetic and environmental factors trigger the onset of autoimmune mechanisms responsible for development of autoimmunity to β cell antigens and subsequent development of T1D. A potential role of virus infections has long been hypothesized, and growing evidence continues to implicate enteroviruses as the most probable triggering viruses. Recent studies have strengthened the association between enteroviruses and development of autoimmunity in T1D patients, potentially through persistent infections. Enterovirus infections may contribute to different stages of disease development. We review data from both human cohort studies and experimental research exploring the potential roles and molecular mechanisms by which enterovirus infections can impact disease outcome.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042320-015952
2022-01-27
2024-05-04
Loading full text...

Full text loading...

/deliver/fulltext/med/73/1/annurev-med-042320-015952.html?itemId=/content/journals/10.1146/annurev-med-042320-015952&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Redondo MJ, Rewers M, Yu L et al. 1999. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 318:7185698–702
    [Google Scholar]
  2. 2. 
    Hyöty H, Knip M. 2014. Developing a vaccine for Type 1 diabetes through targeting enteroviral infections. Expert Rev. Vaccines 13:8989–99
    [Google Scholar]
  3. 3. 
    Noble JA. 2015. Immunogenetics of type 1 diabetes: a comprehensive review. J. Autoimmun. 64:101–12
    [Google Scholar]
  4. 4. 
    Robertson CC, Rich SS. 2018. Genetics of type 1 diabetes. Curr. Opin. Genet. Dev. 50:7–16
    [Google Scholar]
  5. 5. 
    Morahan G, Mehta M, James I et al. 2011. Tests for genetic interactions in type 1 diabetes: linkage and stratification analyses of 4,422 affected sib-pairs. Diabetes 60:31030–40
    [Google Scholar]
  6. 6. 
    Blum SI, Tse HM 2020. Innate viral sensor MDA5 and coxsackievirus interplay in type 1 diabetes development. Microorganisms 8:7993
    [Google Scholar]
  7. 7. 
    Witsø E, Tapia G, Cinek O et al. 2011. Polymorphisms in the innate immune IFIH1 gene, frequency of enterovirus in monthly fecal samples during infancy, and islet autoimmunity. PLOS ONE 6:11e27781
    [Google Scholar]
  8. 8. 
    Witsø E, Cinek O, Tapia G et al. 2015. Genetic determinants of enterovirus infections: polymorphisms in type 1 diabetes and innate immune genes in the MIDIA study. Viral Immunol 28:10556–63
    [Google Scholar]
  9. 9. 
    Cinek O, Tapia G, Witsø E et al. 2012. Enterovirus RNA in peripheral blood may be associated with the variants of rs1990760, a common type 1 diabetes associated polymorphism in IFIH1. PLOS ONE 7:11e48409
    [Google Scholar]
  10. 10. 
    Marroqui L, Santos Dos RS, Fløyel T et al. 2015. TYK2, a candidate gene for type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic β-cells. Diabetes 64:113808–17
    [Google Scholar]
  11. 11. 
    Gamble DR, Kinsley ML, FitzGerald MG et al. 1969. Viral antibodies in diabetes mellitus. BMJ 3:5671627–30
    [Google Scholar]
  12. 12. 
    Gamble DR, Taylor KW, Cumming H. 1973. Coxsackie viruses and diabetes mellitus. BMJ 4:5887260–62
    [Google Scholar]
  13. 13. 
    Green J, Casabonne D, Newton R 2004. Coxsackie B virus serology and Type 1 diabetes mellitus: a systematic review of published case-control studies. Diabetes Med 21:6507–14
    [Google Scholar]
  14. 14. 
    Yin H, Berg A-K, Tuvemo T et al. 2002. Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset. Diabetes 51:61964–71
    [Google Scholar]
  15. 15. 
    Oikarinen M, Tauriainen S, Oikarinen S et al. 2012. Type 1 diabetes is associated with enterovirus infection in gut mucosa. Diabetes 61:3687–91
    [Google Scholar]
  16. 16. 
