Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Nyalwidhe, Julius O.; Gallagher, Glen R.; Glenn, Lindsey; Morris, Margaret A.; Vangala, Pranitha; Jurczyk, Agata; Bortell, Rita; Harlan, David M.; Wang, Jennifer; Nadler, Jerry L.

doi:10.1210/js.2017-00278

Cited by 19 publications

(21 citation statements)

References 47 publications

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“…Cells were also collected at 24, 48, and 72 h for total RNA and protein. Primary human islets were plated and infected as previously described [12], with cells being collected at 72 h for protein.…”

Section: Infectionmentioning

confidence: 99%

“…Samples were processed as previously described [12]. In brief, SC-β cells were harvested and washed three times with PBS prior to processing for mass spectrometry.…”

Section: Proteomicsmentioning

confidence: 99%

“…Of note, class I MHC molecules including HLA-A and HLA-B, as well as the antigen-processing proteins B2M and TAP1 [24], were all increased following CVB infection. We previously reported such proteomic changes in cultured primary human islets infected with CVB [12]. We used upstream regulator analysis and ingenuity pathway analysis (IPA) to analyze SC-β cells with and without CVB infection.…”

Section: Proteomic Analysis Revealed Activation Of Inflammatory Pathwmentioning

confidence: 99%

“…Genome-wide association studies show associations between the risk for human T1D and polymorphisms in interferon (IFN) response genes in the general population [4,[9][10][11]. We and others have reported that inflammatory cytokines and type I IFN pathways are induced following treatment of human islets with coxsackie B virus (CVB)4 ex vivo [12][13][14] and engrafted human islets in vivo [15]. Altogether, such findings suggest a potential relationship between virus infection, IFN induction, and development of autoimmunity.…”

Section: Introductionmentioning

confidence: 96%

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Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge

et al. 2020

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Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant β-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived β (SC-β) cells are insulin-producing cell clusters that closely resemble native β cells. To better understand the events precipitated by enteroviral infection of β cells, we investigated transcriptional and proteomic changes in SC-β cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-β cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following infection, and combined transcriptional and proteomic analysis revealed activation of innate immune pathways, including type I interferon (IFN), IFN-stimulated genes, nuclear factor-kappa B (NF-κB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-β cells was impaired. These transcriptional, proteomic, and functional findings are in agreement with responses in primary human islets infected with CVB ex vivo. Human SC-β cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-β cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.

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Section: Infectionmentioning

confidence: 99%

“…Samples were processed as previously described [12]. In brief, SC-β cells were harvested and washed three times with PBS prior to processing for mass spectrometry.…”

Section: Proteomicsmentioning

confidence: 99%

Section: Proteomic Analysis Revealed Activation Of Inflammatory Pathwmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge

et al. 2020

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“…In the present study, we treated EndoC-βH1 cells with polyinosinic-polycytidylic acid (PolyI:C). PolyI:C is a synthetic dsRNA recognized in the cytoplasm by dsRNA pattern recognition receptors (PRRs) that mimics, at least in part, the effects of viral infection on β cells (16,17). We demonstrated that human β cells dedifferentiate following PolyI:C treatment and enteroviral infection.…”

Section: Introductionmentioning

confidence: 99%

Virus-like infection induces human β cell dedifferentiation

Oshima¹,

Knoch²,

Diedisheim³

et al. 2018

JCI Insight

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Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in β cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human β cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.

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