Regulation of vitamin A metabolism during Schistosoma mansoni infection

描述(申请人提供)：蠕虫，如曼氏血吸虫，在某些宿主中非常有效地确定慢性感染，炎症病理有限，而在其他感染者中，它们可以导致严重的发病率，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曼氏葡萄球菌感染期间肝脏和肠道炎症是如何调节的。也许致病和共生之间的平衡取决于感染者的营养状况。然而，我们对支持蠕虫感染、营养状况和炎症反应之间关系的分子机制的了解非常有限。在蠕虫感染过程中，微量营养素如维生素A可能在调节炎性免疫反应中起关键作用。近年来，维生素A代谢和维甲酸(RA)在调节粘膜免疫中发挥着重要作用。Aldh1a2是调节肠道内抗原提呈细胞产生RA的主要酶。在曼氏血吸虫感染过程中，IL-4诱导的交替激活的巨噬细胞(AAM)在调节肝脏和肠道炎症中发挥重要作用，但其调节机制尚不清楚。在这里，我们假设通过AAM中Aldh1a2活性产生的RA在促进Th2反应中发挥重要作用，从而调节曼氏葡萄球菌感染过程中的肝脏和肠道炎症。我们的初步结果表明，在体外和体内，AAM在蠕虫感染期间上调了Aldh1a2的表达。通过用曼氏葡萄球菌感染维生素A缺乏的小鼠，我们发现Th2反应显著降低，而令人惊讶的是，我们看到调节性T细胞增加。我们先前已经证明，AAM可以将辅助性T细胞的分化途径从Th1细胞转向Th2细胞，因此RA可能提供了一种机制。由于Aldh1a2基因缺陷小鼠是胚胎致死的，我们还设计并培育了一种具有可诱导缺失系统的转基因报告鼠。我们还产生了细胞类型特异的Aldh1a2基因缺失的小鼠(巨噬细胞和树突状细胞)。在这项建议中，我们的具体目标是：(1)确定在体内曼氏血吸虫感染期间，AAM产生的RA是否在增强Th2反应中发挥作用；(2)确定AAM是否在体外通过RA影响辅助性T细胞的分化和功能；(3)鉴定新的小鼠品系，为Aldh1a2在曼氏血吸虫感染过程中促进Th2反应的细胞特异性作用提供遗传功能丧失证据。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代谢的能力来设计新的炎症调控方法。

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.