title: 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Anagandula
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Richardson
authors.forename: M Steven
authors.initials: MS
authors.lastname: Oberste
authors.forename: Amir-Babak
authors.initials: AB
authors.lastname: Sioofy-Khojine
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
authors.forename: Noel G
authors.initials: NG
authors.lastname: Morgan
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.forename: Gun
authors.initials: G
authors.lastname: Frisk
mesh_terms: D016923:Cell Death; D003588:Cytopathogenic Effect, Viral; D029822:Enterovirus B, Human / Q000276:immunology* / Q000502:physiology*; D020869:Gene Expression Profiling; D005934:Glucagon / Q000096:biosynthesis; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000821:virology*; D056189:Viral Tropism; D014779:Virus Replication
chemical_list: D007328:Insulin; D005934:Glucagon
keywords: RNA sensors; enterovirus; human pancreatic islets; innate immunity; type 1 diabetes