uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
Centers for Disease Control and Prevention, Atlanta, Georgia.
School of Medicine, University of Tampere, Tampere, Finland.
Show others and affiliations
2014 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, 1402-1411 p.Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

Place, publisher, year, edition, pages
2014. Vol. 86, no 8, 1402-1411 p.
Keyword [en]
enterovirus, type 1 diabetes, innate immunity, human pancreatic islets, RNA sensors
National Category
Infectious Medicine Microbiology
URN: urn:nbn:se:uu:diva-231113DOI: 10.1002/jmv.23835ISI: 000339486200015PubMedID: 24249667OAI: oai:DiVA.org:uu-231113DiVA: diva2:744042
Available from: 2014-09-05 Created: 2014-09-04 Last updated: 2016-06-01
In thesis
1. Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells
Open this publication in new window or tab >>Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied.

Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1223
Type 1 Diabetes, Enterovirus, Innate Immunity, Pancreas
National Category
Microbiology in the medical area
urn:nbn:se:uu:diva-284370 (URN)978-91-554-9572-5 (ISBN)
Public defence
2016-06-07, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 752 37 Uppsala, Uppsala, 09:00 (English)
Available from: 2016-05-13 Created: 2016-04-18 Last updated: 2016-06-01

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Anagandula, MaheshKorsgren, OlleFrisk, Gun
By organisation
Clinical ImmunologyDepartment of Medical Cell Biology
In the same journal
Journal of Medical Virology
Infectious MedicineMicrobiology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 332 hits
ReferencesLink to record
Permanent link

Direct link