    Ylipaasto P, Klingel K, Lindberg AM et al. 2004. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47:2225–39
    [Google Scholar]
  17. 17. 
    Kim KW, Horton JL, Pang CNI et al. 2019. Higher abundance of enterovirus A species in the gut of children with islet autoimmunity. Sci. Rep. 9:11749
    [Google Scholar]
  18. 18. 
    Hober D, Sauter P. 2010. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat. Rev. Endocrinol. 6:5279–89
    [Google Scholar]
  19. 19. 
    Oikarinen S, Martiskainen M, Tauriainen S et al. 2011. Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 60:1276–79
    [Google Scholar]
  20. 20. 
    Chehadeh W, Weill J, Vantyghem MC et al. 2000. Increased level of interferon-alpha in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J. Infect. Dis. 181:61929–39
    [Google Scholar]
  21. 21. 
    Oikarinen M, Tauriainen S, Honkanen T et al. 2008. Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin. Exp. Immunol. 151:171–75
    [Google Scholar]
  22. 22. 
    Honkanen H, Oikarinen S, Nurminen N et al. 2017. Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity. Diabetologia 60:3424–31
    [Google Scholar]
  23. 23. 
    Harrison LC, Perrett KP, Jachno K et al. 2019. Does rotavirus turn on type 1 diabetes?. PLOS Path 15:10e1007965
    [Google Scholar]
  24. 24. 
    Rogers MAM, Basu T, Kim C. 2019. Lower incidence rate of type 1 diabetes after receipt of the rotavirus vaccine in the United States, 2001–2017. Sci. Rep. 9:1 7727.
    [Google Scholar]
  25. 25. 
    Morgan E, Halliday SR, Campbell GR et al. 2016. Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 59:2237–43
    [Google Scholar]
  26. 26. 
    Coate KC, Cha J, Shrestha S et al. 2020. SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 are expressed in the microvasculature and ducts of human pancreas but are not enriched in β cells. Cell Metab 32:61028–40.e4
    [Google Scholar]
  27. 27. 
    Kusmartseva I, Wu W, Syed F et al. 2020. Expression of SARS-CoV-2 entry factors in the pancreas of normal organ donors and individuals with COVID-19. Cell Metab 32:61041–46
    [Google Scholar]
  28. 28. 
    Bergamin CS, Dib SA. 2015. Enterovirus and type 1 diabetes: What is the matter?. World J. Diabetes 6:6828–39
    [Google Scholar]
  29. 29. 
    Stene LC, Rewers M. 2012. Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies. Clin. Exp. Immunol. 168:112–23
    [Google Scholar]
  30. 30. 
    Balasubramanyam A. 2021. Defining and classifying new subgroups of diabetes. Annu. Rev. Med. 72:63–74
    [Google Scholar]
  31. 31. 
    Krischer JP, Liu X, Vehik K et al. 2019. Predicting islet cell autoimmunity and type 1 diabetes: an 8-year TEDDY study progress report. Diabetes Care 42:61051–60
    [Google Scholar]
  32. 32. 
    Endesfelder D, zu Castell W, Bonifacio E et al. 2019. Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children. Diabetes 68:1119–30
    [Google Scholar]
  33. 33. 
    Rewers M, Hyöty H, Lernmark Å et al. 2018. The environmental determinants of diabetes in the Young (TEDDY) study: 2018 update. Curr. Diabetes Rep 18:12136
    [Google Scholar]
  34. 34. 
    Lönnrot M, Lynch KF, Elding Larsson H et al. 2017. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 60:101931–40
    [Google Scholar]
  35. 35. 
    Vehik K, Fiske SW, Logan CA et al. 2013. Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY. Diabetes Metab. Res. Rev. 29:7557–67
    [Google Scholar]
  36. 36. 
    Lin J-N, Lin C-L, Yang C-H et al. 2016. Risk of nephrotic syndrome following enteroviral infection in children: a nationwide retrospective cohort study. PLOS ONE 11:8e0161004
    [Google Scholar]
  37. 37. 
    Yeung W-CG, Rawlinson WD, Craig ME 2011. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35
    [Google Scholar]
  38. 38. 
