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: 8604128
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604128
• 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; liver inflammation; 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.

描述（由申请人提供）：像曼氏血吸虫这样的蠕虫在一些宿主体内具有非常有效的慢性感染和有限的炎症病理，而在其他被感染的人群中，它们可以导致严重的发病率，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mansoni感染期间肝脏和肠道炎症是如何调节的。也许发病机制和共生关系之间的平衡取决于受感染个体的营养状况。然而，我们对支撑蠕虫感染、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。微量营养素如维生素A可能在调节蠕虫感染期间的炎症免疫反应中发挥关键作用。近年来，维生素A代谢和视黄酸（RA）在调节粘膜免疫中起着重要作用。Aldh1a2是调节肠道中抗原呈递细胞产生RA的主要酶。IL-4诱导的选择性活化巨噬细胞（AAM）在mansoni感染期间调节肝脏和肠道炎症中发挥重要作用，尽管其调节机制尚不清楚。在这里，我们假设通过AAM中Aldh1a2活性产生RA在促进Th2反应中起重要作用，从而调节mansoni感染期间的肝脏和肠道炎症。我们的初步结果表明，在体外和体内，AAM在蠕虫感染过程中上调了Aldh1a2。通过让缺乏维生素A的小鼠感染S. mansoni，我们发现Th2反应显著减少，而令人惊讶的是，我们看到调节性T细胞增加。我们之前的研究表明，AAMs可以使辅助性T细胞从Th1细胞向Th2细胞分化，因此RA可能提供了一种机制。由于Aldh1a2缺陷小鼠具有胚胎致死性，我们还设计并产生了一种具有诱导缺失系统的转基因报告小鼠。我们还培养了具有特定细胞类型（巨噬细胞和树突状细胞）的Aldh1a2基因缺失的小鼠。在本研究中，我们的具体目标是：(1)确定AAM产生RA是否在体内曼氏链球菌感染过程中增强Th2反应中起作用；(2)确定AAM是否可以通过RA体外影响T辅助细胞的分化和功能；(3)表征新的小鼠品系，这些品系将为Aldh1a2在mansoni感染期间促进Th2反应的细胞特异性作用提供遗传功能丧失的证据。这些研究的结果将为我们提供一个框架，设计通过操纵巨噬细胞控制维生素a代谢的能力来调节炎症的新方法。