Regulation of protective pulmonary immunity by innate pathways sensing bacterial viability

肺炎是全世界主要的死亡原因，即使在70多年前引入抗生素之后也是如此。尽管进行了充分的抗生素治疗，但多重耐药菌株的出现越来越多，死亡率仍然居高不下，这说明迫切需要新的治疗方法。与传统的以病原体为中心的抗菌策略一起，提高局部免疫力的概念可以通过预防和限制感染以及提高现有治疗方法的效率来显著降低肺炎相关死亡率。然而，这些新策略的发展需要更深入地了解保护性肺免疫的分子机制。我们最近可以证明，免疫系统具有固有的能力来感知细菌的生存能力，从而具有传染性。免疫细胞可以通过检测细菌信使(M)RNA来区分活细菌和死亡细菌，细菌信使(M)RNA选择性地存在于活细菌中，但不存在于死亡细菌中。我们称这种分子为‘活性相关的PAMP’(VITA-PAMP)。活细菌和VITA-PAMP激活特定的信号通路，引发更强大的免疫反应，从而改善宿主保护和抗体产生。在目前的提案中，我们想要研究已确定的产生保护性肺免疫的途径所起的作用。除了先天免疫反应的激活外，我们还将描述控制肺部抗体产生的机制。鉴于活疫苗和存活感染通常赋予终生保护性免疫，我们将调查“活性检测”和已识别的信号通路是否可以控制肺和B细胞反应，特别是病原体特异性IgA和Ig G的产生，以提高免疫力。值得注意的是，关于肺部先天免疫信号对保护性抗体反应的调节知之甚少。在这个项目中，我们的目标是识别微生物信号、应答的免疫细胞和控制肺部保护性体液免疫反应的分子途径。使用不同的小鼠感染和疫苗模型，包括无毒重组细菌作为表达天然和模型抗原的模型生物，我们将破译中央途径，以便在项目的后期阶段将这些发现转移到临床相关的病原体。我们将特别关注先天和微生物信号对B细胞功能的调节，以及它们与呼吸道其他细胞和相关淋巴组织的相互作用。最后，我们将通过分析原代人类免疫细胞和分离的肺组织样本，将关键发现转移到人类系统。这项拟议的项目将阐明控制保护性肺免疫的细胞和分子机制，这将成为开发针对呼吸道细菌感染的新治疗和疫苗接种策略的基础。

Pneumonia represents a leading cause of death worldwide even after the introduction of antibiotics over 70 years ago. Increasing occurrence of multidrugresistant strains and persistently high mortality rates despite adequate antibiotic therapy, illustrate the urgent need for novel therapeutic approaches. Together with classical pathogen-centered antimicrobial strategies, concepts to improve local immunity could significantly reduce pneumonia-associated mortality by preventing and limiting infections and improving the efficiency of existing therapies. Development of these new strategies however requires a better in-depth understanding of the molecular mechanisms of protective pulmonary immunity.We could recently demonstrate that the immune system has the inherent capacity to sense bacterial viability, and hence infectivity. Immune cells can discriminate live from dead bacteria through the detection of bacterial messenger (m)RNA, which is selectively present in live but not dead bacteria. We call such molecules ‘viability-associated PAMPs’ (vita-PAMPs). Viable bacteria and vita-PAMPs activate specific signaling pathways and elicit more robust immune responses that lead to improved host protection and antibody production. In the current proposal we want to investigate the role of the identified pathways for the generation of protective pulmonary immunity. Besides activation of innate immune responses, we will characterize mechanisms that control antibody production in the lung.Given the often-observed lifelong protective immunity conferred by live vaccines and survived infections, we will investigate if ‘viability-detection’ and the identified signaling pathways can control pulmonary and B cell responses, particularly the production of pathogen-specific IgA and IgG to improve immunity.Notably, very little is known about the regulation of protective antibody responses by innate immune signals in the lung. In this project we aim to identify the microbial signals, the responding immune cells and the molecular pathways that control protective humoral immune responses in the lung. Using various mouse models of infection and vaccination, involving avirulent recombinant bacteria as modelorganisms expressing natural and modelantigens, we will decipher the central pathways, in order to transfer these findings to clinically relevant pathogens at a later stage of the project. We will especially focus on the regulation of B cell functions by innate and microbial signals and their interactions with other cells of the respiratory tract and associated lymphoid tissues. Finally we will transfer key findings to the human system by analyzing primary human immune cells and isolated lung tissue specimen. The proposed project will elucidate cellular and molecular mechanisms that control protective pulmonary immunity, which will form the basis for the development of novel treatments and vaccination strategies against bacterial infections of the respiratory tract.