Anti-inflammatory promoting commensal E. coli

描述（由申请人提供）：先天免疫反应是机体识别外来分子的第一道防线，因此在微生物病原体的检测中起着积极的作用。作为回应，微生物病原体进化出了复杂的手段来解除这种反应。例如，许多革兰氏阴性细菌病原体利用专门的3型分泌系统将数十种细菌蛋白直接传递到宿主细胞蛋白中。这些蛋白质被称为效应物，篡夺宿主细胞的进程来促进细菌的生存。一个常见的新主题是，许多效应物通过抑制导致NF-?激活的信号通路中的步骤来抑制促炎细胞因子的产生。B，中枢先天免疫应答转录因子。迄今为止发现的大多数抗炎效应物都存在于肠道病原体中，包括沙门氏菌、志贺氏菌、耶尔森氏菌和肠致病性大肠杆菌，这些细菌不断与胃肠道中的各种细胞类型相结合。先天免疫系统失调与许多炎症性自身免疫性疾病有关，包括炎症性肠病、牛皮癣和类风湿性关节炎。这些疾病治疗的一个重大进展是包括TNF抑制剂在内的治疗方法的发展，TNF抑制剂是阻断这种促炎细胞因子活性的人源化抗体（即英夫利昔单抗）。然而，像大多数治疗方式一样，这些药物是全身给药，在TNF -拮抗剂的情况下，导致全身免疫抑制增加严重感染的发生率，包括结核病再激活和脑脓肿，这些疾病可以通过靶向免疫抑制疾病部位来预防。有趣的是，尽管许多革兰氏阴性病原体，特别是那些以胃肠道为目标的病原体，使用专门的分泌系统将蛋白质直接传递到宿主细胞中，但尚未发现哺乳动物的共生生物编码这样的系统。该项目的长期目标是开发能够分泌3型的共生细菌，并对这些细菌进行基因工程改造，以传递细菌效应蛋白，特异性抑制NF-？B激活。人们设想，这些细菌可以作为治疗炎症性肠病的新手段给予患者，其中免疫抑制仅限于肠道。

DESCRIPTION (provided by applicant): The innate immune response is the first line of defense in the body's recognition of foreign molecules and, as such, plays an active role in the detection of microbial pathogens. In response, microbial pathogens have evolved intricate means to disarm this response. For example, many Gram-negative bacterial pathogens utilize specialized type 3 secretion systems to deliver tens of bacterial proteins directly into host cells proteins. These proteins, which are referred to as effectors, usurp host cell processes to promote bacterial survival. A common emerging theme is that many effectors suppress the production of pro-inflammatory cytokines by inhibiting steps in signaling pathways that lead to activation of NF-?B, a central innate immune response transcription factor. The majority of the anti-inflammatory effectors characterized to date are found in enteric pathogens, including Salmonella, Shigella, Yersinia and enteropathogenic E. coli species, bacterial, which are constantly interfacing with a variety of cell types in the gastrointestinal tract. Dysregulation ofthe innate immune system is linked to many inflammatory autoimmune-based diseases, including inflammatory bowel disease, psoriasis and rheumatoid arthritis. A major advance in the treatment of these diseases has been the development of therapeutics including TNF¿ inhibitors, humanized antibodies that block activity of this proinflammatory cytokine (i.e., infliximab). However, these agents, like most therapeutic modalities, are delivered systemically, which, in the case of TNF¿ antagonists, results in systemic immunosuppression increasing the incidence of severe infections, including tuberculosis reactivation and brain abscesses, diseases which could be prevented by targeting immunosuppression to sites of disease. Interestingly, although many gram-negative pathogens, particularly those that target the gastrointestinal tract, use specialized secretion systems to deliver proteins directly into host cells, no commensal organism of mammals has yet been identified to encode such a system. The long-term goal of this project is to develop commensal bacteria that are capable of type 3 secretion and to genetically engineer these bacteria to deliver bacterial effector proteins which specifically inhibit NF-?B activation. It is envisioned that these bacteria could be given to patients as a new means to treat inflammatory bowel disease where immunosuppression is limited to the intestines.