Infection of human islets of langerhans with two strains of coxsackie B virus serotype 1: Assessment of virus replication, degree of cell death and induction of genes involved in the innate immunity pathway

Abstract

Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1.Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFNβ, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFNβ, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential β-cell tropism of the virus.

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

“…Viruses produce proteins that efficiently inhibit the production of antiviral genes and use the cellular machinery for its own replication. Different strains and serotypes of a virus vary in their capacity to induce an innate immune response (29), dramatically affecting the outcome of infection. A strong innate immune response may limit viral replication, but at the same time contribute to unwanted tissue damage.…”

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells

“…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, 2003Paananen et al, , 2013Roivainen 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).…”

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

“…[15][16][17] However this scenario of acute massive infection is not compatible with T1D which is an autoimmune disease with a progressive evolution, and the implication of the virus is believed to rely on the immune response. 5 Therefore, the most likely situation would be a persistent CVB infection probably with low grade viral replication.…”