Genetic Adaptation of Coxsackievirus B1 during Persistent Infection in Pancreatic Cells.

Anni Honkimaa,Bryn Kimura,Sami Oikarinen,Amir-Babak Sioofy-Khojine,Jake Lin,Heikki Hyöty,Jutta Laiho

doi:10.3390/microorganisms8111790

Abstract

Coxsackie B (CVB) viruses have been associated with type 1 diabetes. We have recently observed that CVB1 was linked to the initiation of the autoimmune process leading to type 1 diabetes in Finnish children. Viral persistency in the pancreas is currently considered as one possible mechanism. In the current study persistent infection was established in pancreatic ductal and beta cell lines (PANC-1 and 1.1B4) using four different CVB1 strains, including the prototype strain and three clinical isolates. We sequenced 5′ untranslated region (UTR) and regions coding for structural and non-structural proteins and the second single open reading frame (ORF) protein of all persisting CVB1 strains using next generation sequencing to identify mutations that are common for all of these strains. One mutation, K257R in VP1, was found from all persisting CVB1 strains. The mutations were mainly accumulated in viral structural proteins, especially at BC, DE, EF loops and C-terminus of viral capsid protein 1 (VP1), the puff region of VP2, the knob region of VP3 and infection-enhancing epitope of VP4. This showed that the capsid region of the viruses sustains various changes during persistency some of which could be hallmark(s) of persistency.

Highlights

Coxsackie B group viruses (CVBs) belong to Enterovirus (EV) genus in the family of Picornaviridae
This study aims at identifying the changes that occur in the CVB1 genome during the development of persistence
The results of the present study indicate that the CVB1 strains that have adapted to viral persistence differ from the parental CVB1 strains which have not been exposed to such selection pressure—they produced smaller plaques and shared common mutations in their genome

Summary

Introduction

Coxsackie B group viruses (CVBs) belong to Enterovirus (EV) genus in the family of Picornaviridae. EVs have positive-sense single-stranded RNA genomes, approximately 7400 nucleotides (nt) long, inside a 30 nm icosahedral protein capsid [1]. The protein capsid consists of 12 pentameric subunits, built up of five protomers. Each protomer contains viral structural proteins VP1-4. EVs have fivefold, threefold, and twofold symmetry axes. The VP1 protein is located around fivefold axes, whereas VP2 and 3 are found around threefold axes. EVs have a deep depression, called the canyon, which encircles the fivefold axes below VP1. Often the canyon is a receptor binding site [2,3]. A possible externalization site for the RNA genome is located near the twofold axes [4]

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