    Faulkner CL, Luo YX, Isaacs S et al. 2020. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: a systematic review and meta-analysis of observational studies. Rev. Med. Virol Dec 30:e2209
    [Google Scholar]
  39. 39. 
    Allen DW, Kim KW, Rawlinson WD et al. 2018. Maternal virus infections in pregnancy and type 1 diabetes in their offspring: systematic review and meta-analysis of observational studies. Rev. Med. Virol. 28:3e1974
    [Google Scholar]
  40. 40. 
    Rešić Lindehammer S, Honkanen H, Nix WA et al. 2012. Seroconversion to islet autoantibodies after enterovirus infection in early pregnancy. Viral Immunol 25:4254–61
    [Google Scholar]
  41. 41. 
    Vehik K, Lynch KF, Wong MC et al. 2019. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nat. Med. 25:121865–72
    [Google Scholar]
  42. 42. 
    Richardson SJ, Willcox A, Bone AJ et al. 2009. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 52:61143–51
    [Google Scholar]
  43. 43. 
    Dotta F, Censini S, van Halteren AGS et al. 2007. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. PNAS 104:125115–20
    [Google Scholar]
  44. 44. 
    Krogvold L, Edwin B, Buanes T et al. 2014. Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia 57:841–43
    [Google Scholar]
  45. 45. 
    Krogvold L, Edwin B, Buanes T et al. 2015. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 64:51682–87
    [Google Scholar]
  46. 46. 
    Lundberg M, Krogvold L, Kuric E et al. 2016. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes 65:103104–10
    [Google Scholar]
  47. 47. 
    Ylipaasto P, Kutlu B, Rasilainen S et al. 2005. Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48:81510–22
    [Google Scholar]
  48. 48. 
    Eizirik DL, Sammeth M, Bouckenooghe T et al. 2012. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLOS Genet 8:3e1002552
    [Google Scholar]
  49. 49. 
    Richardson SJ, Rodriguez-Calvo T, Gerling IC et al. 2016. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59:112448–58
    [Google Scholar]
  50. 50. 
    Busse N, Paroni F, Richardson SJ et al. 2017. Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes. Oncotarget 8:812620–36
    [Google Scholar]
  51. 51. 
    Chehadeh W, Kerr-Conte J, Pattou F et al. 2000. Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J. Virol. 74:2110153–64
    [Google Scholar]
  52. 52. 
    Kim K-S, Tracy S, Tapprich W et al. 2005. 5′-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA. J. Virol. 79:117024–41
    [Google Scholar]
  53. 53. 
    Sharma N, Ogram SA, Morasco BJ et al. 2009. Functional role of the 5′ terminal cloverleaf in Coxsackievirus RNA replication. Virology 393:2238–49
    [Google Scholar]
  54. 54. 
    Lévêque N, Renois F, Talmud D et al. 2012. Quantitative genomic and antigenomic enterovirus RNA detection in explanted heart tissue samples from patients with end-stage idiopathic dilated cardiomyopathy. J. Clin. Microbiol. 50:103378–80
    [Google Scholar]
  55. 55. 
    Nguyen Y, Renois F, Lévêque N et al. 2013. Virus detection and semiquantitation in explanted heart tissues of idiopathic dilated cardiomyopathy adult patients by use of PCR coupled with mass spectrometry analysis. J. Clin. Microbiol. 51:72288–94
    [Google Scholar]
  56. 56. 
    Chapman NM, Kim K-S, Drescher KM et al. 2008. 5′ terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology 375:2480–91
    [Google Scholar]
  57. 57. 
    Tracy S, Smithee S, Alhazmi A et al. 2015. Coxsackievirus can persist in murine pancreas by deletion of 5′ terminal genomic sequences. J. Med. Virol. 87:2240–47
    [Google Scholar]
  58. 58. 
    Chen Y-H, Du W, Hagemeijer MC et al. 2015. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160:4619–30
    [Google Scholar]
  59. 59. 
