Regulation of host innate and adaptive immunity by bacterial type III effectors

描述（由申请人提供）：微生物病原体利用毒力因子来破坏或抵消宿主的先天免疫反应。反过来，宿主可以利用毒力因子的存在来检测病原体并发动保护性适应性免疫反应。了解这种双重性质的毒力因素仍然是一个目标，在微生物发病机制和免疫学领域。由于许多病原体编码多种毒力因子，另一个重要的目标是确定一种毒力因子对先天反应的改变是否可以形成对另一种毒力因子的适应性免疫。目前正在研究一种被称为III型分泌的多因子毒力机制，这种机制保存在大量引起重要人类疾病的革兰氏阴性细菌中。III型分泌系统（T3SS）的功能是将效应蛋白传递到宿主细胞中。效应蛋白调节先天和适应性免疫反应，促进细菌感染和毒力。该项目的重点是一种T3SS，它对细菌性病原体耶尔森氏菌的毒力至关重要，耶尔森氏菌可引起从鼠疫到肠胃炎等人类疾病。小鼠感染模型用于深入了解效应物破坏先天免疫反应的机制。同样的感染模型被用来理解宿主如何利用效应物产生保护性适应性免疫反应。两个观察结果构成了这个项目的基础。首先，在感染耶尔森菌的小鼠的先天免疫应答过程中，YopM效应是产生高水平的全身免疫抑制细胞因子IL-10所必需的。其次，在感染耶尔森菌后存活的小鼠对效应物YopE中的保护性表位产生显性CD8 T细胞应答。该项目将解决三个问题。首先，YopM如何诱导全身高水平的IL-10，这一过程是否有助于发病机制？其次，YopE特异性CD8 T细胞是如何保护的，YopE的哪些特征对产生这种反应很重要？第三，YopM诱导IL-10是否会延迟或减少CD8 T细胞对YopE的反应？该项目的成功完成将有助于更好地了解病原体中多种毒力因子之间的相互作用如何影响宿主免疫反应的结果。从这些基础研究中获得的知识将影响微生物发病机理和免疫学领域，并可转化为诸如开发有效启动适应性免疫的新型活疫苗等应用。

DESCRIPTION (provided by applicant): Microbial pathogens utilize virulence factors to subvert or counteract the innate immune response of the host. In turn, the host can exploit the presence of virulence factors to detect pathogens and mount a protective adaptive immune response. Understanding this dual nature of virulence factors remains a goal in the fields of microbial pathogenesis and immunology. Because many pathogens encode multiple virulence factors, an additional important goal is to determine if alteration of innate responses by one virulence factor can shape adaptive immunity to another virulence factor. A multi-factorial virulence mechanism known as type III secretion that is conserved in a large number of Gram-negative bacteria that cause important human diseases is being studied. The type III secretion system (T3SS) functions to deliver effector proteins into host cells. The effector proteins regulate innate and adaptive immune responses to promote bacterial infection and virulence. A T3SS that is critical for virulence in the bacterial pathogen Yersinia, which causes human diseases ranging from plague to gastroenteritis, is the focus of the project. A mouse infection model is used to gain insights into mechanisms used by effectors to subvert innate immune responses. The same infection model is used to understand how the host exploits effectors to generate a protective adaptive immune response. Two observations form the basis of the project. First, the YopM effector is required for production of high systemic levels of the immunosuppressive cytokine IL-10 during the innate immune response in mice infected with Yersinia. Second, mice that survive infection with Yersinia generate a dominant CD8 T cell response to a protective epitope in the effector YopE. The project will address three questions. First, how does YopM induce high systemic levels of IL-10 and does this process contribute to pathogenesis? Second, how do YopE- specific CD8 T cells protect and what features of YopE are important for generating this response? Third, does induction of IL-10 by YopM delay or decrease the generation of a CD8 T cell response to YopE? Successful completion of this project will lead to better understanding of how the interplay between multiple virulence factors in a pathogen can impact the outcome of the host immune response. The knowledge gained from these basic research studies will impact the fields of microbial pathogenesis and immunology, and could be translated into applications such as the development of novel live vaccines that effectively prime adaptive immunity. PUBLIC HEALTH RELEVANCE: This basic research project seeks to understand how microbial virulence factors can play a duel role in response of the immune system to infection. Virulence factors can function to subvert or counteract the innate immune response of the host. Alternatively, the host can exploit the presence of virulence factors to detect pathogens and mount a protective adaptive immune response. Understanding this dual nature of virulence factors in the context of a multi-factorial mechanism remains a major challenge in the fields of microbial pathogenesis and immunology. Successful completion of the project will increase our knowledge of virulence mechanisms of pathogens and of the basic workings of the immune system, as well as lead to the development of more effective vaccines that can be used to protect the public against infectious diseases.