Obesity associated viral pathogenesis

肥胖相关的病毒发病机制

• 批准号: 10231137
• 负责人: JASON Kyle WHITMIRE
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231137
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Affect; Anti-Inflammatory Agents; Antigens; Antiviral Agents; Blood; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Cell Count; Cell Proliferation; Cell physiology; Cells; Child; Chronic; Cytokine Receptors; Developing Countries; Disease; Fatty Acids; Frequencies; Goals; Health; Human; Hypocalcemia result; Immune; Immune response; Immune system; Immunity; Incidence; Individual; Infection; Inflammatory; Interferons; Learning; Leptin; Lipase; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Maintenance; Mediating; Memory; Mus; Necrosis; Obese Mice; Obesity; Outcome; Pancreas; Pancreatitis; Pathogenesis; Phenotype; Production; Role; Site; Systemic infection; T cell differentiation; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Temperature; Therapeutic; Time; Tissues; Translating; Vaccines; Viral Pathogenesis; Virus; Virus Diseases; Weight; adiponectin; calcium supplementation; cell motility; cell type; chemokine; chemokine receptor; chronic infection; cytokine; diet-induced obesity; effector T cell; epidemiology study; exhaustion; experimental study; functional decline; human subject; improved; in vivo; interest; mouse model; obese person; phenotypic biomarker; recruit; transcriptome sequencing; vaccine effectiveness; vaccine efficacy

PROJECT SUMMARY It is estimated that nearly 10% of adults globally are obese and it is a common problem in children. The incidence of obesity continues to grow in the US and in developing nations. There is an urgent need to understand how obesity affects immunity to infections. T cells are a principle cell type responsible for protection against virus infections, and there is evidence from epidemiological studies and in mouse models that obesity reduces immune protection against infections and vaccine efficacy. Our goal is to use a mouse model of virus infection to interrogate how adipose tissue and obesity affect T cell responses to infection. Lymphocytic choriomeningitis virus (LCMV) causes a systemic infection but is resolved within a week by CD8+ T cells. Many of these virus-reactive T cells go on to establish a pool of memory T cells that expedite protection against re-infection. Recently, we discovered that very large frequencies of virus-specific memory T cells reside within adipose tissue. These cells are phenotypically and functionally distinct from memory T cells in lymphoid tissues. Interestingly, diet-induced obesity increased the abundance of these adipose memory T cells, however, immune obese mice developed severe T cell-mediated pathogenesis upon re-infection. The pathogenesis included necrosis of adipose and pancreatic tissues, elevated lipase levels, and reduced levels of circulating calcium. The experiments outlined in this application will allow us to better understand how obesity and adipose tissue interactions affect T cell memory and immune defenses. In Aim1, we will learn how memory T cells develop and are maintained in adipose tissue. In Aim2, we investigate how obesity and adipose cytokines alter memory T cell number, function and distribution. In Aim3, we will determine which T cell effector function causes lethal outcomes during obesity and whether lipase inhibition or calcium supplementation can be used to protect against lethality. These efforts will support our long-term goal to better understand how T cell-adipose tissue interactions worsen outcomes to infection. We plan to eventually translate these findings into therapies for human subjects with weight disorders.

项目摘要 据估计，全球近10%的成年人肥胖，这是儿童的常见问题。的 肥胖症的发病率在美国和发展中国家持续增长。迫切需要 了解肥胖如何影响对感染的免疫力。T细胞是一种主要的细胞类型， 预防病毒感染，流行病学研究和小鼠模型中有证据表明 肥胖会降低对感染的免疫保护和疫苗的效力。我们的目标是用鼠标 病毒感染模型，以询问脂肪组织和肥胖如何影响T细胞对感染的反应。 淋巴细胞性脉络丛脑膜炎病毒（LCMV）引起全身感染，但在一周内通过CD 8 + T细胞。这些病毒反应性T细胞中的许多细胞继续建立一个记忆T细胞库，加速保护 防止再次感染最近，我们发现病毒特异性记忆T细胞 存在于脂肪组织中。这些细胞在表型和功能上与记忆T细胞不同， 淋巴组织有趣的是，饮食引起的肥胖增加了这些脂肪记忆T的丰度 然而，免疫性肥胖小鼠在再感染时发展了严重的T细胞介导的发病机制。的 发病机制包括脂肪和胰腺组织坏死，脂肪酶水平升高， 循环中的钙本申请中概述的实验将使我们更好地了解 肥胖和脂肪组织相互作用影响T细胞记忆和免疫防御。在Aim 1中，我们将学习如何 记忆T细胞在脂肪组织中发育和维持。在目标2中，我们研究了肥胖和 脂肪细胞因子改变记忆T细胞的数量、功能和分布。在目标3中，我们将确定哪个T 细胞效应器功能导致肥胖期间的致命结果， 补充剂可用于防止致死性。这些努力将支持我们的长期目标， 了解T细胞-脂肪组织相互作用如何恶化感染结果。我们计划最终 将这些发现转化为对患有体重障碍的人类受试者的治疗。