    Santiana M, Ghosh S, Ho BA et al. 2018. Vesicle-cloaked virus clusters are optimal units for inter-organismal viral transmission. Cell Host Microbe 24:2208–20.e8
    [Google Scholar]
  60. 60. 
    Netanyah E, Calafatti M, Arvastsson J et al. 2020. Extracellular vesicles released by enterovirus-infected EndoC-βH1 cells mediate non-lytic viral spread. Microorganisms 8:111753
    [Google Scholar]
  61. 61. 
    Vehik K, Bonifacio E, Lernmark Å et al. 2020. Hierarchical order of distinct autoantibody spreading and progression to type 1 diabetes in the TEDDY Study. Diabetes Care 43:92066–73
    [Google Scholar]
  62. 62. 
    Eberle KE, Nguyen VT, Freistadt MS. 1995. Low levels of poliovirus replication in primary human monocytes: possible interactions with lymphocytes. Arch. Virol. 140:122135–50
    [Google Scholar]
  63. 63. 
    Wahid R, Cannon MJ, Chow M. 2005. Dendritic cells and macrophages are productively infected by poliovirus. J. Virol. 79:1401–9
    [Google Scholar]
  64. 64. 
    Alidjinou EK, Sané F, Engelmann I et al. 2013. Serum-dependent enhancement of coxsackievirus B4-induced production of IFNα, IL-6 and TNFα by peripheral blood mononuclear cells. J. Mol. Biol. 425:245020–31
    [Google Scholar]
  65. 65. 
    Alidjinou EK, Sané F, Trauet J et al. 2015. Coxsackievirus B4 can infect human peripheral blood-derived macrophages. Viruses 7:116067–79
    [Google Scholar]
  66. 66. 
    Schulte BM, Kers-Rebel ED, Prosser AC et al. 2013. Differential susceptibility and response of primary human myeloid BDCA1+ dendritic cells to infection with different enteroviruses. PLOS ONE 8:4e62502
    [Google Scholar]
  67. 67. 
    Hämäläinen S, Nurminen N, Ahlfors H et al. 2014. Coxsackievirus B1 reveals strain specific differences in plasmacytoid dendritic cell mediated immunogenicity. J. Med. Virol. 86:81412–20
    [Google Scholar]
  68. 68. 
    Schulte BM, Kramer M, Ansems M et al. 2010. Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells. Diabetes 59:51182–91
    [Google Scholar]
  69. 69. 
    Alidjinou EK, Chehadeh W, Weill J et al. 2015. Monocytes of patients with type 1 diabetes harbour enterovirus RNA. Eur. J. Clin. Investig. 45:9918–24
    [Google Scholar]
  70. 70. 
    Sané F, Bertin A, Sioofy-Khojine A-B et al. 2020. Enhancing and neutralizing anti-coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes. Diabetes Metab. Res. Rev. 36:6e3305
    [Google Scholar]
  71. 71. 
    Rojas M, Restrepo-Jiménez P, Monsalve DM et al. 2018. Molecular mimicry and autoimmunity. J. Autoimmun. 95:100–123
    [Google Scholar]
  72. 72. 
    Hou J, Said C, Franchi D et al. 1994. Antibodies to glutamic acid decarboxylase and P2-C peptides in sera from coxsackie virus B4-infected mice and IDDM patients. Diabetes 43:101260–66
    [Google Scholar]
  73. 73. 
    Ashton MP, Eugster A, Walther D et al. 2016. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. Sci. Rep. 6:32899
    [Google Scholar]
  74. 74. 
    Li Q, Parikh H, Butterworth MD et al. 2020. Longitudinal metabolome-wide signals prior to the appearance of a first islet autoantibody in children participating in the TEDDY study. Diabetes 69:3465–76
    [Google Scholar]
  75. 75. 
    Christen U, Edelmann KH, McGavern DB et al. 2004. A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J. Clin. Investig. 114:91290–98
    [Google Scholar]
  76. 76. 
    Ifie E, Russell MA, Dhayal S et al. 2018. Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells. Diabetologia 61:112344–55
    [Google Scholar]
  77. 77. 
