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

Intestinal Viruses Unit, National Institute for Health and Welfare (THL), P.O. Box 30, FI-00271, Helsinki, Finland.
Diabetologia (Impact Factor: 6.67). 09/2012; 55(12). DOI: 10.1007/s00125-012-2713-z
Source: PubMed


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.

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Available from: Lorenzo Piemonti, Feb 23, 2015
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    • "Although enteroviruses are often implicated as triggers of type 1 diabetes, it is not known precisely which of the enterovirus serotypes or strains are involved in type 1 diabetes development. In-vitro studies suggest that enterovirus serotypes and strains within a given serotype differ in their capability to induce destruction and cytokine response in human pancreatic islets (Anagandula et al., 2014; Paananen et al., 2003, 2013; Roivainen et al., 2002; Sarmiento et al., 2013; Smura et al., 2010; Ylipaasto et al., 2012). In addition, virus strain-dependent differences have been detected in plasmacytoid dendritic cell mediated immunogenicity (Hamalainen et al., 2014). "
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    ABSTRACT: Enterovirus infections have been suspected to be involved in the development of type 1 diabetes. However, the pathogenetic mechanism of enterovirus-induced type 1 diabetes is not known. Pancreatic ductal cells are closely associated with pancreatic islets. Therefore, enterovirus infections in ductal cells may affect also beta-cells and be involved in the induction of type 1 diabetes. The aim of this study was to assess the ability of different enterovirus strains to infect, replicate and produce cytopathic effect in human pancreatic ductal cells. Furthermore, the viral factors that affect these capabilities were studied. The pancreatic ductal cells were highly susceptible to enterovirus infections. Both viral growth and cytolysis were detected for several enterovirus serotypes. However, the viral growth and capability to induce cytopathic effect (cpe) did not correlate completely. Some of the virus strains replicated in ductal cells without apparent cpe. Furthermore, there were strain-specific differences in the growth kinetics and the ability to cause cpe within some serotypes. Viral adaptation experiments were carried out to study the potential genetic determinants behind these phenotypic differences. The blind-passage of non-lytic CV-B6-Schmitt strain in HPDE-cells resulted in lytic phenotype and increased progeny production. This was associated with the substitution of a single amino acid (K257E) in the virus capsid protein VP1 and the viral ability to use decay accelerating factor (DAF) as a receptor. This study demonstrates considerable plasticity in the cell tropism, receptor usage and cytolytic properties of enteroviruses and underlines the strong effect of single or few amino acid substitutions in cell tropism and lytic capabilities of a given enterovirus. Since ductal cells are anatomically close to pancreatic islets, the capability of enteroviruses to infect and destroy pancreatic ductal cells may also implications in respect to enterovirus induced type 1 diabetes. In addition, the capability for rapid adaptation to different cell types suggests that, on occasion, enterovirus strains with different pathogenetic properties may arise from less pathogenic ancestors. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Virus Research
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    • "Even though the capsid coding region is the most variable part of the enterovirus genome and thus carrying the most robust phylogenetic signal connected to serotype specificity, there is increasing evidence that pathogenic properties of a viral strains strongly depend upon small sequence variations within a virus population (i.e. quasispecies biology) [40]. As suggested by studies by Al-Hello et al [43], it is possible that the most critical determinants for islet cell destruction might be hiding in their genomes or, outside of the structural protein coding region. "
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    ABSTRACT: Three large-scale Echovirus (E) epidemics (E4,E16,E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.
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    ABSTRACT: Our objective is to elucidate the nature of the autoimmune disregulation in diabetes through the antigen specificity of the T-cell receptor (TCR) sequences generated by patients with type 1 diabetes mellitus (T1DM). Previously we demonstrated that TCR from T1DM patients and NOD mice mimic insulin, glucagon and their receptors. We hypothesize that these TCR will bind to each other (as insulin and glucagon do to their receptors) and also be targets of anti-insulin and anti-glucagon antibodies. The hypervariable regions of multiple TCR from three patients were synthesized and their binding specificities determined using UV spectroscopy. ELISA was used to determine whether these TCR were recognized by anti-insulin and anti-glucagon antibodies. Each patient produced TCR that recognized insulin, glucagon and the insulin receptor (IR). These TCR also recognized each other as complementary (possibly idiotype-antiidiotype) pairs. In addition, each TCR peptide was recognized with nanomolar affinity as an antigen by an antibody against insulin, glucagon, and/or IR. Finally, each of the antibodies against insulin, glucagon and IR formed a complementary antibody (or idiotype-antiidiotype) pair with another antibody involved in the disease, again at nanomolar affinities. Every possible expression of complementarity (or idiotype-antiidiotype cross-reactivity) involving TCRs and antibodies was manifested by each patient. Two interpretations of these observations are offered. One, following Marchelonis, is that TCR-antibody complementarity is a mechanism for down-regulating the autoimmune process to re-establish tolerance to self-antigens. A non-exclusive alternative is that the trigger for autoimmunity is antigenic complementarity, which results in the production of complementary TCR and antibodies that appear to have idiotype-antiidiotype relationships among themselves.
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