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破坏或抵消宿主的先天免疫应答。 反过来，宿主可以利用毒力因子的存在来检测病原体，并建立保护性免疫系统。 适应性免疫反应理解毒力因子的这种双重性质仍然是以下领域的目标： 微生物致病机理和免疫学。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个毒力因子对先天性应答的改变是否可以形成 对其他毒力因子的适应性免疫一种多因素的毒力机制，称为III型 在大量引起重要人类疾病的革兰氏阴性细菌中保守的分泌物 正在被研究。III型分泌系统（T3 SS）的功能是将效应蛋白递送到宿主细胞中。的 效应蛋白调节先天性和适应性免疫应答以促进细菌感染和毒力。 一种T3 SS，对细菌病原体耶尔森氏菌的毒力至关重要，导致人类疾病， 从鼠疫到肠胃炎，是该项目的重点。小鼠感染模型用于深入了解 效应器用来破坏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产生保护性适应性免疫反应。两 观察是项目的基础。首先，需要YopM效应子来产生高系统性免疫应答。 感染的小鼠先天免疫应答期间免疫抑制细胞因子IL-10的水平 耶尔森氏菌第二，感染耶尔森氏菌后存活的小鼠产生显性CD 8 T细胞应答， 保护性表位在效应YopE。该项目将解决三个问题。首先，YopM如何诱导 IL-10的高全身水平，这一过程是否有助于发病机制？第二，你怎么办-- 特异性CD 8 T细胞保护，YopE的哪些特征对产生这种反应很重要？第三， YopM诱导IL-10延迟或减少CD 8 T细胞对YopE的应答？成功 该项目的完成将导致更好地了解多种毒力之间的相互作用， 病原体中的因子可以影响宿主免疫应答的结果。知识来自于 这些基础研究将影响微生物发病机理和免疫学领域， 转化为应用，例如开发有效启动适应性的新型活疫苗 免疫力

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.