|Haider, Al-Hello - KTL HELSINKI FINLAND|
|Davydova, Berta - KTL HELSINKI FINLAND|
|Smura, Teemu - KTL HELSINKI FINLAND|
|Kaialainen, Svetlana - KTL HELINSKI FINLAND|
|Ylipaasto, Petri - KTL HELINSKI FINLAND|
|Saario, Elise - KTL HELINSKI FINLAND|
|Hovi, Tapani - KTL HELINSKI FINLAND|
|Roivainen, Merja - KTL HELINSKI FINLAND|
Submitted to: Journal of Medical Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 7, 2004
Publication Date: April 1, 2005
Citation: Haider, A., Davydova, B., Smura, T., Kaialainen, S., Ylipaasto, P., Saario, E., Hovi, T., Rieder, A.E., Roivainen, M. 2005. Phenotypic and genetic changes in coxsackievirus b5 following repeated passaging in mouse pancreas in vivo. Journal of Medical Virology. 75 (4), 566-574 Interpretive Summary: Insulin-dependent diabetes mellitus is a chronic disease where insulin-producing B-cells in pancreatic Langerhans islets are gradually destroyed. Several lines of epidemiological evidence suggest that enterovirus infections increase the risk for type 1 diabetes in humans, however the mechanims by which enteroviruses are involved in pathogenesis of the disease have not yet been defined. This study represent an important step in the understanding of the role of coxsackieviruses type B in the tropism to pancreas and the consequences of virus grow in this organ. We have shown that fifteen successive passages of a parental CBV-5 strain in mouse pancreas resulted in apparent changes in the virus phenotype resulting in a capacity to induce chronic pancreatic inflammation together with transient hyperglycaemia in CD-1 mice. The passaged variant together with the parental virus strain was cloned for molecular characterization and the genetic modification responsible for the altered phenotype were determined.
Technical Abstract: Common enterovirus infections appear to initiate or facilitate the pathogenetic processes leading to type 1 diabetes (T1D), and also sometimes precipitate the clinical disease. In experimental infection of mice coxsackieviruses have shown to have propensity particularly to exocrine tissue while even in lethal cases the islets remain unaffected. The virus strain most intensively studied in this respect is the diabetogenic variant E2 of coxsackievirus B4. In addition, it is known that all six serotypes of coxsackie B viruses could be made diabetogenic by repeated passages in either mouse pancreas in vivo or in cultured mouse beta-cells in vitro. However, the genetic determinants of the phenomenon have not been determined. In the present study a laboratory strain of coxsackievirus B5 was passaged repeatedly in mouse pancreas in vivo. After 15 passages the virus phenotype was clearly changed and infection of the variant resulted in a diabetes like syndrome in mice characterized by chronic pancreatic inflammation together with transient increases in blood glucose if measured after glucose tolerance, loss of pancreatic acinar tissue, and mild insulitis. In order to found out genetic determinants involved in mouse pancreas adaptation the passaged virus variant together with the parental virus strain was cloned for molecular characterization. The whole genome sequencing of both virus strains revealed only limited differences. Altogether, eight nucleotides were changed resulting in five amino acid substitutions out of which three were located in capsid proteins.