Innate mechanisms for virus-induced diabetes

项目摘要/摘要 病毒感染与1型糖尿病(T1D)的发展有关。研究病毒- 由于宿主物种的差异，实验室动物的相关糖尿病一直是有问题的 对包括柯萨奇B病毒(CVB)在内的病毒病原体的易感性和免疫反应。为了更好地 评估CVB对人类T1D的影响，我们在免疫缺陷小鼠中建立了病毒感染模型 携带对血糖控制至关重要的人类胰岛移植物。在该模型中，感染CVB4株JVB 导致近一半的受感染动物患上糖尿病。含有病毒的感染小鼠的人胰岛移植 RNA，表达病毒蛋白，与胰岛移植物相比，表现出轻度到中度的细胞变性 来自模拟感染的小鼠。人类移植物的基因表达谱显示干扰素的诱导- 刺激基因和内质网应激，以及胰岛素和转录因子Pdx1表达下降。 在拟议的研究中，我们将使用这种人类胰岛移植的小鼠模型以及补充研究。 在培养的人β细胞中描述CVB后β细胞功能障碍和/或死亡的机制 感染。我们将比较不同的CVB毒株以及突变病毒，以确定哪些病毒更多或更多 糖尿病诱因较少。最终目标是设计一种针对TID的预防性疫苗。

Project Summary/Abstract Viral infection has been associated with the development of type 1 diabetes (T1D). Studying virus- associated diabetes in laboratory animals has been problematic due to differences in host species-specific susceptibility and immune responses to viral pathogens including Coxsackie B virus (CVB). In order to better evaluate CVB's impact on causing human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts that are crucial for glycemic control. In this model, infection with CVB4 strain JVB leads to diabetes in nearly half of all infected animals. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and exhibited mild to moderate cell degeneration compared to the islet grafts from mock-infected mice. Gene expression profiles from the human grafts revealed induction of interferon- stimulated genes and ER stress, as well as decreased expression of insulin and the transcription factor Pdx1. In the proposed study, we will use this human islet-engrafted mouse model along with complementary studies in cultured human beta cells to delineate the mechanisms of beta cell dysfunction and/or death following CVB infection. We will compare different CVB strains as well as mutant viruses to identify which viruses are more or less diabetogenic. The ultimate goal is to design a preventive vaccine against TID.