    Dorner A, Xiong D, Couch K et al. 2004. Alternatively spliced soluble coxsackie-adenovirus receptors inhibit coxsackievirus infection. J. Biol. Chem. 279:1818497–503
    [Google Scholar]
  78. 78. 
    Ifie E, Russell MA, Dhayal S et al. 2018. Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells. Diabetologia 61:112344–55
    [Google Scholar]
  79. 79. 
    Hodik M, Anagandula M, Fuxe J et al. 2016. Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes. BMJ Open Diabetes Res. Care 4:1e000219
    [Google Scholar]
  80. 80. 
    Miao C, Chang J, Zhang G et al. 2018. MicroRNAs in type 1 diabetes: new research progress and potential directions. Biochem. Cell Biol. 96:5498–506
    [Google Scholar]
  81. 81. 
    Engelmann I, Alidjinou EK, Bertin A et al. 2017. Persistent coxsackievirus B4 infection induces microRNA dysregulation in human pancreatic cells. Cell. Mol. Life Sci. 74:203851–61
    [Google Scholar]
  82. 82. 
    Kim KW, Ho A, Alshabee-Akil A et al. 2016. Coxsackievirus B5 infection induces dysregulation of microRNAs predicted to target known type 1 diabetes risk genes in human pancreatic islets. Diabetes 65:4996–1003
    [Google Scholar]
  83. 83. 
    Kracht MJL, van Lummel M, Nikolic T et al. 2017. Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat. Med. 23:4501–7
    [Google Scholar]
  84. 84. 
    Piganelli JD, Mamula MJ, James EA. 2020. The role of β cell stress and neo-epitopes in the immunopathology of type 1 diabetes. Front. Endocrinol. 11:624590
    [Google Scholar]
  85. 85. 
    Scheuner D, Kaufman RJ. 2008. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr. Rev. 29:3317–33
    [Google Scholar]
  86. 86. 
    Berglund P, Finzi D, Bennink JR et al. 2007. Viral alteration of cellular translational machinery increases defective ribosomal products. J. Virol. 81:137220–29
    [Google Scholar]
  87. 87. 
    Rahnefeld A, Ebstein F, Albrecht N et al. 2011. Antigen-presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis. Eur. J. Immunol. 41:92774–81
    [Google Scholar]
  88. 88. 
    Ferreira RC, Guo H, Coulson RMR et al. 2014. A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes. Diabetes 63:72538–50
    [Google Scholar]
  89. 89. 
    Xhonneux L-P, Knight O, Lernmark Å et al. 2021. Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression. Sci. Transl. Med. 13:587eabd5666
    [Google Scholar]
  90. 90. 
    Xia C-Q, Peng R, Chernatynskaya AV et al. 2014. Increased IFN-α-producing plasmacytoid dendritic cells (pDCs) in human Th1-mediated type 1 diabetes: pDCs augment Th1 responses through IFN-α production. J. Immunol. 193:31024–34
    [Google Scholar]
  91. 91. 
    Huang X, Yuang J, Goddard A et al. 1995. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44:6658–64
    [Google Scholar]
  92. 92. 
    Marroqui L, dos Santos RS, Op de Beeck A et al. 2017. Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes. Diabetologia 60:4656–67
    [Google Scholar]
  93. 93. 
    Newby BN, Mathews CE. 2017. Type I interferon is a catastrophic feature of the diabetic islet microenvironment. Front. Endocrinol. 8:232
    [Google Scholar]
  94. 94. 
    Kahrs CR, Chuda K, Tapia G et al. 2019. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ 364:l231
    [Google Scholar]
  95. 95. 
    Oikarinen M, Puustinen L, Lehtonen J et al. 2020. Enterovirus infections are associated with the development of celiac disease in a birth cohort study. Front. Immunol 11:604529
    [Google Scholar]
  96. 96. 
    Lindfors K, Lin J, Lee HS et al. 2020. Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study. Gut 69:81416–22
    [Google Scholar]
/content/journals/10.1146/annurev-med-042320-015952
Loading
/content/journals/10.1146/annurev-med-042320-015952
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error