Regulation of vitamin A metabolism during Schistosoma mansoni infection

曼氏血吸虫感染期间维生素A代谢的调节

基本信息

批准号：
8227934
负责人：
Png Loke
金额：
$ 42.25万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8227934
关键词：
Affect Antigen-Presenting Cells Cell Differentiation process Cell physiology Cells Cessation of life Chronic Coculture Techniques Dendritic Cells Dichloromethylene Diphosphonate Disease Enzymes Equilibrium Feedback Genes Genetic Goals Health Helminths Human ITGAX gene Immune Immune response In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine Interleukin-4 Internal Ribosome Entry Site Intervention Intestines Knock-in Mouse Knowledge Kupffer Cells Lamina Propria Lead Liposomes Liver Mediating Metabolism Micronutrients Molecular Morbidity - disease rate Mouse Strains Mucosal Immunity Mus Nutritional status Pathogenesis Pathology Pathway interactions Play Process Production Regulation Regulatory T-Lymphocyte Reporter Retinoic Acid Receptor Role Schistosoma mansoni Schistosoma mansonii infection Schistosomiasis Splenocyte Symbiosis System T-Lymphocyte Testing Th2 Cells Transgenic Organisms Tretinoin Vitamin A Vitamin A Deficiency cell type cytokine design egg in vivo loss of function macrophage mortality novel therapeutic intervention public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Helminths such as Schistosoma mansoni are remarkably efficient at establishing chronic infections with limited inflammatory pathology in some of their hosts, while in other infected people they can cause severe morbidity and they are a major health problem worldwide. Our long-term goal is to understand how liver and intestinal inflammation is regulated during S. mansoni infection. Perhaps the balance between pathogenesis and symbiosis is dependent on the nutritional status of infected individuals. However, we have a very limited understanding of the molecular mechanisms that underpin the relationship between helminth infections, nutritional status and inflammatory responses. Micronutrients such as vitamin A may play a critical role in regulating the inflammatory immune response during helminth infection. Recently, vitamin A metabolism and retinoic acid (RA) has emerged to be important in regulating mucosal immunity. Aldh1a2 is the major enzyme regulating RA production by antigen presenting cells in the gut. Alternatively activated macrophages (AAM) induced by IL-4 have been shown to play an important role in regulating liver and intestinal inflammation during S. mansoni infection, although the mechanism of regulation is not known. Here, we hypothesize that RA production via Aldh1a2 activity in AAM plays an important role in promoting Th2 responses and hence regulating liver and intestinal inflammation during S. mansoni infection. We have preliminary results showing that Aldh1a2 is upregulated by AAM in vitro and in vivo during helminth infection. By infecting vitamin A deficient mice with S. mansoni, we have found that Th2 responses are strikingly reduced, whereas surprisingly, we see an increase in regulatory T cells. We have previously shown that AAMs could bias T helper cell differentiation pathways from Th1 to Th2 cells and RA might therefore provide a mechanism. Since the Aldh1a2 deficient mice are embryonically lethal, we have also designed and generated a transgenic reporter mouse with an inducible deletion system. We are also generating mice with cell type specific (macrophage and dendritic cell) deletions of the Aldh1a2 gene. In this proposal, our specific aims are: (1) to determine if RA production by AAM plays a role in enhancing Th2 responses during in vivo S. mansoni infection; (2) to determine if AAM can influence T helper cell differentiation and function through RA in vitro; (3) to characterize new mouse strains that will provide genetic loss of function evidence for cell specific roles of Aldh1a2 in promoting Th2 responses during S. mansoni infection. The results of these studies will provide us with a framework to devise new ways of regulating inflammation through manipulating the capacity of macrophages to control vitamin A metabolism. PUBLIC HEALTH RELEVANCE: Schistosomiasis affects 200 million people worldwide and is associated with serious morbidity and mortality, causing more than 200,000 deaths annually. Many of these people also suffer from Vitamin A deficiency, which has important effects on the immune response. The goals of this proposal are to understand how Vitamin A metabolites are regulated during infection and apply this knowledge towards designing better interventional strategies to reduce the pathogenesis of schistosomiasis and other inflammatory diseases.

描述（由申请人提供）：诸如Mansoni血吸虫之类的蠕虫分子在建立一些宿主的炎症病理学有限的慢性感染方面非常有效，而在其他受感染的人中，它们可能引起严重的发病率，并且在全球范围内是主要的健康问题。我们的长期目标是了解曼氏链球菌感染期间如何调节肝脏和肠炎。发病机理和共生之间的平衡可能取决于感染个体的营养状况。但是，我们对基于蠕虫感染，营养状况和炎症反应之间关系的分子机制的理解非常有限。维生素A等微量营养素在调节蠕虫感染期间的炎症免疫反应中可能起关键作用。最近，维生素A代谢和视黄酸（RA）在调节粘膜免疫方面已经重要。 ALDH1A2是调节肠中抗原产生RA产生的主要酶。否则，IL-4诱导的活化的巨噬细胞（AAM）已被证明在调节曼氏链球菌感染期间在调节肝脏和肠炎中起重要作用，尽管调节机制尚不清楚。在这里，我们假设AAM中通过ALDH1A2活性产生的RA在促进Th2反应中起着重要作用，因此调节曼氏链球菌感染期间的肝脏和肠炎。我们的初步结果表明，在蠕虫感染期间，AAM在体外和体内被AAM上调。通过用曼氏链球菌感染维生素A缺乏小鼠，我们发现TH2反应大大降低，而令人惊讶的是，我们看到调节性T细胞的增加。我们先前已经表明，AAM可能会偏向从Th1到Th2细胞的T辅助细胞分化途径，因此RA可能会提供一种机制。由于ALDH1A2缺乏的小鼠具有胚胎致死性，因此我们还设计并生成了具有诱导型缺失系统的转基因记者小鼠。我们还生成具有细胞类型特异性的小鼠（巨噬细胞和树突状细胞）的缺失。在此提案中，我们的具体目的是：（1）确定AAM的RA产生是否在增强体内S. Mansoni感染期间的Th2反应中发挥作用；（2）确定AAM是否可以通过体外RA影响T辅助细胞分化和功能；（3）表征新的小鼠菌株，这些菌株将为ALDH1A2在促进曼氏链球菌感染期间促进Th2反应中的细胞特异性作用提供遗传丧失。这些研究的结果将为我们提供一个框架，以通过操纵巨噬细胞控制维生素A代谢的能力来设计新方法来调节炎症。公共卫生相关性：血吸虫病在全球范围内影响2亿人，并与严重的发病率和死亡率有关，每年造成超过200,000人死亡。这些人中的许多人也患有维生素A缺乏症，这会对免疫反应产生重要影响。该提案的目标是了解如何调节维生素A代谢物在感染过程中，并将这些知识应用于设计更好的介入策略，以减少血吸虫病和其他炎症性疾病的发病机理。