Laboratory Diagnosis of Enterovirus Infection: Optimal Methods for Studies of Diabetes

Chapter

Abstract

Laboratory diagnosis of enterovirus infections is more complex than that of many other virus infections. Careful design of study protocols and sample collection procedures is crucial for studies evaluating the role of enteroviruses in type 1 diabetes. Possible viral persistence creates an additional challenge, since the virus may be present in low quantities and in the form of double-stranded RNA. Both direct virus detection and serology have their own advantages and disadvantages, depending on the individual research questions, technologies, and sample types used in the studies. In many cases, their combined use would give the best view on the relationship between enteroviruses and type 1 diabetes. Standardization of enterovirus assays by international collaboration would help identify the optimal diagnostic approaches for type 1 diabetes studies.

Keywords

Europe Microbe Glucagon 

Notes

Acknowledgments

We wish to thank the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation International (JDRF) for the pancreas samples. Organ Procurement Organi­zations (OPO) partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. We thank Professor Markku Mäki and Dosent Katri Kaukinen for small intestine biopsy samples. Also we are grateful to The Juvenile Diabetes Research Foundation International, EU commission (PEVET Research Program, Grant Agreement Number 261441), and The Academy of Finland for funding our research.

References

  1. Chapman NM, Kim KS, Drescher KM, Oka K, Tracy S (2008) 5′ terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology 2:480–491CrossRefGoogle Scholar
  2. Chehadeh W, Kerr-Conte J, Pattou F, Alm G, Lefebvre J, Wattre P, Hober D (2000) Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J Virol 21:10153–10164CrossRefGoogle Scholar
  3. Elfving M, Svensson J, Oikarinen S, Jonsson B, Olofsson P, Sundkvist G, Lindberg B, Lernmark A, Hyoty H, Ivarsson SA (2008) Maternal enterovirus infection during pregnancy as a risk factor in offspring diagnosed with type 1 diabetes between 15 and 30 years of age. Exp Diabetes Res 2008:271958PubMedCrossRefGoogle Scholar
  4. Foulis AK (1996) The pathology of the endocrine pancreas in type 1 (insulin-dependent) diabetes mellitus. Acta Pathol Microbiol Immunol Scand 3:161–167Google Scholar
  5. Foulis AK, McGill M, Farquharson MA, Hilton DA (1997) A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia 1:53–61CrossRefGoogle Scholar
  6. Harkonen T, Puolakkainen M, Sarvas M, Airaksinen U, Hovi T, Roivainen M (2000) Picornavirus proteins share antigenic determinants with heat shock proteins 60/65. J Med Virol 3:383–391CrossRefGoogle Scholar
  7. Harkonen T, Lankinen H, Davydova B, Hovi T, Roivainen M (2002) Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR. J Med Virol 3:340–350CrossRefGoogle Scholar
  8. Hohenadl C, Klingel K, Mertsching J, Hofschneider PH, Kandolf R (1991) Strand-specific detection of enteroviral RNA in myocardial tissue by in situ hybridization. Mol Cell Probes 1:11–20CrossRefGoogle Scholar
  9. Hovi T, Roivainen M (1993) Peptide antisera targeted to a conserved sequence in poliovirus capsid VP1 cross-react widely with members of the genus Enterovirus. J Clin Microbiol 5:1083–1087Google Scholar
  10. Hyöty H, Hiltunen M, Knip M, Laakkonen M, Vähäsalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, Åkerblom HK, DiMe-study group (1995) A prospective study of the role of Coxsackie B and other enteroviruses in the pathogenesis of IDDM. Diabetes 44:652–657PubMedCrossRefGoogle Scholar
  11. Imagawa A, Hanafusa T, Tamura S, Moriwaki M, Itoh N, Yamamoto K, Iwahashi H, Yamagata K, Waguri M, Nanmo T, Uno S, Nakajima H, Namba M, Kawata S, Miyagawa JI, Matsuzawa Y (2001) Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity. Diabetes 6:1269–1273CrossRefGoogle Scholar
  12. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci U S A 1:314–318CrossRefGoogle Scholar
  13. Klingel K, Sauter M, Bock CT, Szalay G, Schnorr JJ, Kandolf R (2004) Molecular pathology of inflammatory cardiomyopathy. Med Microbiol Immunol 2–3:101–107CrossRefGoogle Scholar
  14. Kroneman A, Vennema H, Deforche K, v d Avoort H, Peñaranda S, Oberste MS, Vinjé J, Koopmans M (2011) An automated genotyping tool for enteroviruses and noroviruses. J Clin Virol 51(2):121–125CrossRefGoogle Scholar
  15. Miao LY, Pierce C, Gray-Johnson J, DeLotell J, Shaw C, Chapman N, Yeh E, Schnurr D, Huang YT (2009) Monoclonal antibodies to VP1 recognize a broad range of enteroviruses. J Clin Microbiol 10:3108–3113CrossRefGoogle Scholar
  16. Nix WA, Oberste MS, Pallansch MA (2006) Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 8:2698–2704CrossRefGoogle Scholar
