Anti-inflammatory promoting commensal E. coli

描述(申请人提供)：先天免疫反应是人体识别外来分子的第一道防线，因此在检测微生物病原体方面发挥着积极作用。作为回应，微生物病原体已经进化出错综复杂的方法来解除这种反应。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质直接输送到宿主细胞蛋白质中。这些蛋白质被称为效应器，它们侵占宿主细胞的过程以促进细菌的生存。一个常见的新出现的主题是，许多效应器通过抑制信号通路中的步骤来抑制促炎细胞因子的产生，信号通路导致核因子-βB的激活，核因子是一种中央先天免疫反应转录因子。到目前为止，大多数抗炎效应的特征是在肠道病原体中发现的，包括沙门氏菌、志贺氏菌、耶尔森氏菌和肠源性大肠杆菌，这些细菌不断地与胃肠道中的各种细胞类型接触。先天免疫系统的失调与许多炎症性自身免疫疾病有关，包括炎症性肠病、牛皮癣和类风湿性关节炎。治疗这些疾病的一个重大进展是治疗方法的发展，包括肿瘤坏死因子抑制剂，人源化抗体可以阻断这种促炎细胞因子(即英夫利昔单抗)的活性。然而，与大多数治疗方法一样，这些药物是全身给药的，对于肿瘤坏死因子拮抗剂，这会导致全身免疫抑制，增加严重感染的发生率，包括结核病复发和脑脓肿，这些疾病可以通过将免疫抑制定向到发病部位来预防。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靶标的病原体，使用专门的分泌系统将蛋白质直接输送到宿主细胞，但尚未发现哺乳动物的共生体编码这种系统。该项目的长期目标是开发能够产生3型分泌物的共生菌，并对这些细菌进行基因工程，使其携带细菌效应蛋白，这种蛋白能特异性地抑制核因子？B的激活。据设想，这些细菌可以作为治疗炎症性肠病的一种新方法，因为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.