Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine

Alidjinou, Enagnon Kazali; Sané, Famara; Bertin, Antoine; Caloone, Delphine; Hober, Didier

doi:10.1016/j.antiviral.2015.01.010

Cited by 32 publications

(29 citation statements)

References 15 publications

(20 reference statements)

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“…To test this hypothesis, persistent infection was completely cured by fluoxetine, as previously reported. 44 One year after the end of treatment we found that PDX-1 expression was still significantly reduced in persistently infected cells that had been cured by fluoxetine (18.2% and 17.8% respectively in untreated and cured cells, compared with uninfected cells) (Fig. 4a).…”

Section: Resistance Of Cvb4 Persistently Infected Cells To Lysis Uponmentioning

confidence: 82%

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

et al. 2017

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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.

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Section: Resistance Of Cvb4 Persistently Infected Cells To Lysis Uponmentioning

confidence: 82%

“…44 Briefly Panc-1 cells persistently infected with CVB4 were treated twice a week with fluoxetine at 5.5mM, and virus was completely cleared within 3 weeks.…”

Section: Fluoxetine Treatmentmentioning

confidence: 99%

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

et al. 2017

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“…The availability of drugs targeting different steps of the viral cycle enables combined treatment to avoid viral resistance to the antiviral therapy. Some compounds have shown efficacy to reduce coxsackievirus amplification and to protect pancreatic islets from coxsackievirus-induced cytopathogenic effects 138–141 ; to eradicate the virus in infected pancreatic β cell lines 142 ; and to prevent and/or reduce the incidence of virally-induced diabetes mellitus in mice 140,141 . Adapted antiviral treatment at the pre-diabetic stage could eliminate persistent infection, thus reducing inflammation and the risk of autoimmunity and T1DM.…”

Section: Prevention Of T1dmmentioning

confidence: 99%

Viral infections in type 1 diabetes mellitus — why the β cells?

2016

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Type 1 diabetes mellitus (T1DM) is caused by progressive autoimmune-mediated loss of pancreatic β-cell mass via apoptosis. The onset of T1DM depends on environmental factors that interact with predisposing genes to induce an autoimmune assault against β cells. Epidemiological, clinical and pathology studies in humans support viral infection -particularly by enteroviruses (for example, coxsackievirus) -as an environmental trigger for the development of T1DM. Many candidate genes for T1DM, such as MDA5, PTPN2 and TYK2, regulate antiviral responses in both β cells and the immune system. Cellular permissiveness to viral infection is modulated by innate antiviral responses that vary among different tissues or cell types. Some data indicate that pancreatic islet α cells trigger a more efficient antiviral response to infection with diabetogenic viruses than do β cells, and so are able to eradicate viral infections without undergoing apoptosis. This difference could account for the varying ability of islet-cell subtypes to clear viral infections and explain why chronically infected pancreatic β cells, but not α cells, are targeted by an autoimmune response and killed during the development of T1DM. These issues and attempts to target viral infection as a preventive therapy for T1DM are discussed in the present Review.Type 1 diabetes mellitus (T1DM) arises when the pancreatic β cells undergo long-term autoimmune attack, killing the majority of the β-cell population while the neighbouring α cells and δ cells are spared 1 . Destruction of the β cells manifests as a failure to produce insulin; consequently, patients with T1DM remain insulin-dependent for their lifespan.In most cases, T1DM is characterized by pancreatic islet inflammation (insulitis) and progressive β-cell loss by apoptosis 1,2 . Histological analysis has demonstrated the presence of increased β-cell apoptosis among both patients with new-onset T1DM and those with

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“…Also, Fluoxetine may show efficacy during a persistent infection, and this antiviral molecule was recently shown to “cure” human pancreatic cells infected in culture with CVB (Alidjinou, Sane et al, 2015). The mechanism of action remains unclear, and utilizing fluoxetine as an antiviral may be problematic based on its neurological effects on serotonin uptake and involvement with an increased risk of bleeding when given with inhibitors of platelet function (Alderman, Moritz et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

et al. 2015

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Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis.

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Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine

Cited by 32 publications

References 15 publications

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

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

Viral infections in type 1 diabetes mellitus — why the β cells?

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

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