Vitamin A mediated protection from gastrointestinal infection

 描述（由申请人提供）：营养状况，免疫功能和肠道微生物群都是保护肠道感染的因素。啮齿类柠檬酸杆菌引起小鼠的胃肠道（GI）感染，其模拟人类中肠致病性大肠杆菌的食源性感染。该项目的目标是确定维生素A缺乏症和维生素A代谢物维甲酸（RA）的干预如何提供对C的保护。啮齿类感染我们的初步数据表明，维生素A缺乏（A-）导致慢性C。啮齿类感染，在40%的A-小鼠中是致命的。相反，长期以来， 用RA治疗的感染的A-小鼠能够清除感染。在这里，我们将确定维生素A缺乏导致无法清除感染和RA有助于解决这种GI感染的机制。我们假设维生素A/RA是由以下介导的保护所必需的：1）T细胞，2）肠上皮细胞，和3）维持肠道微生物群的稳态。我们的方法包括使用维生素A缺乏和充足的小鼠，以及用RA治疗的A-小鼠，以及使用3种新的动物模型：在T细胞或肠上皮细胞中缺乏类维生素A信号传导的小鼠，以及无菌小鼠。具有组织特异性显性负性RA受体的小鼠将用于选择性地阻断T细胞（目的1）和肠上皮细胞（目的2）中的类维生素A信号传导，以探索维生素A控制GI感染的机制。使用的方法将包括生物发光C的成像。啮齿动物肠道细菌定位和免疫学和组织学方法来表征细胞类型，功能和组织病理学。此外，无菌小鼠将用于确定微生物群在维生素A介导的抗C保护中的作用。啮齿动物（目标3）。预计C.啮齿类感染（清除）将需要肠T细胞和上皮中的维生素A信号传导以及维持肠道微生物群的稳态。了解维生素A缺乏和RA干预调节这些过程的机制对于告知公共卫生信息以及可能使用维生素A/RA保护免受GI感染至关重要。

 DESCRIPTION (provided by applicant): Nutritional status, immune function, and the gut microbiota are all factors in protection against gut infection. Citrobacter rodentium causes a gastrointestinal (Gl) infection in mice that models foodborne infections with enteropathogenic Escherichia coli in humans. The goal of this project is to determine how vitamin A deficiency worsens and intervention with the vitamin A metabolite retinoic acid (RA) affords protection against C. rodentium infection. Our preliminary data show that vitamin A deficiency (A-) resulted in a chronic C. rodentium infection that was lethal in 40% of the A- mice. In contrast, chronically infected A- mice treated with RA were able to clear the infection. Here we will determine the mechanisms by which vitamin A deficiency results in failure to clear infection and RA helps to resolve this GI infection. We hypothesize that vitamin A/RA is required for protection mediated by: 1) T cells, 2) intestinal epithelial cells, and 3) maintaining homoeostasis of the gut microbiota. Our approach includes the use of vitamin A deficient and adequate mice, and A- mice treated with RA, and the use of 3 novel animal models: mice lacking retinoid signaling in T cells or in intestinal epithelial cells specifically, and germfree mice. Mice with a tissue-specifi dominant negative RA receptor will be used to block retinoid signaling selectively in T cells (aim 1) and intestinal epithelial cells (aim 2) to probe mechanisms by which vitamin A controls GI infection. Methods to be used will include imaging of bioluminescent C. rodentium to localize the bacteria in the intestine and immunological and histological methods to characterize cell types, functions and tissue histopathology. In addition, germfree mice will be used to determine the role of the microbiota in the vitamin A-mediated protection from C. rodentium (aim 3). It is expected that resolution of C. rodentium infection (clearance) will require vitamin A signaling in both intestinal T cells and epithelium as well as maintaining homeostasis of gut microbiota. Understanding the mechanisms by which vitamin A deficiency and RA intervention regulate these processes will be critical for informing public health messages as well as for the possible use of vitamin A/RA for protection from GI infection.