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区系都是防止肠道感染的因素。轮状柠檬酸杆菌引起小鼠的胃肠道(Gl)感染，这是人类食源性大肠杆菌感染的模型。该项目的目标是确定维生素A缺乏是如何恶化的，并通过干预维生素A代谢物维甲酸(RA)来预防轮状芽胞杆菌感染。我们的初步数据显示，维生素A缺乏(A-)导致了一种慢性轮状芽胞杆菌感染，在A-小鼠中有40%是致命的。相比之下，长期以来 用RA治疗感染的A系小鼠能够清除感染。在这里，我们将确定维生素A缺乏导致感染无法清除的机制，而RA有助于解决这种胃肠道感染。我们假设维生素A/RA是通过以下途径进行保护的：1)T细胞，2)肠上皮细胞，3)维持肠道微生物区系的动态平衡。我们的方法包括使用维生素A缺乏和充足的小鼠，以及使用RA治疗的A-小鼠，并使用3种新的动物模型：在T细胞或肠上皮细胞中缺乏维甲酸信号的小鼠，以及无菌小鼠。具有组织特异性显性阴性RA受体的小鼠将被用来选择性地阻断T细胞(AIM 1)和肠上皮细胞(AIM 2)中的维甲酸信号，以探索维生素A控制胃肠道感染的机制。将使用的方法包括对生物发光的罗齿梭菌进行成像，以定位肠道中的细菌，以及免疫学和组织学方法，以表征细胞类型、功能和组织病理学。此外，无菌小鼠将被用来确定微生物区系在维生素A介导的轮状芽胞杆菌保护作用中的作用(目标3)。预计轮状芽胞杆菌感染的解决(清除)将需要肠道T细胞和上皮中的维生素A信号以及维持肠道微生物区系的动态平衡。了解维生素A缺乏和RA干预调节这些过程的机制对于宣传公共卫生信息以及可能使用维生素A/RA预防胃肠道感染至关重要。

 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.