Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
Virol J. 2017 Dec 20;14(1):237. doi: 10.1186/s12985-017-0905-3.
An association between hepatitis C virus (HCV) and type 2 diabetes (T2D) is supported by numerous epidemiologic studies. We hypothesized that HCV could infect human pancreatic islet cells in vitro.
Measures of HCV RNA synthesis and protein production were used to evaluate HCV infection of pancreatic islets recovered from human donors.
Significant co-staining of insulin and the HCV entry factor CD81 was observed in pancreatic islets. Positive- and negative-sense HCV RNA were detected in HCV-exposed islets at days 1, 3, 7, and 14 post-infection. The HCV core and NS3 proteins were expressed and increased with time providing further evidence of viral replication. Interferon and an HCV polymerase inhibitor reduced viral replication in islet cells. In HCV-infected islets, TNFα levels were elevated at days 1, 3, and 7 post-infection, while IL-6 levels were elevated at day 1 but not days 3 or 7. Overall, the expression of miR-122 was low in islets compared to the Huh7.5 hepatocyte-derived cell line, although the relative expression of miR-122 increased in islet cells after viral infection (1, 6.63, and 5.83 at days 1, 3, and 7, respectively).
In this pilot study, viral infection was demonstrated in pancreatic islet cells from multiple donors using complementary measures of viral replication, thus providing evidence of in vitro infection. Altered cytokine expression may contribute to the development of insulin deficiency, and understanding the etiology of diabetes in individuals with HCV infection may facilitate the development of novel treatment modalities and prevention strategies. This in vitro system provides an important model for mechanistic studies of HCV-pancreas interactions and facilitates future studies of the potential impact of viral infection on islet cell function.
大量流行病学研究支持丙型肝炎病毒(HCV)与 2 型糖尿病(T2D)之间存在关联。我们假设 HCV 可以在体外感染人类胰岛细胞。
使用 HCV RNA 合成和蛋白产生的测量来评估从人类供体中回收的胰岛中的 HCV 感染。
在胰岛中观察到胰岛素和 HCV 进入因子 CD81 的明显共染色。在 HCV 暴露的胰岛中,在感染后第 1、3、7 和 14 天检测到正、负义 HCV RNA。HCV 核心和 NS3 蛋白表达并随时间增加,进一步证明了病毒复制。干扰素和 HCV 聚合酶抑制剂降低了胰岛细胞中的病毒复制。在 HCV 感染的胰岛中,TNFα 水平在感染后第 1、3 和 7 天升高,而 IL-6 水平在第 1 天升高,但在第 3 天或第 7 天没有升高。总体而言,与 Huh7.5 肝细胞系相比,miR-122 在胰岛中的表达较低,但在病毒感染后胰岛细胞中 miR-122 的相对表达增加(第 1、3 和 7 天分别为 1、6.63 和 5.83)。
在这项初步研究中,使用病毒复制的互补测量方法在来自多个供体的胰岛细胞中证明了病毒感染,从而提供了体外感染的证据。细胞因子表达的改变可能导致胰岛素缺乏的发生,了解 HCV 感染个体中糖尿病的病因可能有助于开发新的治疗方法和预防策略。该体外系统为 HCV-胰腺相互作用的机制研究提供了重要模型,并促进了未来对病毒感染对胰岛细胞功能潜在影响的研究。