Commensal Bacteria in Regulation Of T gondii Induced IBD

本研究旨在探讨弓形虫和共生菌群在病原体驱动的炎症性肠病(IBD)实验模型免疫调节中的相互作用。需要检验的假设是，来自共生肠道菌群的特定细菌产物可以与寄生虫感染的宿主相互作用，防止实验性IBD的发展。我们观察到，在口腔寄生虫感染后，无菌小鼠比常规小鼠更容易受到回肠和结肠的急性坏死性条件的影响，这表明需要肠道微生物或其衍生产物来防止弓形虫诱导的IBD的发展。在第一个特定目标中，我们将比较肠道组织样本(表型，趋化因子细胞因子产生)在 口服弓形虫感染常规小鼠的无菌耐药株(BALB/c)和敏感株(C57BL/6)小鼠。我们已经确定了一种特殊的脆弱芽孢杆菌被膜多糖，它可以调节肠道炎症过程。用脆弱类杆菌提取的囊膜多糖(PS A)治疗常规小鼠可防止弓形虫诱导的IBD的发展。粘膜组织，更具体地说，来自固有层、Peyer‘s斑块和其他组织的淋巴样细胞 PS A治疗的常规小鼠和无菌小鼠的器官将被评估免疫组织学差异。PS A诱导免疫调节的机制(产生IL-10、转化生长因子-β)有待进一步研究。根据我们的初步数据，我们将特别关注产生CD8上皮内淋巴细胞(IEL)的转化生长因子-b，以及依赖IL-10的CD4调节性T细胞(CD45RB low，CD25)。我们将评估这些调节性CD4T细胞在PS A处理的小鼠的固有层和Peyer‘s斑块中的表达，并确定这些细胞群体是否可以适应性地转移到幼鼠身上，并预防弓形虫驱动的IBD。NKT细胞也是对多糖做出反应的重要调节细胞。我们将评估PS A治疗是否能诱导NKT细胞群发挥效应和免疫调节活性。

The proposed studies investigate the interaction of Toxoplasma gondii and commensal bacterial flora in the immune regulation of an experimental model of pathogen-driven inflammatory bowel disease (IBD). The hypothesis to be tested is that specific bacterial products derived from commensal intestinal flora can interact with the parasite-infected host and prevent the development of experimental IBD. We have observed that germ free mice are more susceptible to an acute necrotizing condition of the ileum and colon than conventional mice following oral parasite infection suggesting that intestinal microflora or their derived products are required to prevent the development of Toxoplasma induced IBD. In the first specific aim, we will compare intestinal tissue samples (phenotyping, chemokines cytokines production) in germ-free strains of resistant (BALB/c) and susceptible (C57BL/6) mice following oral Toxoplasma infection to conventional mice. We have identified a specific capsular polysaccharide of B. fragilis that can modulate the gut inflammatory process. Treatment of conventional mice with capsular polysaccharide (PS A) derived from Bacteroides fragilis prevents the development of T. gondii induced IBD. The mucosal tissue and more specifically lymphoid cells from the lamina propria, Peyer's patches and other organs from PS A treated conventional and germ free mice will be assessed for immunohistologic differences. Mechanisms (IL-10, TGF-b production) of immunomodulation induced by the PS A will be further investigated. As suggested by our preliminary data, particular attention will focus on TGF-b producing CD8+ intraepithelial lymphocytes (IEL) and on a population of IL-10 dependent CD4 regulatory T cells (CD45RB low, CD25). We will evaluate for the expression of these regulatory CD4+ T cells in the lamina propria and Peyer's patches of PS A treated mice and determine whether this cell population can be adaptively transferred to naive mice and prevent toxoplasma-driven IBD. NKT cells are also important regulatory cells that respond to polysaccharides. We will evaluate whether PS A treatment can induce a population of NKT cells that exert effector and immunoregulatory activity.