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

• 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
• 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

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）：蠕虫如曼氏血吸虫（Schistosoma mansoni）在其某些宿主中建立慢性感染方面非常有效，具有有限的炎症病理学，而在其他感染者中，它们可导致严重的发病率，并且它们是世界范围内的主要健康问题。我们的长期目标是了解S.曼氏感染。也许致病和共生之间的平衡取决于受感染个体的营养状况。然而，我们有一个非常有限的了解的分子机制，支持蠕虫感染，营养状况和炎症反应之间的关系。营养素如维生素A可能在蠕虫感染期间调节炎症免疫反应中起关键作用。 最近，维生素A代谢和视黄酸（RA）已成为重要的调节粘膜免疫。Aldh 1a 2是调节肠道中抗原呈递细胞产生RA的主要酶。IL-4诱导的选择性激活的巨噬细胞（AAM）在S. mansoni感染，尽管调控机制尚不清楚。在这里，我们假设RA生产通过Aldh 1a 2活性在AAM中起着重要的作用，促进Th 2反应，从而调节肝脏和肠道炎症在S。曼氏感染。 我们有初步的结果表明，Aldh 1a 2是上调AAM在体外和体内蠕虫感染过程中。通过用S. mansoni，我们发现Th 2应答显著降低，而令人惊讶的是，我们看到调节性T细胞增加。我们以前已经表明，AAMs可以偏置辅助性T细胞分化途径从Th 1到Th 2细胞和RA可能因此提供了一种机制。由于Aldh 1a 2缺陷小鼠是胚胎致死的，我们还设计并产生了具有诱导缺失系统的转基因报告小鼠。我们还产生了细胞类型特异性（巨噬细胞和树突状细胞）缺失Aldh 1a 2基因的小鼠。 在本研究中，我们的具体目标是：（1）确定AAM产生的RA是否在体内S.曼氏感染;（2）确定AAM是否可以通过RA影响体外T辅助细胞分化和功能;（3）表征新的小鼠品系，其将为Aldh 1a 2在S.曼氏感染。这些研究的结果将为我们提供一个框架，通过操纵巨噬细胞控制维生素A代谢的能力来设计调节炎症的新方法。 公共卫生相关性：血吸虫病影响全世界2亿人，并与严重的发病率和死亡率有关，每年造成20多万人死亡。其中许多人还患有维生素A缺乏症，这对免疫反应有重要影响。该提案的目标是了解维生素A代谢物在感染过程中是如何调节的，并将这些知识应用于设计更好的干预策略，以减少血吸虫病和其他炎症性疾病的发病机制。