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Antiviral Treatment of Coxsackie B Virus Infection in Human Pancreatic Islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Gustafsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Gustafsson)
2007 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 74, no 1, 65-71 p.Article in journal (Refereed) Published
Abstract [en]

Enterovirus infections of the pancreatic islets are believed to trigger or precipitate the near total destruction of β-cells that constitutes type 1 diabetes (T1D). This study investigated the ability of an anti-picornaviral compound, pleconaril, to block the replication of two β-cell tropic Coxsackie B4 virus (CBV-4) strains in isolated human islets. The two strains, VD2921 and V89 4557, with demonstrated abilities to cause non-lytic persistence or lytic infection, respectively, in islets, represented two different potential mechanisms behind virus-induced T1D. The virus replication in the islets was studied with and without addition of pleconaril. In addition, islet morphology was studied every day. To test the effects of pleconaril and/or DMSO on the β-cells’ insulin secretion, glucose perifusions were performed on treated and untreated islets. Virus titrations showed a clear reduction of the replication of both strains after pleconaril treatment. The VD2921 strain was inhibited to undetectable levels. The V89 4557 strain, however, showed an initial reduction of titers but virus titers then increased despite the addition of a second dose of pleconaril. This incomplete inhibition of viral replication suggested the existence of a resistant subtype within this strain. Pleconaril treatment reduced the β-cells’ insulin secretion in response to glucose stimulation in some experiments and induced slight morphological changes to the islets compared to untreated controls. In summary, pleconaril reduced the replication of the two β-cell tropic CBV-4 strains in human islets. However, genetic differences between these strains influenced the effectiveness of pleconaril treatment. This stresses the importance of using multiple viral strains in antiviral tests.

Place, publisher, year, edition, pages
2007. Vol. 74, no 1, 65-71 p.
Keyword [en]
β-Cell, Enterovirus, Islet of langerhans, Picornavirus, Pleconaril, Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93622DOI: 10.1016/j.antiviral.2006.12.001ISI: 000245614400009PubMedID: 17239967OAI: oai:DiVA.org:uu-93622DiVA: diva2:167153
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
Opponent
Supervisors
Available from: 2005-10-27 Created: 2005-10-27Bibliographically approved

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Berg, Anna-KarinKorsgren, OlleFrisk, Gun

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