Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models

Jaïdane, Hela; Sané, Famara; Gharbi, Jawhar; Aouni, Mahjoub; Romond, Marie-Bénédicte; Hober, Didier

doi:10.1002/dmrr.995

Cited by 53 publications

(36 citation statements)

References 124 publications

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“…5 Moreover, experimental studies, in vitro and in vivo animal models, revealed that CV-B4 may be involved in the pathogenesis of T1D through several mechanisms. 2,6,7,8 It has been shown that non-neutralizing anti-CV-B4 IgG obtained from serum of patients can increase the infection of peripheral blood mononuclear cells (PBMC) with CV-B4, which results in production of IFNa and other inflammatory cytokines. 9,10,11,12,13,14 The role of enhancing IgG levels in the outcome of CVB4 infections and other conditions such type 1 diabetes, cannot be ignored.…”

Section: Introductionmentioning

confidence: 99%

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

et al. 2016

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In previous studies it was shown that inoculation of Swiss albino mice with CV-B4 E2 resulted in the production of serum IgG capable of enhancing the CV-B4 E2 infection of murine spleen cells cultures. To investigate whether such an enhancing activity of serum can play a role in vivo, we decided to study the CV-B4 E2 infection in mice exposed to successive inoculations of virus. In Swiss albino mice infected with CV-B4 E2 at the age of 21 days, anti-CV-B4 E2 neutralizing and enhancing activities of their serum peaked after 55 d. In contrast, mice inoculated at the age of 55 d expressed much lower activities. Despite the neutralizing activity of serum, CV-B4 E2 inoculated a second time to 55 day-old animals spread into the host. At the age of 72 and 89 d the levels of viral RNA and infectious particles were higher in organs of animals exposed to 2 successive infections compared with animals infected once at the age of 21 d or 55 d. In animals with 2 successive inoculations of CV-B4 E2 there was a relationship between the anti-CV-B4 E2 enhancing activity of serum and the level of viral RNA in organs and an enhancement of pathology was observed as displayed by histological analysis of pancreas and hyperglycaemia. Altogether our data strongly suggest that an anti-CV-B4 E2 enhancing activity in the host can play a role in the outcome of a secondary infection with this virus.

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Section: Introductionmentioning

confidence: 99%

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

et al. 2016

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“…2 Indeed epidemiological data evidenced an association between enteroviruses, especially CV-B and type 1 diabetes (T1D) in genetically predisposed individuals, and experimental studies, in vitro and in vivo in animal models, revealed several mechanisms through which CV-B infection may be involved in the pathogenesis of T1D. [2][3][4][5] Plasma, serum and IgG from CV-B4 E2 seropositive subjects have been shown to strongly increase the CV-B4 E2-induced production of IFNa by human peripheral blood mononuclear cells (PBMCs), in vitro. 6,7 That increase was the consequence of an enhancement of the infection of PBMC with CV-B4 E2 by non-neutralizing anti-CV-B4 E2 IgG.…”

Section: Introductionmentioning

confidence: 99%

“…It was reported that CV-B4 E2 could infect mice and that the diabetogenic strain CV-B4 E2 could infect outbred Swiss albino mice. 3,10 Therefore, we decided to investigate whether the inoculation of CV-B4 E2 to mice results in an anti-CV-B4 E2 enhancing activity of their sera.…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin G-dependent enhancement of the infection with Coxsackievirus B4 in a murine system

et al. 2016

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It was demonstrated that specific IgG can enhance the infection with CV-B4, in vitro, in the human system. This enhancement could be involved in the pathophysiology of CV-B4 induced diseases. To investigate further the role of enhancing IgG in the infection with CV-B4 E2 in vivo, animal models are needed. Therefore, it was decided to assess whether inoculation of CV-B4 E2 to mice results in the appearance of IgG able to enhance the infection with this virus. Swiss albino mice were inoculated with CV-B4 E2 intraperitoneally. Serum samples were obtained from tail vein blood collected from day 0 to day 80 p.i. IgG were isolated by Protein G affinity chromatography. Seroneutralisation assays were carried out. In total murine spleen cells cultures inoculated with CV-B4 E2 mixed with various dilutions of serum or IgG samples, the enhancing activity was assayed through i) the antiviral activity titer of supernatants ii) the detection of intracellular viral RNA by RT-PCR iii) the level of infectious particles in supernatants.In most serum samples (76/105), neutralizing and enhancing activities were detected peaking between days 14 and 30 p.i and were higher in sera from mice inoculated with 2.10 6 TCID50 units than with lower doses. The enhancing activity was due to the IgG-enriched fraction of serum from CV-B4 E2 infected animals but not from control animals.These data show that IgG from immune mice can enhance the infection of splenocytes with CV-B4 E2 in vitro and open the way to explore whether such an enhancing activity can play a role in vivo.

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“…The discovery of IFIH1 as a risk gene for T1D has recently offered a feasible mechanistic explanation for this association [32,34]. Other support comes from ecological studies (polio hypothesis) [35], in vitro models (EV infection in islet cell cultures) [43], and mouse models of EV-caused diabetes [3]. However, the general consensus is that the currently existing evidence is not strong enough to prove causal relationship.…”

Section: How To Prove Causality?mentioning

confidence: 99%

“…During the last few decades, several different animal models have been developed to study the mechanisms of virusinduced diabetes. These studies have shown that several viruses have an ability to cause diabetes in animals by various mechanisms [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

Nurminen

Oikarinen²,

Hyöty

2012

Rev Diabet Stud

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Environmental factors play an important role in the pathogenesis of type 1 diabetes, and are attractive targets for preventive interventions. Several studies have shown that viruses can cause diabetes in animals, indicating their potential as candidates for environmental triggering agents. However, human studies have been hampered by the complex nature of the disease pathogenesis, leaving the question of viral etiology unanswered. Significant progress has recently been made in this field by searching for viruses within pancreatic tissue samples, and by carrying out prospective studies. Consequently, there is increasing evidence for a group of enteroviruses acting as possible environmental key triggers. In past studies, these viruses have been linked to type 1 diabetes. Recent studies have shown that they exert tropism to pancreatic islets, and that they are associated with the start of the beta-cell damaging process. Also, polymorphisms of the gene coding for the innate immune system sensor for enteroviruses (IFIH1) were found to modulate the risk of diabetes. Based on these findings, interest in the possible development of vaccines against these viruses has increased. However, even if enterovirus vaccines (polio vaccines) are effective and safe, we currently lack necessary information for the development of a vaccine against diabetogenic enteroviruses, e.g. regarding the identification of their specific serotypes and the causal relationship between these viruses and diabetes initiation. Ongoing research projects are currently addressing these questions, and will hopefully increase the consensus in this field. Also, new sequencing technologies will provide additional information about the whole virome, which could enable the discovery of new candidate viruses.

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Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models

Cited by 53 publications

References 124 publications

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

Immunoglobulin G-dependent enhancement of the infection with Coxsackievirus B4 in a murine system

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

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