Identifying a role for commensal bacteria on the liver immune priming environment

确定共生细菌在肝脏免疫启动环境中的作用

• 批准号: 8566554
• 负责人: Jean Publicover
• 金额: $ 14.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566554
• 关键词: Acute Hepatitis; Adult; Affect; Age; Antibiotics; Antibody Formation; Bacteria; Blood; CXCL13 gene; Cecum; Cells; Child; Chronic; Chronic Disease; Chronic Hepatitis; Cirrhosis; Data; Defensins; Dichloromethylene Diphosphonate; Disease; Disease Outcome; Distal; Double Stranded DNA Virus; Effectiveness; Environment; Exposure to; Gastrointestinal tract structure; Genes; Helper-Inducer T-Lymphocyte; Hepatic; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunity; Individual; Infant; Infection; Intestines; Kupffer Cells; Lead; Life; Liver; Liver diseases; Lymphocyte; Lymphoid; Malaria; Malignant neoplasm of liver; Microarray Analysis; Modeling; Molecular; Mus; Mutation; Newborn Infant; Outcome; Pathway interactions; Pattern recognition receptor; Pharmaceutical Preparations; Phase; Portal vein structure; Predisposition; Primary carcinoma of the liver cells; Production; Relative (related person); Ribosomal RNA; Risk; Risk Factors; Role; Series; Serum; Site; Splenocyte; Supplementation; System; T cell response; T-Lymphocyte; Time; Transgenic Mice; Viral; Viral Proteins; Virus; Virus Diseases; Water; Weaning; age related; antimicrobial peptide; commensal microbes; cost; experience; gastrointestinal; gastrointestinal system; genome-wide; killings; liver function; liver injury; macrophage; mesenteric vein; microbial; microbiome; monocyte; mouse model; pathogen; public health relevance; receptor; research study; response; young adult

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a partially double-stranded DNA virus that causes acute and hepatitis in humans. The risk of developing a chronic infection varies depending on the age at the time of exposure with a predisposition to chronic disease outcome when one is infected as an infant or child. Over 90% of infants exposed to HBV will become chronically infected with the virus. Of the 400 million individuals chronically infected with HBV, 25% will experience liver disease, cirrhosis and hepatocellular carcinoma. Alternatively, 95% of adults infected with HBV experience a self-limiting disease and life-long immunity. The steps that lead to the divergent responses are largely unknown. We have recently developed a transgenic mouse model of primary HBV infection that mimics key differences in HBV clearance and persistence in humans, including the age-related dichotomy in human HBV infection outcome. Data recently generated from our model, supported by our preliminary studies in humans, strongly implicate the relative maturity of immune priming within the liver microenvironment as a pivotal factor that guides HBV-specific immune responses. Using this model, we will investigate the key age- dependent cellular and molecular immune mechanisms in the liver that are responsible for the divergent disease outcomes. One difference we have identified is in the expression of the lymphocyte organizational molecule, CXCL13, on liver resident macrophages. We have already defined a role for this molecule and its receptor in HBV disease outcome. We will now identify the role of this molecule in priming and organizing lymphocytes and initiating immune responses in the liver by using mice with mutation in CXCL13 and mice treated with clodronate, a drug known to kill macrophages Another identified difference in adult and young mouse liver is the expression of many genes associated with microbial defenses. It is known that upon weaning, the commensal bacteria in the intestines changes dramatically in both young mice and infants. Additionally, blood from the mesenteric veins flows directly to the liver via the portal vein, allowing for the liver to be directly expose to bacterial products and potentially bacteria. Preliminary data from our model shows that manipulation of adult commensal bacteria by administering broad-spectrum antibiotic in the water of mice results in a change in HBV disease outcome from one of clearance to one of persistence. We now will identify if alterations of GI microbiota influences the liver priming environment and HBV disease outcome with a series of depletion and supplementation experiments. We will also identify age-related differences in presence or abundance of distinct species of bacteria that might direct the HBV response or alter the immune priming environment in the liver. We also will identify if changes in commensal bacteria or exposure to bacterial products affects the expression of CXCL13 or other molecules associated with maturation, on macrophages in the liver.

描述（由申请人提供）：丙型肝炎病毒（HBV）是一种部分双链DNA病毒，可引起人类急性和肝炎。发生慢性感染的风险取决于暴露时的年龄，当一个人被感染为婴儿或儿童时，慢性疾病结局倾向。暴露于HBV的婴儿中有超过90％会长期感染该病毒。在长期感染HBV的4亿个人中，有25％将患有肝病，肝硬化和肝细胞癌。另外，感染HBV的成年人中有95％患有自限性疾病和终身免疫力。导致不同响应的步骤在很大程度上未知。我们最近开发了一种原发性HBV感染的转基因小鼠模型，该模型模仿了人类HBV清除和持久性的关键差异，包括人类HBV感染结果中与年龄相关的二分法。最近从我们的模型中产生的数据得到了我们在人类的初步研究的支持，这强烈暗示了肝微环境中免疫启动的相对成熟度是指导HBV特异性免疫反应的关键因素。使用该模型，我们将研究肝脏中关键年龄依赖性的细胞和分子免疫机制，这些机制负责发散疾病结果。我们确定的一个差异是淋巴细胞组织分子CXCL13在肝脏常驻巨噬细胞上的表达。我们已经定义了该分子及其受体在HBV疾病结局中的作用。现在，我们将通过在CXCL13中使用与突变的小鼠和用克洛德膦酸盐治疗的小鼠使用小鼠在肝脏中启动淋巴细胞中该分子的作用，并启动肝脏中的免疫反应，该药物已知杀死巨噬细胞的药物，杀死巨噬细胞的另一种鉴定在成人和年轻小鼠肝脏中的差异是许多与麦微生物防御相关的基因的表达。众所周知，断奶后，肠道中的共生细菌在幼鼠和婴儿中都发生了巨大变化。此外，肠系膜静脉的血液通过门静脉直接流向肝脏，使肝脏直接暴露于细菌产物和潜在的细菌。来自我们模型的初步数据表明，通过在小鼠水中施用广谱抗生素来操纵成人共生细菌，从而导致HBV疾病结果从清除率的一种变为持久性之一。现在，我们将通过一系列耗竭和补充实验来确定胃肠道菌群的改变是否会影响肝脏启动环境和HBV疾病结果。我们还将确定可能导致HBV反应或改变肝脏中的免疫启动环境的不同细菌的存在或丰富的年龄相关差异。我们还将确定共生细菌的变化或暴露于细菌产物会影响肝脏中巨噬细胞对CXCL13的表达或与成熟相关的其他分子的表达。