Abstract
Coxsackievirus-B4 (CV-B4) can persist in pancreatic cell lines and impair the phenoytpe and/or gene expressions in these cells; however, the models used to study this phenomenon did not produce insulin. Therefore, we investigated CV-B4 persistence and its consequences in insulin-producing pancreatic β cells. The insulin-secreting rat β cell line, INS-1, was infected with CV-B4. After lysis of a large part of the cell layer, the culture was still maintained and no additional cytopathic effect was observed. The amount of insulin in supernatants of cell cultures persistently infected with CV-B4 was not affected by the infection; in fact, a larger quantity of proinsulin was found. The mRNA expression of pro-hormone convertase 2, an enzyme involved in the maturation of proinsulin into insulin and studied using real-time reverse transcription-polymerase chain reaction, was inhibited in infected cultures. Further, the pattern of 47 cell proteins analyzed using Shotgun mass spectrometry was significantly modified. The DNA of persistently infected cell cultures was hypermethylated unlike that of controls. The persistent infection of INS-1 cells with CV-B4 had a deep impact on these cells, especially on insulin metabolism. Cellular changes caused by persistent CV-B4 infection of β cells can play a role in type 1 diabetes pathogenesis.
Highlights
Type 1 diabetes (T1D) is a metabolic disease characterized by chronic hyperglycemia, resulting from defective production of insulin due to the selective destruction or loss of functional insulin-producing β cells through an autoimmune process occurring in genetically predisposed individuals
Enteroviruses, especially coxsackieviruses-B (CV-B), are the most suspected environmental factors associated with the development of islet autoimmunity or the onset and progression of T1D [6]; the underlying mechanisms leading to defective synthesis or secretion of insulin in pancreatic β cells remain an open issue
We previously demonstrated that the persistence of CV-B4 E2 in human pancreatic ductal-like cells leads to a decrease in the expression of viral receptors [23], a disruption of microRNA profiles [23,32], an alteration of expression of the transcription factor Pdx-1 required for the formation of the endocrine pancreas, and an impaired differentiation of these cells into islet-like cell aggregates (ICA) [23,33]
Summary
Type 1 diabetes (T1D) is a metabolic disease characterized by chronic hyperglycemia, resulting from defective production of insulin due to the selective destruction or loss of functional insulin-producing β cells through an autoimmune process occurring in genetically predisposed individuals. Enteroviruses, especially coxsackieviruses-B (CV-B), are the most suspected environmental factors associated with the development of islet autoimmunity or the onset and progression of T1D [6]; the underlying mechanisms leading to defective synthesis or secretion of insulin in pancreatic β cells remain an open issue. Coxsackieviruses-B (CV-B1–6) are small, non-enveloped, positive-sense single-stranded RNA genome viruses belonging to the Enterovirus genus of the Picornaviridae family [7]. These ubiquitous pathogens are transmitted mainly through the fecal–oral and respiratory routes and are involved in several mild or severe acute clinical infections or in chronic diseases such as chronic myocarditis, dilated cardiomyopathy, and T1D [6,8,9,10]. A study using quantitative mass spectrometry-based proteomics revealed that HIV-1 infection can activate a molecular inhibitor of cell apoptosis, BIRC5, leading to long-term survival of infected CD4+ cells and persistence of the virus in infected individuals [27]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
