Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction
Tóm tắt
Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains. The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice. The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion. The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.
Từ khóa
Tài liệu tham khảo
Onkamo P, Vaananen S, Karvonen M, Tuomilehto J (1999) Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 42:1395–1403
Pitkaniemi J, Onkamo P, Tuomilehto J, Arjas E (2004) Increasing incidence of type 1 diabetes—role for genes? BMC Genet 5:5
Yeung WG, Rawlinson WD, Craig ME (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35
Dotta F, Censini S, van Halteren AG et al (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 104:5115–5120
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
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 47:225–239
Shibasaki S, Imagawa A, Tauriainen S et al (2010) Expression of Toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr J 57:211–219
Tanaka S, Nishida Y, Aida K et al (2009) Enterovirus Infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes 58:2285–2291
Vreugdenhil GR, Schloot NC, Hoorens A et al (2000) Acute onset of type I diabetes mellitus after severe echovirus 9 infection: putative pathogenic pathways. Clin Infect Dis 31:1025–1031
Yoon JW, Austin M, Onodera T, Notkins AL (1979) Virus-induced diabetes-mellitus—isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300:1173–1179
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 59:1182–1191
Filippi C, von Herrath M (2005) How viral infections affect the autoimmune process leading to type I diabetes. Cell Immunol 233:125–132
Knowles NJ, Hovi T, Hyypiä T et al (2012) Picornaviridae. In: King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ (eds) Virus taxonomy: classification and nomenclature of viruses: ninth report of the International Committee on Taxonomy of Viruses. Elsevier, San Diego, pp 855–880
Roivainen M, Rasilainen S, Ylipaasto P et al (2000) Mechanisms of coxsackievirus-induced damage to human pancreatic beta-cells. J Clin Endocrinol Metab 85:432–440
Roivainen M, Ylipaasto P, Savolainen C, Galama J, Hovi T, Otonkoski T (2002) Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains. Diabetologia 45:693–702
Smura T, Ylipaasto P, Klemola P et al (2010) Cellular tropism of human enterovirus d species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. J Med Virol 82:1940–1949
Paananen A, Ylipaasto P, Rieder E, Hovi T, Galama J, Roivainen M (2003) Molecular and biological analysis of echovirus 9 strain isolated from a diabetic child. J Med Virol 69:529–537
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 74:10153–10164
Ylipaasto P, Kutlu B, Rasilainen S et al (2005) Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48:1510–1522
Colli ML, Nogueira TC, Allagnat F et al (2011) Exposure to the viral by-product dsRNA or coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim/Mcl-1 imbalance. PLoS Pathog 7:e1002267
Delaney CA, Pavlovic D, Hoorens A, Pipeleers DG, Eizirik DL (1997) Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology 138:2610–2614
Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133
Johansson U, Olsson A, Gabrielsson S, Nilsson B, Korsgren O (2003) Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation. Biochem Biophys Res Commun 308:474–479
Al-Hello H, Davydova B, Smura T et al (2005) Phenotypic and genetic changes in coxsackievirus B5 following repeated passage in mouse pancreas in vivo. J Med Virol 75:566–574
Al-Hello H, Ylipaasto P, Smura T, Rieder E, Hovi T, Roivainen M (2009) Amino acids of Coxsackie B5 virus are critical for infection of the murine insulinoma cell line, MIN-6. J Med Virol 81:296–304
Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273
Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550
Oresic M, Simell S, Sysi-Aho M et al (2008) Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med 205:2975–2984
Pluskal T, Castillo S, Villar-Briones A, Oresic M (2010) MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinformatics 11:395
Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5:219–226
Ferguson TA, Choi J, Green DR (2011) Armed response: how dying cells influence T-cell functions. Immunol Rev 241:77–88
Hultcrantz M, Huhn MH, Wolf M et al (2007) Interferons induce an antiviral state in human pancreatic islet cells. Virology 367:92–101
Cardozo AK, Kruhoffer M, Leeman R, Orntoft T, Eizirik DL (2001) Identification of novel cytokine-induced genes in pancreatic beta-cells by high-density oligonucleotide arrays. Diabetes 50:909–920
Moore F, Naamane N, Colli ML et al (2011) STAT1 is a master regulator of pancreatic β-cell apoptosis and islet inflammation. J Biol Chem 286:929–941
Berg A, Korsgren O, Frisk G (2006) Induction of the chemokine interferon-gamma-inducible protein-10 in human pancreatic islets during enterovirus infection. Diabetologia 49:2697–2703
Skog O, Korsgren O, Frisk G (2011) Modulation of innate immunity in human pancreatic islets infected with enterovirus in vitro. J Med Virol 83:658–664
Nair S, Leung K, Rawlinson WD, Naing Z, Craig ME (2010) Enterovirus infection induces cytokine and chemokine expression in insulin-producing cells. J Med Virol 82:1950–1957
Bendtzen K, Mandrup-poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M (1986) Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232:1545–1547
Rabinovitch A, Sumoski W, Rajotte RV, Warnock GL (1990) Cytotoxic effects of cytokines on human pancreatic-islet cells in monolayer-culture. J Clin Endocrinol Metab 71:152–156
Hoorens A, Pipeleers D (1999) Nicotinamide protects human beta cells against chemically-induced necrosis, but not against cytokine-induced apoptosis. Diabetologia 42:55–59
Hoorens A, Stange G, Pavlovic D, Pipeleers D (2001) Distinction between interleukin-1-induced necrosis and apoptosis of islet cells. Diabetes 50:551–557
Rasilainen S, Ylipaasto P, Roivainen M, Lapatto R, Hovi T, Otonkoski T (2004) Mechanisms of coxsackievirus B5 mediated beta-cell death depend on the multiplicity of infection. J Med Virol 72:586–596
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486
Nicotera P, Melino G (2004) Regulation of the apoptosis-necrosis switch. Oncogene 23:2757–2765
Saldeen J (2000) Cytokines induce both necrosis and apoptosis via a common bcl-2-inhibitable pathway in rat insulin-producing cells. Endocrinology 141:2003–2010
Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429
Hyslop PA, Hinshaw DB, Halsey WA Jr et al (1988) Mechanisms of oxidant-mediated cell injury. The glycolytic and mitochondrial pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide. J Biol Chem 263:1665–1675
Heller B, Wang ZQ, Wagner EF et al (1995) Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric-oxide toxicity in islet cells. J Biol Chem 270:11176–11180