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Field strains of Echovirus 6 infect human endocrine and exocrine pancreatic cells and induce pro-inflammatory innate immune responses.
Cellular Autoimmunity Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmo, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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(English)Article in journal (Refereed) In press
Abstract [en]

Increasing evidence suggests that type 1 diabetes (T1D) is a combined endocrine-exocrine disease. Human enteroviruses (HEV) have been suggested to induce T1D, but so far evidence on HEV infection in human pancreas has been reported only in islets and ductal cells. Aim of this study was to investigate the capability of HEV strains to infect primary human endocrine and exocrine pancreatic cells and to induce the expression of innate immunity genes in both cell types. Isolated human pancreatic islets and exocrine cells were either mock-infected or inoculated with seven field isolates of Echovirus 6 (E6). Beta-cell tropic strains of E4, E16 and E30 were assayed in primary exocrine cells. Viral infection, replication, virus-induced cytopathic effect (CPE) and expression of innate immunity genes were measured. All the seven strains of E6 replicated in both pancreatic endocrine and exocrine cells with infectious progeny production and appearance of CPE. By contrast, no virus titer increase or CPE were observed in exocrine cells exposed to E4, E16 and E30. Virus particles were found in E6-infected acinar cells, both free in cytoplasm and enclosed in vacuoles. Insulin granules accumulation in proximity to virus particles and beta cells functional impairment were demonstrated in E6-infected islets. Endocrine and exocrine cells responded to E6 infection by upregulating the transcription of genes involved in viral recognition (IF1H1), antiviral defense (OAS1, IFN-β) and inflammation (CXCL10, CCL5). Our results indicate that islets and exocrine pancreatic cells productively support the E6 infection and suggest that HEV-associated T1D may involve both endocrine and exocrine pancreas.

National Category
Clinical Medicine Microbiology
URN: urn:nbn:se:uu:diva-283276OAI: oai:DiVA.org:uu-283276DiVA: diva2:918879
Available from: 2016-04-12 Created: 2016-04-12 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

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