Program in Molecular Medicine; Department of Medicine; Department of Bioinformatics and Integrative Biology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Bioinformatics | Cell Biology | Computational Biology | Endocrine System Diseases | Immune System Diseases | Immunology and Infectious Disease | Nutritional and Metabolic Diseases | Virology | Viruses
Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant beta-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived beta (SC-beta) cells are insulin-producing cell clusters that closely resemble native beta cells. To better understand the events precipitated by enteroviral infection of beta cells, we investigated transcriptional and proteomic changes in SC-beta cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-beta 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-kappaB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-beta 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-beta cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-beta cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.
coxsackie B virus, beta cells, type 1 diabetes
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DOI of Published Version
Nyalwidhe JO, Jurczyk A, Satish B, Redick S, Qaisar N, Trombly MI, Vangala P, Racicot R, Bortell R, Harlan DM, Greiner DL, Brehm MA, Nadler JL, Wang JP. Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge. Microorganisms. 2020 Feb 20;8(2):E295. doi: 10.3390/microorganisms8020295. PMID: 32093375. Link to article on publisher's site
Nyalwidhe JO, Jurczyk A, Satish B, Redick SD, Qaisar N, Trombly MI, Vangala P, Racicot R, Bortell R, Harlan DM, Greiner DL, Brehm MA, Nadler JL, Wang JP. (2020). Proteomic and Transcriptional Profiles of Human Stem Cell-Derived beta Cells Following Enteroviral Challenge. Open Access Articles. https://doi.org/10.3390/microorganisms8020295. Retrieved from https://escholarship.umassmed.edu/oapubs/4163
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