Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection

Michaux, Hélène; Halouani, Aymen; Trussart, Charlotte; Renard, Chantal; Jaïdane, Hela; Martens, Henri; Geenen, Vincent; Hober, Didier

doi:10.3390/microorganisms9020402

Cited by 3 publications

(5 citation statements)

References 64 publications

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“…CVB4 can infect mice following intraperitoneal or oral inoculation of the virus, as it has been previously reported by our team and others [67,68,75]. In TECs obtained from outbred mice infected intraperitoneally with CVB4, the dominant IGF2 transcript V3 and thymic IGF2 protein level had decreased [89]. Thus, CVB4 infection can modulate the expression of IGF2 in a model of TECs in vitro and can downregulate the IGF2 V3 expression and protein synthesis in vivo.…”

Section: Coxsackievirus B4 the Thymus Gland And Type 1 Diabetessupporting

confidence: 71%

“…This transcription factor regulates the promoter and mRNA expression of IGF2 in humans and mice. Interestingly, the phosphorylation of STAT3 decreased in MTE4-14 cells infected with CVB4 [89]. These observations suggest that the loss of STAT3 phosphorylation in TECs could result in a decrease in IGF2 P3 promoter activity, and consequently, in the decrease of IGF2 expression.…”

Section: Coxsackievirus B4 the Thymus Gland And Type 1 Diabetesmentioning

confidence: 80%

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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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Section: Coxsackievirus B4 the Thymus Gland And Type 1 Diabetessupporting

confidence: 71%

Section: Coxsackievirus B4 the Thymus Gland And Type 1 Diabetesmentioning

confidence: 80%

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 effect of CV-B4 in utero infection of the thymus on transcription factors and autoantigens expression, especially in TECs for which we could not prove the infection, might be indirect via epigenetic regulation [ 60 , 61 , 62 ]. Similar to our results, a downregulation of IGF2 expression in enriched TECs of mice following CV-B4 infection was observed, despite the absence of a proof of infection of those cells, which raises this hypothesis [ 38 ]. Indeed, demethylation of DNA was one of the suggested mechanisms of epigenetic control of autoantigens expression in murine mTECs, such as Igf2 [ 63 ].…”

Section: Discussionsupporting

confidence: 90%

“…Nevertheless, we failed to detect CV-B4 RNA in the thymus of fetuses harvested 48 h after inoculation (data not shown). In a recent study, viral RNA was detected only in the pancreas of CV-B4-inoculated Swiss mice, but not in sorted total thymic cells isolated after enzymatic digestion [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus

et al. 2021

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Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset.

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“…The long-term presence of viral RNA in the pancreas of CD-1 mice infected with CVB4 E2 was associated with chronic islet inflammation, increased islet autoantibodies and development of diabetes mellitus 6–12 months after infection 29 . The infection of Swiss albino mice with CVB4 alters Igf2 expression in TECs, which leads to a decrease in pro-IGF2 protein 119 . Furthermore, deficient Igf2 expression in the thymus has been implicated in the development of autoimmune diabetes mellitus in BBDP rats 120 .…”

Section: Experimental Evidence For Cvb Persistencementioning

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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Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection

Cited by 3 publications

References 64 publications

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

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

Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

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