  17. Oberste MS, Maher K, Kilpatrick DR, Flemister MR, Brown BA, Pallansch MA (1999a) Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol 5:1288–1293Google Scholar
  18. Oberste MS, Maher K, Kilpatrick DR, Pallansch MA (1999b) Molecular evolution of the human enteroviruses: correlation of serotype with VP1 sequence and application to picornavirus classification. J Virol 3:1941–1948Google Scholar
  19. Oikarinen S, Tauriainen S, Viskari H, Simell O, Knip M, Virtanen S, Hyoty H (2009) PCR inhibition in stool samples in relation to age of infants. J Clin Virol 3:211–214CrossRefGoogle Scholar
  20. Oikarinen M, Tauriainen S, Penttila P, Keim J, Rantala I, Honkanen T, Hyoty H (2010) Evaluation of immunohistochemistry and in situ hybridization methods for the detection of enteroviruses using infected cell culture samples. J Clin Virol 3:224–228CrossRefGoogle Scholar
  21. Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R, Simell O, Knip M, Hyoty H (2011) Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 1:276–279CrossRefGoogle Scholar
  22. Racaniello VR (2001) Picornaviridae: the viruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 685–722Google Scholar
  23. 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 6:1143–1151CrossRefGoogle Scholar
  24. Richardson SJ, Willcox A, Hilton DA, Tauriainen S, Hyoty H, Bone AJ, Foulis AK, Morgan NG (2010) Use of antisera directed against dsRNA to detect viral infections in formalin-fixed paraffin-embedded tissue. J Clin Virol 3:180–185CrossRefGoogle Scholar
  25. Richardson SJ, Willcox A, Bone AJ, Morgan NG, Foulis AK (2011) Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol 1:9–21CrossRefGoogle Scholar
  26. Saliba GS, Franklin SL, Jackson GG (1968) ECHO-11 as a respiratory virus: quantitation of infection in man. J Clin Invest 6:1303–1313CrossRefGoogle Scholar
  27. Samuelson A, Forsgren M, Johansson B, Wahren B, Sallberg M (1994) Molecular basis for serological cross-reactivity between enteroviruses. Clin Diagn Lab Immunol 3:336–341Google Scholar
  28. Samuelson A, Forsgren M, Sallberg M (1995) Characterization of the recognition site and diagnostic potential of an enterovirus group-reactive monoclonal antibody. Clin Diagn Lab Immunol 3:385–386Google Scholar
  29. Schulte BM, Bakkers J, Lanke KH, Melchers WJ, Westerlaken C, Allebes W, Aanstoot HJ, Bruining GJ, Adema GJ, Van Kuppeveld FJ, Galama JM (2010) Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol 1:99–104CrossRefGoogle Scholar
  30. Stene LC, Oikarinen S, Hyoty H, Barriga KJ, Norris JM, Klingensmith G, Hutton JC, Erlich HA, Eisenbarth GS, Rewers M (2010) Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). Diabetes 12:3174–3180CrossRefGoogle Scholar
  31. Tam PE, Messner RP (1999) Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution. J Virol 12:10113–10121Google Scholar
  32. Tapia G, Cinek O, Rasmussen T, Witso E, Grinde B, Stene LC, Ronningen KS (2011) Human enterovirus RNA in monthly fecal samples and islet autoimmunity in Norwegian children with high genetic risk for type 1 diabetes: the MIDIA study. Diabetes Care 1:151–155CrossRefGoogle Scholar
  33. Tauriainen S, Oikarinen S, Oikarinen M, Hyoty H (2010) Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol 1:45–55Google Scholar
  34. Terletskaia-Ladwig E, Meier S, Hahn R, Leinmuller M, Schneider F, Enders M (2008) A convenient rapid culture assay for the detection of enteroviruses in clinical samples: comparison with conventional cell culture and RT-PCR. J Med Microbiol 8:1000–1006CrossRefGoogle Scholar
  35. Torfason EG, Galindo R, Keyserling HL (1988) Comparison of five ELISA assays for IgG antibody against coxsackievirus B1. J Med Virol 1:53–60CrossRefGoogle Scholar
  36. Trabelsi A, Grattard F, Nejmeddine M, Aouni M, Bourlet T, Pozzetto B (1995) Evaluation of an enterovirus group-specific anti-VP1 monoclonal antibody, 5-D8/1, in comparison with neutralization and PCR for rapid identification of enteroviruses in cell culture. J Clin Microbiol 9:2454–2457Google Scholar
  37. Yagi S, Schnurr D, Lin J (1992) Spectrum of monoclonal antibodies to coxsackievirus B-3 includes type- and group-specific antibodies. J Clin Microbiol 9:2498–2501Google Scholar
  38. Yeung WC, Rawlinson WD, Craig ME (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. Br Med J 342:d35CrossRefGoogle Scholar
  39. 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 2:225–239CrossRefGoogle Scholar
  40. Yousef GE, Brown IN, Mowbray JF (1987) Derivation and biochemical characterization of an enterovirus group-specific monoclonal antibody. Intervirology 3:163–170Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.School of MedicineUniversity of TampereTampereFinland

Personalised recommendations