Enteroviruses and Type 1 Diabetes Mellitus: An Overlooked Relationship in Some Regions

Sané, Famara; Lazrek, Mouna; Nekoua, Magloire Pandoua; Badia-Boungou, Francis; Alidjinou, Enagnon Kazali; Hober, Didier

doi:10.3390/microorganisms8101458

Cited by 13 publications

(13 citation statements)

References 60 publications

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“…Epidemiological and clinical evidence in favour of enterovirus-associated pathogenesis of T1DM have been previously discussed and are based on findings in many parts of the world that enteroviral components (VP1 capsid protein and/or RNA) in serum, monocytes, gut mucosa and pancreas, and circulating anti-enterovirus immunoglobulins (IgM, IgG and IgA), are more frequently detected in patients with T1DM than in healthy individuals 11 , 19 , 39 – 41 . The significance of the association between the presence of enteroviral infection markers in various human biological samples and the risk of developing islet autoimmunity or T1DM was confirmed in Europe, Africa, Asia, Australia, North America and South America in two case–control meta-analyses of 24 and 38 studies including 4,448 and 5,921 participants, respectively 16 , 42 .…”

Section: Enterovirus Persistence In T1dmmentioning

confidence: 99%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

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Section: Enterovirus Persistence In T1dmmentioning

confidence: 99%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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“…The genetic background alone cannot explain all T1D cases [51]. For example, the concordance index of T1D in monozygotic twins is less than 50%, and there is a huge variation in T1D incidence in different regions globally [4,52]. Infections, immunotherapy, endocrine disruptors and sex steroids, nutrition and vitamin deficiency, gut microbiota, and stress have been suggested as important environmental factors that may contribute to autoimmune diseases [48,49].…”

Section: Coxsackievirus B4 the Thymus Gland And Type 1 Diabetesmentioning

confidence: 99%

“…T1D is a multifactorial disease leading to β-cell destruction that disrupts insulin production. EV infections have been proposed as an important environmental factor with a major role in T1D pathogenesis [4]. Stewart et al provide a link between viral infection and autoimmune diabetes by developing transgenic mice in which the insulinproducing β-cells express interferon-α (IFN-α).…”

Section: Introductionmentioning

confidence: 99%

Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

et al. 2021

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The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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“…A body of circumstantial evidence supports this hypothesis 13 – 20 and much of this has emerged from the detailed study of human pancreas samples recovered post mortem 11 – 16 . Collectively, however, this work has also prompted a further and much less anticipated conclusion by indicating that the enteroviral infections present in beta-cells may develop in an atypical, persistent, form 15 – 20 . Verification of this hypothesis would offer new insights into the role of environmental factors in the development of type 1 diabetes but it has been difficult to evaluate fully using human tissue samples because they present the disease process at only a single point in time.…”

Section: Introductionmentioning

confidence: 96%

Investigation of the utility of the 1.1B4 cell as a model human beta cell line for study of persistent enteroviral infection

Chaffey

Young

Kaiyven

et al. 2021

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The generation of a human pancreatic beta cell line which reproduces the responses seen in primary beta cells, but is amenable to propagation in culture, has long been an important goal in diabetes research. This is particularly true for studies focussing on the role of enteroviral infection as a potential cause of beta-cell autoimmunity in type 1 diabetes. In the present work we made use of a clonal beta cell line (1.1B4) available from the European Collection of Authenticated Cell Cultures, which had been generated by the fusion of primary human beta-cells with a pancreatic ductal carcinoma cell, PANC-1. Our goal was to study the factors allowing the development and persistence of a chronic enteroviral infection in human beta-cells. Since PANC-1 cells have been reported to support persistent enteroviral infection, the hybrid 1.1B4 cells appeared to offer an ideal vehicle for our studies. In support of this, infection of the cells with a Coxsackie virus isolated originally from the pancreas of a child with type 1 diabetes, CVB4.E2, at a low multiplicity of infection, resulted in the development of a state of persistent infection. Investigation of the molecular mechanisms suggested that this response was facilitated by a number of unexpected outcomes including an apparent failure of the cells to up-regulate certain anti-viral response gene products in response to interferons. However, more detailed exploration revealed that this lack of response was restricted to molecular targets that were either activated by, or detected with, human-selective reagents. By contrast, and to our surprise, the cells were much more responsive to rodent-selective reagents. Using multiple approaches, we then established that populations of 1.1B4 cells are not homogeneous but that they contain a mixture of rodent and human cells. This was true both of our own cell stocks and those held by the European Collection of Authenticated Cell Cultures. In view of this unexpected finding, we developed a strategy to harvest, isolate and expand single cell clones from the heterogeneous population, which allowed us to establish colonies of 1.1B4 cells that were uniquely human (h1.1.B4). However, extensive analysis of the gene expression profiles, immunoreactive insulin content, regulated secretory pathways and the electrophysiological properties of these cells demonstrated that they did not retain the principal characteristics expected of human beta cells. Our data suggest that stocks of 1.1B4 cells should be evaluated carefully prior to their use as a model human beta-cell since they may not retain the phenotype expected of human beta-cells.

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Enteroviruses and Type 1 Diabetes Mellitus: An Overlooked Relationship in Some Regions

Cited by 13 publications

References 60 publications

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Investigation of the utility of the 1.1B4 cell as a model human beta cell line for study of persistent enteroviral infection

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