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Expression of innate immunity genes and damage of primary human pancreatic islets by epidemic strains of Echovirus: implication for post-virus islet autoimmunity.

Sarmiento L, Frisk G, Anagandula M, Cabrera-Rode E, Roivainen M, Cilio CM - PLoS ONE (2013)

Bottom Line: The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cellular Autoimmunity Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmo, Sweden ; Department of Virology, "Pedro Kouri" Tropical Medicine Institute, Havana, Cuba.

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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Virus-induced cytopathic effect in primary human pancreatic islets cells.A. Uninfected islet. B. Islets infected with the E4 isolate 5 days post infection. C. Islets infected with E16 isolates 3 days post infection. D. Islets infected with E30 isolates 3 days post infection. The figure is representative of seven islet donors.
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pone-0077850-g001: Virus-induced cytopathic effect in primary human pancreatic islets cells.A. Uninfected islet. B. Islets infected with the E4 isolate 5 days post infection. C. Islets infected with E16 isolates 3 days post infection. D. Islets infected with E30 isolates 3 days post infection. The figure is representative of seven islet donors.

Mentions: Clinical strains of E16 and E30 caused destruction of the isolated human pancreatic islet from seven different donors. The first morphological changes were seen as early as one day after infection in all islet infected with E16 and E30. At three days after infection the virus-induced cytopathic effect became more pronounced. Islet degeneration was characterized by the loss of islet integrity, disintegration, and partial dispersion of islets. There was no difference in degree of islet destruction between islets infected with E16 or E30 (Fig. 1). Islets infected with E4 did not show any virus-induced effect at any time post infection (Fig. 1). Isolates of E16 and E30 did replicate well in islet cell with a titer rise from day 0 to day 3. The mean CCID50 titers increase in islet infected with strains of E16 and E30 was 0.7 logCCID50 and 1.2 logCCID50, respectively. The CCID50 titers were decreased (1.3 logCCID50) in E4-infected islets from 5 donors (Fig. 2). Strikingly, the CCID50 titers increased (1 logCCID50) in 2 out of 7 (28.5%) donor islets infected with E4 between day 3 and 5 post infection (not shown). However, no CPE could be seen in islets from any of the seven donors suggesting there was replication in islets from two donors without inducing CPE.


Expression of innate immunity genes and damage of primary human pancreatic islets by epidemic strains of Echovirus: implication for post-virus islet autoimmunity.

Sarmiento L, Frisk G, Anagandula M, Cabrera-Rode E, Roivainen M, Cilio CM - PLoS ONE (2013)

Virus-induced cytopathic effect in primary human pancreatic islets cells.A. Uninfected islet. B. Islets infected with the E4 isolate 5 days post infection. C. Islets infected with E16 isolates 3 days post infection. D. Islets infected with E30 isolates 3 days post infection. The figure is representative of seven islet donors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815302&req=5

pone-0077850-g001: Virus-induced cytopathic effect in primary human pancreatic islets cells.A. Uninfected islet. B. Islets infected with the E4 isolate 5 days post infection. C. Islets infected with E16 isolates 3 days post infection. D. Islets infected with E30 isolates 3 days post infection. The figure is representative of seven islet donors.
Mentions: Clinical strains of E16 and E30 caused destruction of the isolated human pancreatic islet from seven different donors. The first morphological changes were seen as early as one day after infection in all islet infected with E16 and E30. At three days after infection the virus-induced cytopathic effect became more pronounced. Islet degeneration was characterized by the loss of islet integrity, disintegration, and partial dispersion of islets. There was no difference in degree of islet destruction between islets infected with E16 or E30 (Fig. 1). Islets infected with E4 did not show any virus-induced effect at any time post infection (Fig. 1). Isolates of E16 and E30 did replicate well in islet cell with a titer rise from day 0 to day 3. The mean CCID50 titers increase in islet infected with strains of E16 and E30 was 0.7 logCCID50 and 1.2 logCCID50, respectively. The CCID50 titers were decreased (1.3 logCCID50) in E4-infected islets from 5 donors (Fig. 2). Strikingly, the CCID50 titers increased (1 logCCID50) in 2 out of 7 (28.5%) donor islets infected with E4 between day 3 and 5 post infection (not shown). However, no CPE could be seen in islets from any of the seven donors suggesting there was replication in islets from two donors without inducing CPE.

Bottom Line: The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cellular Autoimmunity Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmo, Sweden ; Department of Virology, "Pedro Kouri" Tropical Medicine Institute, Havana, Cuba.

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.

Show MeSH
Related in: MedlinePlus