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Enterovirus Implications in Type 1 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human enteroviruses (HEVs), particularly Coxsackie B viruses (CVBs), might trigger the onset of type 1 diabetes (T1D), either by direct infection of the insulin-producing beta-cells or by an indirect inflammatory response. The overall aim of this thesis was to study the tropism of HEVs in isolated human pancreatic cell clusters in vitro including virus effects on islet function, gene-expression and ultrastructure. Furthermore, the expression of the major CVB-receptor, CAR, was investigated in pancreatic tissue from T1D-related subjects and CVB-infected islets. Also, tissues and isolated islets from two adult organ-donors who died close to disease onset were studied.The results showed that beta-cells were destroyed through lytic infections with different strains of CVBs and that islets function did not depend on replication per se but on the degree of islet destruction. Virus particles were observed in beta-cells in association with insulin granules, however no virus replication or particles could be observed in the exocrine cell clusters, as opposed to in mice models. The virus-infected islets had a decreased expression of insulin mRNA and CAR mRNA/protein, possibly reflecting virus-killed beta-cells. Infected beta-cells contained a high number of insulin granules, which might indicate an impaired function.The in vivo studies showed presence of virus proteins in the islets of both donors who died close to onset of T1D and elevated expression of innate immunity genes, potentially indicating viral infection, but direct evidence is lacking. Both donors were immune-reactive for insulin but the isolated islets had an impaired or completely lacking glucose response. Ultrastructural analysis showed both damaged beta-cells and normal-looking beta-cells, indicating that the latter might still have the potential to function but were blocked. CAR-expression was significantly increased in T1D-related subjects which might indicate tissue damage and/or inflammation in these subjects.To conclude, these results showed that CVBs could infect human primary beta-cells, likely by binding to CAR and lead to functional abnormalities, indicating that they could cause T1D in vivo. Exocrine cells were not permissive to CVB, which raises the question if mice-models should be used to study human pancreatitis. Also, unique materials from two T1D organ-donors were described.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 918
Keyword [en]
Enterovirus, Coxsackie B virus, Type 1 diabetes, Pancreatitis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-204378ISBN: 978-91-554-8709-6 (print)OAI: oai:DiVA.org:uu-204378DiVA: diva2:638719
Public defence
2013-09-13, Rudbecklaboratoriet stora aulan, Dag Hammarskjöldsv 20, Uppsala, 09:15 (English)
Supervisors
Available from: 2013-08-30 Created: 2013-08-01 Last updated: 2014-01-07
List of papers
1. Tropism Analysis of Two Coxsackie B5 Strains Reveals Virus Growth in Human Primary Pancreatic Islets but not in Exocrine Cell Clusters In Vitro
Open this publication in new window or tab >>Tropism Analysis of Two Coxsackie B5 Strains Reveals Virus Growth in Human Primary Pancreatic Islets but not in Exocrine Cell Clusters In Vitro
2013 (English)In: Open Virology Journal, ISSN 1874-3579, Vol. 7, 49-56 p.Article in journal (Refereed) Published
Abstract [en]

Human Enteroviruses (HEVs) have been implicated in human pancreatic diseases such as pancreatitis and type 1 diabetes (T1D). Human studies are sparse or inconclusive and our aim was to investigate the tropism of two strains of Coxsackie B virus 5 (CBV-5) in vitro to primary human pancreatic cells. Virus replication was measured with TCID50 titrations of aliquots of the culture medium at different time points post inoculation. The presence of virus particles or virus proteins within the pancreatic cells was studied with immunohistochemistry (IHC) and electron microscopy (EM). None of the strains replicated in the human exocrine cell clusters, in contrast, both strains replicated in the endocrine islets of Langerhans. Virus particles were found exclusively in the endocrine cells, often in close association with insulin granules. In conclusion, CBV-5 can replicate in human endocrine cells but not in human exocrine cells, thus they might not be the cause of pancreatitis in humans. The association of virus with insulin granules might reflect the use of these as replication scaffolds.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204368 (URN)10.2174/1874357901307010049 (DOI)23723955 (PubMedID)
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2017-12-06Bibliographically approved
2. Enterovirus Infection Reduces Beta-cell Function and Leads to Decreased Glucose Stimulated Insulin Secretion in Dissociated but not In Intact Pancreatic Human Islets
Open this publication in new window or tab >>Enterovirus Infection Reduces Beta-cell Function and Leads to Decreased Glucose Stimulated Insulin Secretion in Dissociated but not In Intact Pancreatic Human Islets
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204372 (URN)
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2014-01-07Bibliographically approved
3. Expression of Coxsackie and Adenovirus Receptor in islets of Langerhans from Type 1 diabetes, islet autoantibody positive and non-diabetic subjects
Open this publication in new window or tab >>Expression of Coxsackie and Adenovirus Receptor in islets of Langerhans from Type 1 diabetes, islet autoantibody positive and non-diabetic subjects
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204373 (URN)
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2014-01-07Bibliographically approved
4. 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
Show others...
(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: 2014-01-07

Open Access in DiVA

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