title: Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells.
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 also affect 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 implicate 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.
authors.affiliation: Virology Unit, National Institute for Health and Welfare (THL), Helsinki, Finland; Department of Virology, University of Helsinki, Helsinki, Finland. Electronic address: Teemu.Smura@helsinki.fi.
authors.forename: Teemu
authors.initials: T
authors.lastname: Smura
authors.affiliation: Aalto University, Espoo, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Natri
authors.affiliation: Virology Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Ylipaasto
authors.affiliation: Aalto University, Espoo, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Hellman
authors.affiliation: Virology Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Haider
authors.initials: H
authors.lastname: Al-Hello
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Virology Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Roivainen
mesh_terms: D000220:Adaptation, Biological; D018958:CD55 Antigens / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics; D003588:Cytopathogenic Effect, Viral; D004770:Enterovirus / Q000254:growth & development*; D004847:Epithelial Cells / Q000502:physiology* / Q000821:virology*; D006801:Humans; D020125:Mutation, Missense; D011991:Receptors, Virus / Q000378:metabolism
chemical_list: D018958:CD55 Antigens; D036022:Capsid Proteins; D011991:Receptors, Virus
keywords: Cell tropism; Coxsackievirus; Enterovirus; Pancreatic duct; Type 1 diabetes