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Antiviral effect of nicotinamide on enterovirus-infected human islets in vitro: effect on virus replication and chemokine secretion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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2009 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 81, no 6, 1082-1087 p.Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes is a chronic disease characterized by the selective destruction of insulin-producing cells in the pancreas. Enterovirus (EV) is the prime candidate to initiate this destruction and several inflammatory chemokines are induced by EV infection. Nicotinamide has been shown to protect isolated human islets, and to modulate chemokine expression. The aim of this study was to evaluate the effect of nicotinamide on EV replication and EV-induced chemokine secretion and cytolysis of human islets. Two EV strains were used to infect human islets in vitro, one lytic (Adrian) isolated from a child at onset of type 1 diabetes, and one non-lytic (VD2921). Secretion of the chemokines IP-10 and MCP-1, viral replication, and virus-induced cytopathic effect (CPE), were measured at different time points post-infection. Addition of nicotinamide to the culture medium reduced viral replication and virus-induced islet destruction/CPE, significantly. Both EV strains increased secretion of IP-10 and MCP-1, when measured days 2-3, and days 5-7 post infection, compared to mock-infected control islets. IP-10 was not produced by uninfected isolated islets, whereas a basal secretion of MCP-1 was detected. Interestingly, addition of nicotinamide blocked completely (Adrian), or reduced significantly (VD2921), the virus-induced secretion of IP-10. Secretion of MCP-1 was also reduced in the presence of nicotinamide, from infected and uninfected islets. The reported antiviral effects of nicotinamide could have implications for the treatment/prevention of virus- and immune-mediated disease. Also, this study highlights a possible mechanism of virus-induced type 1 diabetes through the induction of MCP-1 and IP-10 in pancreatic islets.

Place, publisher, year, edition, pages
2009. Vol. 81, no 6, 1082-1087 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-104989DOI: 10.1002/jmv.21476ISI: 000265658100019PubMedID: 19382275OAI: oai:DiVA.org:uu-104989DiVA: diva2:220330
Available from: 2009-05-31 Created: 2009-05-31 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans
Open this publication in new window or tab >>Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on enteroviral effects on human pancreatic islets. Most knowledge of viral effects on host cells relies on studies of immortalized cell lines or animal models. The islets represent a fundamentally different and less well studied cellular host. Also, enterovirus has been implicated in the etiology of type 1 diabetes (T1D). We show that when enterovirus replicates in human islets it activates innate immunity genes and induces secretion of the chemokines MCP-1 and IP-10. An important difference in activation of innate immunity by replicating EV and synthetic dsRNA is suggested, since the chemokine secretion induced by EV infection but not by dsRNA is reduced by female sex hormone. We also demonstrate a direct antiviral effect of nicotinamide, and even though this substance failed to prevent T1D in a large-scale study, this finding could have implications for the treatment/prevention of virus- and/or immune-mediated disease.

We also had access to human pancreata from two organ donors with recent onset T1D and several donors with T1D-related autoantibodies, which gave us the opportunity to study ongoing pathogenic processes at and before the onset of T1D. Despite this, we could neither confirm nor reject the hypothesis that EV is involved in T1D development. Several observations, such as ultrastructural remodeling of the beta cell, activation of innate immunity, and immunopositivity to EV capsid protein 1, supported an ongoing virus infection, but direct evidence is still lacking.

An interesting finding in the donors with recent onset T1D was that the islets were positively stained for insulin, but did not secrete insulin in response to glucose-stimulation. A similar effect was observed in EV-infected islets in vitro; EV destroyed islet function and insulin gene expression, but the islets still stained positive for insulin. This may be indicative of that a functional block in addition to beta cell destruction is involved in T1D pathogenesis.

In conclusion, these studies of EV in isolated human islets in vitro support that this virus can cause T1D in vivo, but future studies will have to show if and how frequently this happens. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 766
Keyword
Type 1 diabetes, Enterovirus, Coxsackievirus, Innate immunity, Pancreatic islets, Islet function
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-172586 (URN)978-91-554-8350-0 (ISBN)
Public defence
2012-05-30, Fåhreussalen, Rudbecklaboratoriet, Dag Hammarskjölds V. 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2012-05-09 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved

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Skog, OskarKorsgren, OlleFrisk, Gun

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