TLR2/NLR Signal Regulation of Protective Immunity to F. Tularensis

项目总结(见说明)； Toll样受体(TLR)和Nod样受体(NLR)在感染先天反应中的信号转导 影响宿主细胞对细菌胞质复制的允许性和细菌的发展 保护豁免权。然而，目前还不完全清楚这些信号事件是如何由 TLR和NLR通过以下途径影响对致死性细菌感染的保护能力 接种疫苗。目前还不清楚抗体是如何以灭活的形式与图拉氏弗朗西斯菌结合的 Ff-单抗(IFF-mAb)复合体，在本方案中评估的疫苗原(1，2)，改变 通过TLR2或NLRs的先天信号，从而产生适应性/保护性免疫反应。 病原体抵抗氧化还原介导的宿主防御或改变基于氧化还原的宿主细胞的能力的变化 信号，如已显示的Ft缺乏超氧化物歧化酶的活疫苗株(LVS) 活性(3，4)，影响TLR和NLR依赖的炎症反应。因此，病原体起源于 抗氧化剂可能会影响不同疫苗原产生适应性/保护性免疫的能力。 因此，我们假设通过TLR2和/或NLR传递的信号影响了 疫苗接种和这些信号受Ft和/或细菌抗体调理的影响 促炎症能力。这一假设将通过1)建立mAb结合Ft的影响来检验 和Ft抗氧化剂突变体在先天性免疫(诱导)阶段协同TLR2/NLR信号转导中的作用 分子水平上的抗Ft免疫反应和2)评估TLR2和/或NLR信号 在接种不同的FF配方疫苗后，影响保护性免疫的诱导。 协同作用：在子项目2中获得的结果将为TLR和NLR导向的先天提供一个新的视角 在次级项目1采用的正在进行的疫苗战略的背景下作出的反应，使改进 这些方法。参与巨噬细胞ROS/RNS产生的信号通路与 被FCR、TLR和NLR激活，即PI3激酶、NF-KB和MAPK通路； 因此，这些目标的结果与实验密切相关，并将有助于了解 分项目3.此外，将通过提供具有特征的抗氧化剂突变体来促进这一协同作用 来自子项目3，从而使我们的子项目能够阐明Ft抗氧化剂途径如何影响

PROJECT SUMMARY (See instructions); Toll-like receptor (TLR) and NOD-like receptor (NLR) signaling during the innate response to infection influences the host cell's permissiveness for cytosolic replication of bacteria and the development of protective immunity. However, it is not entirely clear how these signaling events initiated by engagement of TLRs and NLRs influences the capacity to confer protection against lethal bacterial infection through vaccination. It also is unclear how antibody bound to Francisella tularensis (Ft) in the form of an inactivated Ff-monoclonal antibody (IFf-mAb) complex, the vaccinogen (1,2) under evaluation in this proposal, alters innate signaling via TLR2 or NLRs and thereby the adaptive/protective immune response. Changes in a pathogen's capacity to resist redox-mediated host defenses or alter redox-based host cell signaling, as has been shown for the live vaccine strain (LVS) of Ft deficient for superoxide dismutase activity (3, 4), impacts both TLR and NLR-dependent inflammatory responses. Thus, pathogen-derived antioxidants likely influence the ability of different vaccinogens to engender adaptive/protective immunity. Therefore, we hypothesize that signals transduced via TLR2 and/or NLRs influence the efficacy of vaccination and these signals are impacted by antibody opsonization of Ft and/or the bacterium's proinflammatory capacity. This hypothesis will be tested by 1) Establishing the impact of mAb bound Ft and Ft antioxidant mutants on synergistic TLR2/NLR signaling during the innate immune (inductive) phase of the anti-Ft immune response at the molecular level and 2) Evaluating whether TLR2 and/or NLR signaling impacts induction of protective immunity after vaccination with various Ff formulations. Synergy: Results obtained in Subproject 2 will provide a new view of TLR and NLR-directed innate responses in the context of the ongoing vaccine strategies employed in Subproject 1, enabling refinement of these approaches. The signaling pathways involved in macrophage ROS/RNS production intersect those activated by FcR, TLR, and NLR stimulation, namely the PI3 kinase, NF-KB, and MAPK pathways; accordingly, the results of these Aims are significantly relevant to, and will help inform, experiments in Subproject 3. Further, this synergy will be facilitated by the provision of characterized antioxidant mutants from Subproject 3, thus enabling our Subproject to shed light on how Ft antioxidant pathways impact