Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction

P. Ylipaasto, T. Smura, Peddinti Gopalacharyulu, A. Paananen, Tuulikki Seppänen-Laakso, S. Kaijalainen, H. Ahlfors, O. Korsgren, J.R.T. Lakey, R. Lahesmaa, L. Piemonti, Matej Oresic, J. Galama, M. Roivainen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

29 Citations (Scopus)

Abstract

Aims/hypothesis
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.

Methods
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.

Results
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.

Conclusions/interpretation
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.
Original languageEnglish
Pages (from-to)3273-3283
Number of pages10
JournalDiabetologia
Volume55
Issue number12
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

Enterovirus
Islets of Langerhans
Transcriptome
Enterovirus Infections
Viruses
Cytokines
Gene Expression
Type 1 Diabetes Mellitus
Interleukin-1
Cell Death
Double-Stranded RNA
Autoantigens
Glycolysis
Oligonucleotide Array Sequence Analysis
Chemokines
Genes
Antiviral Agents
Necrosis
Down-Regulation
Insulin

Keywords

  • Coxsackievirus
  • echovirus
  • enterovirus
  • interleukin 1
  • microarray analysis
  • pancreatic beta cells
  • pancreatic islets
  • tumour necrosis factor
  • type 1 diabetes

Cite this

Ylipaasto, P., Smura, T., Gopalacharyulu, P., Paananen, A., Seppänen-Laakso, T., Kaijalainen, S., ... Roivainen, M. (2012). Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. Diabetologia, 55(12), 3273-3283. https://doi.org/10.1007/s00125-012-2713-z
Ylipaasto, P. ; Smura, T. ; Gopalacharyulu, Peddinti ; Paananen, A. ; Seppänen-Laakso, Tuulikki ; Kaijalainen, S. ; Ahlfors, H. ; Korsgren, O. ; Lakey, J.R.T. ; Lahesmaa, R. ; Piemonti, L. ; Oresic, Matej ; Galama, J. ; Roivainen, M. / Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. In: Diabetologia. 2012 ; Vol. 55, No. 12. pp. 3273-3283.
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abstract = "Aims/hypothesisVirally 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.MethodsThe 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.ResultsThe 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.Conclusions/interpretationThe 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.",
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Ylipaasto, P, Smura, T, Gopalacharyulu, P, Paananen, A, Seppänen-Laakso, T, Kaijalainen, S, Ahlfors, H, Korsgren, O, Lakey, JRT, Lahesmaa, R, Piemonti, L, Oresic, M, Galama, J & Roivainen, M 2012, 'Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction', Diabetologia, vol. 55, no. 12, pp. 3273-3283. https://doi.org/10.1007/s00125-012-2713-z

Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. / Ylipaasto, P.; Smura, T.; Gopalacharyulu, Peddinti; Paananen, A.; Seppänen-Laakso, Tuulikki; Kaijalainen, S.; Ahlfors, H.; Korsgren, O.; Lakey, J.R.T.; Lahesmaa, R.; Piemonti, L.; Oresic, Matej; Galama, J.; Roivainen, M. (Corresponding Author).

In: Diabetologia, Vol. 55, No. 12, 2012, p. 3273-3283.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction

AU - Ylipaasto, P.

AU - Smura, T.

AU - Gopalacharyulu, Peddinti

AU - Paananen, A.

AU - Seppänen-Laakso, Tuulikki

AU - Kaijalainen, S.

AU - Ahlfors, H.

AU - Korsgren, O.

AU - Lakey, J.R.T.

AU - Lahesmaa, R.

AU - Piemonti, L.

AU - Oresic, Matej

AU - Galama, J.

AU - Roivainen, M.

PY - 2012

Y1 - 2012

N2 - Aims/hypothesisVirally 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.MethodsThe 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.ResultsThe 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.Conclusions/interpretationThe 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.

AB - Aims/hypothesisVirally 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.MethodsThe 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.ResultsThe 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.Conclusions/interpretationThe 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.

KW - Coxsackievirus

KW - echovirus

KW - enterovirus

KW - interleukin 1

KW - microarray analysis

KW - pancreatic beta cells

KW - pancreatic islets

KW - tumour necrosis factor

KW - type 1 diabetes

U2 - 10.1007/s00125-012-2713-z

DO - 10.1007/s00125-012-2713-z

M3 - Article

VL - 55

SP - 3273

EP - 3283

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 12

ER -