Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

ABSTRACT

Introduction: Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. Methods: A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. Results: The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Conclusion: Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

KEYWORDS:

• CAR
• Coxsackievirus B4
• miRNA
• pancreatic cells
• PDX-1
• persistence

This article is referred to by:

Acute and chronic disease caused by enteroviruses

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank Jacques Trauet for technical assistance.

Funding

This work was supported by Ministère de l'Education Nationale de l'Enseignement Supérieur et de la Recherche, Université Lille 2 (Equipe d'accueil 3610) and Center Hospitalier Régional et Universitaire de Lille, and by EU FP7 (GA-261441-PEVNET : Persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes - an innovative research program of biobanks and expertise).