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Complete nucleotide sequence of a Coxsackievirus B-4 strain capable of establishing persistent infection in human pancreatic islet cells: effects on insulin release, proinsulin synthesis, and cell morphology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2002 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 68, no 4, 544-57 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present investigation was to study the effect of infection of human pancreatic islet cells with a strain (VD2921) of Coxsackie B virus serotype 4 capable of establishing persistent infection in these cells, as well as to sequence the strain, to study the determinants of virulence and persistence. Groups of islets were infected and assessments of proinsulin, insulin content, and virus replication were made. Insulin release in response to high glucose was measured. Infected and control islets displayed a strong insulin response to high glucose 3-4 days as well as 7-8 days post-infection (dpi). At 11-17 dpi, the infected islets did not respond at all to high glucose, and the response of the control islets was at this late time point somewhat reduced. The insulin and proinsulin content of the infected islets did not differ significantly from that of the control islets. TCID(50) titrations showed that the VD2921 strain replicated in the islet cells during the whole study. Electron microscopic examination of infected islets did not reveal any virus-induced changes of cell morphology compared with the controls, although higher magnifications of the infected beta-cells showed virus-like particles in the cytoplasm. These results show that certain strains of Coxsackievirus B-4 in vitro can establish a persistent infection that might mimic, the more gradual loss of beta-cell function seen during the clinical course of autoimmune diabetes. The ability of this Coxsackievirus B-4 strain to establish a persistent infection might be due to substitution of 11 amino acids located at the surface of the structural protein VP1, adjacent to the predicted receptor binding canyon of the virus.

Place, publisher, year, edition, pages
2002. Vol. 68, no 4, 544-57 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93620DOI: 10.1002/jmv.10236PubMedID: 12376963OAI: oai:DiVA.org:uu-93620DiVA: diva2:167151
Available from: 2005-10-27 Created: 2005-10-27 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Enterovirus Infections of β-Cells: A Mechanism of Induction of Type 1 Diabetes?
Open this publication in new window or tab >>Enterovirus Infections of β-Cells: A Mechanism of Induction of Type 1 Diabetes?
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound.

It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets.

Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect.

All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo.

Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study.

To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 79
Keyword
Pediatrics, enterovirus, type 1 diabetes, β-cells, human pancreatic islets, picornavirus, chemokines, nitric oxide, Pediatrik
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-6019 (URN)91-554-6373-8 (ISBN)
Public defence
2005-11-17, Rosénsalen, Akademiska Barnsjukhuset, ing. 95/96 nbv, Uppsala, 09:15
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Available from: 2005-10-27 Created: 2005-10-27Bibliographically approved

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