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

项目摘要 微生物病原体利用毒力因子来颠覆或中和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安装保护性的 适应性免疫反应。了解这种毒力因子的双重性质仍然是该领域的一个目标 微生物发病机制和免疫学。由于许多病原体编码多种毒力因子，因此 另一个重要的目标是确定由一个毒力因子引起的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。一种称为III型的多因素毒力机制 大量革兰氏阴性细菌分泌的分泌物，这些细菌会导致人类重大疾病 正在研究中。III型分泌系统(T3SS)的功能是将效应蛋白输送到宿主细胞。这个 效应蛋白调节先天和获得性免疫反应，促进细菌感染和毒力。 一种对细菌病原体耶尔森氏菌的毒力至关重要的T3SS，它能引起一系列人类疾病 从鼠疫到胃肠炎，是该项目的重点。一个老鼠感染模型被用来深入了解 效应器用于颠覆先天免疫反应的机制。同样的感染模型被用于 了解宿主如何利用效应器来产生保护性适应性免疫反应。二 观察结果构成了该项目的基础。首先，YopM效应器是生产高系统性的 免疫抑制细胞因子IL-10在小鼠先天免疫反应中的水平 耶尔西尼亚。其次，感染耶尔森氏菌后存活的小鼠产生主导的CD8 T细胞对 效应器YopE中的保护性表位。该项目将解决三个问题。首先，YopM是如何诱导 全身高水平的IL-10，这个过程是否在发病机制中起作用？第二，YopE如何- 特定的CD8 T细胞保护，YopE的哪些功能对产生这种反应是重要的？第三，有没有 YopM诱导IL-10延迟或减少CD8T细胞对YopE的反应？成功 该项目的完成将有助于更好地理解多种毒力之间的相互作用 病原体中的因素可以影响宿主免疫反应的结果。从以下方面获得的知识 这些基础研究将影响微生物发病机制和免疫学领域，并可能 转化为应用，如开发有效地启动适应性的新型活疫苗 豁免权。

Project Summary 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.