Modular Subunit Vaccine for Salmonella

描述（由申请人提供）：沙门氏菌每年导致数百万人因摄入受污染的食物或水而患病或死亡。沙门氏菌感染后存活的个体会产生强大的免疫力，这依赖于促进巨噬细胞吞噬细菌的抗体，以及来自CD4+ T细胞的淋巴因子，刺激巨噬细胞杀死吞噬的细菌。出于实际原因，需要能够诱导可由活生物体诱导的免疫水平的亚单位疫苗。不幸的是，用单个沙门氏菌蛋白免疫通常仅诱导部分免疫。该项目的长期目标是克服这种低效率并生产有效的沙门氏菌亚单位疫苗。我们的假设是，单个沙门氏菌蛋白的保护性低于减毒微生物，因为在感染过程中始终缺乏呈递，固有的弱佐剂活性，以及进入粘膜淋巴器官的能力差。我们的具体目标是生产一种单一的疫苗，解决这些弱点。我们建议从S.鼠伤寒沙门氏菌感染后早期和晚期激活CD4+ T细胞的蛋白。鼠伤寒感染这些肽将与S的Toll样受体5结合部分一起沿着掺入颗粒中。作为佐剂起作用并含有B细胞表位的鼠伤寒沙门氏菌FliC，以及促进颗粒进入派尔集合淋巴结的M细胞易位的假结核耶尔森氏菌的β 1整联蛋白结合结构域。将测试含有所有这些组分的颗粒产生对沙门氏菌的保护性免疫的能力，并采用跟踪肽：MHC II复合物、特异性CD4+ T细胞和抗体的新方法来评估负责免疫的细胞机制。这些目标的完成将为合理设计沙门氏菌、其他感染因子和癌症的有效亚单位疫苗提供一个框架。

DESCRIPTION (provided by applicant): Salmonella species cause disease or death in millions of individuals every year who ingest contaminated food or water. Individuals who survive Salmonella infection develop robust immunity that is dependent on antibodies that facilitate bacterial phagocytosis by macrophages, and lymphokines from CD4+ T cells that stimulate macrophages to kill engulfed bacteria. For practical reasons, a subunit vaccine capable of inducing the level of immunity that can be induced by live organisms, is desirable. Unfortunately, immunization with individual Salmonella proteins usually induces only partial immunity. The long-term goal of this project is to overcome this inefficiency and produce an effective subunit vaccine for Salmonella. Our hypothesis is that individual Salmonella proteins are less protective than attenuated organisms because of a lack of presentation at all times during infection, inherently weak adjuvant activity, and poor entry into the mucosal lymphoid organs. Our specific aim is to produce a single vaccine that addresses each of these weaknesses. We propose to identify immunodominant peptides from S. typhimurium proteins that activate CD4+ T cells early and late after S. typhimurium infection. These peptides will be incorporated into particles along with the Toll-like receptor 5-binding portion of S. typhimurium FliC, which functions as an adjuvant and contains B cell epitopes, and the beta 1 integrin-binding domain of Yersinia pseudotuberculosis, which facilitates M cell translocation of particles into the Peyer's patches. The particles containing all of these components will be tested for the ability to generate protective immunity to Salmonella, and novel methods to track peptide:MHC II complexes, specific CD4+ T cells, and antibodies will be employed to assess the cellular mechanisms responsible for immunity. Completion of these aims will provide a framework for the rational design of effective subunit vaccines for Salmonella, other infectious agents, and cancer.