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Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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 [en]
Type 1 diabetes, Enterovirus, Coxsackievirus, Innate immunity, Pancreatic islets, Islet function
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-172586ISBN: 978-91-554-8350-0 (print)OAI: oai:DiVA.org:uu-172586DiVA: diva2:515158
Public defence
2012-05-30, Fåhreussalen, Rudbecklaboratoriet, Dag Hammarskjölds V. 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-09 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved
List of papers
1. Antiviral effect of nicotinamide on enterovirus-infected human islets in vitro: effect on virus replication and chemokine secretion
Open this publication in new window or tab >>Antiviral effect of nicotinamide on enterovirus-infected human islets in vitro: effect on virus replication and chemokine secretion
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-104989 (URN)10.1002/jmv.21476 (DOI)000265658100019 ()19382275 (PubMedID)
Available from: 2009-05-31 Created: 2009-05-31 Last updated: 2017-12-13Bibliographically approved
2. Modulation of Innate Immunity in Human Pancreatic Islets Infected With Enterovirus In Vitro
Open this publication in new window or tab >>Modulation of Innate Immunity in Human Pancreatic Islets Infected With Enterovirus In Vitro
2011 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 4, 658-664 p.Article in journal (Refereed) Published
Abstract [en]

Present knowledge of innate immunity in infected cells relies on studies of cell lines and animal models. In this study, primary human pancreatic islets of Langerhans were used to study virus-host interactions in a model of the possible induction of type 1 diabetes by enterovirus (EV). Human islets were infected with a strain of EV isolated at onset of type 1 diabetes, or exposed to synthetic dsRNA (poly(I:C)), used commonly to mimic viral infection. Induction of innate immunity and the effect of the female sex hormone 17 beta-estradiol, known to have cell-protective effects, on islet chemokine secretion were investigated. 17 beta-Estradiol reduced EV but not poly(I:C)-induced IP-10/CXCL10 secretion from human islets, suggesting that separate signaling pathways of the innate immune response are triggered by EV and poly(I:C), respectively. Infection with EV increased the gene-expression of toll-like receptor 3, interferon-beta, and the intracellular helicase MDA5, involved in antiviral innate immunity, multi-fold over time, whereas poly(I:C) increased the expression of these genes transiently. The induced expression pattern was similar in all donors, but the expression levels varied greatly. Pre-exposure to poly(I:C) blocked viral replication in islets from 56% of the donors. These data provide insight on the innate immune responses induced by EV in human islets, and show that this can be modulated by 17 beta-estradiol, and suggest an important difference between virus- and poly(I:C)-induced signaling.

Keyword
type 1 diabetes, CVB, IP-10/CXCL10, estradiol, gender difference
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149592 (URN)10.1002/jmv.21924 (DOI)000287570400014 ()21328381 (PubMedID)
Available from: 2011-03-21 Created: 2011-03-21 Last updated: 2017-12-11Bibliographically approved
3. Ongoing Pathogenic Processes in the Pancreas at Onset of Type 1 Diabetes in Humans
Open this publication in new window or tab >>Ongoing Pathogenic Processes in the Pancreas at Onset of Type 1 Diabetes in Humans
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-172584 (URN)
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2018-01-12
4. Enterovirus-induced disintegration of human pancreatic islets, but not viral replication per se, reduces beta cell function selectively
Open this publication in new window or tab >>Enterovirus-induced disintegration of human pancreatic islets, but not viral replication per se, reduces beta cell function selectively
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-172585 (URN)
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2018-01-12

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