Regulation of protective pulmonary immunity by innate pathways sensing bacterial viability
通过感知细菌活力的先天途径调节保护性肺部免疫
基本信息
- 批准号:224703840
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Independent Junior Research Groups
- 财政年份:2012
- 资助国家:德国
- 起止时间:2011-12-31 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
即使在70多年前引入抗生素之后,肺炎仍然是全球死亡的主要原因。尽管有足够的抗生素治疗,但多重耐药菌株的发生率不断增加,死亡率持续高企,这说明迫切需要新的治疗方法。结合经典的以病原体为中心的抗菌策略,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疗法的效率来显著降低肺炎相关的死亡率。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,免疫系统具有感知细菌活力的固有能力,因此具有感染性。免疫细胞可以通过检测细菌信使(m)RNA来区分活的和死的细菌,这种信使RNA选择性地存在于活的而不是死的细菌中。我们称这种分子为“活力相关PAMPs”(vita-PAMPs)。活菌和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,我们希望研究已确定的途径对保护性肺免疫产生的作用。除了先天免疫应答的激活,我们还将描述控制肺中抗体产生的机制。鉴于活疫苗和存活感染所赋予的经常观察到的终身保护性免疫,我们将研究"活力检测"和已鉴定的信号通路是否可以控制肺和B细胞应答,特别是病原体特异性IgA和IgG的产生以提高免疫力。值得注意的是,关于肺中先天免疫信号对保护性抗体应答的调节知之甚少。在这个项目中,我们的目标是确定微生物信号,响应免疫细胞和控制肺中保护性体液免疫反应的分子途径。使用各种感染和疫苗接种的小鼠模型,包括无毒重组细菌作为表达天然和模式抗原的模式生物,我们将破译中心途径,以便在项目的后期阶段将这些发现转移到临床相关病原体。我们将特别关注先天和微生物信号对B细胞功能的调节,以及它们与呼吸道和相关淋巴组织的其他细胞的相互作用。最后,我们将通过分析原代人类免疫细胞和分离的肺组织标本将关键发现转移到人类系统。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型治疗和疫苗接种策略的基础。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses
- DOI:10.1038/s41590-018-0068-4
- 发表时间:2018-04-01
- 期刊:
- 影响因子:30.5
- 作者:Ugolini, Matteo;Gerhard, Jenny;Sander, Leif E.
- 通讯作者:Sander, Leif E.
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Professor Dr. Leif Erik Sander其他文献
Professor Dr. Leif Erik Sander的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Professor Dr. Leif Erik Sander', 18)}}的其他基金
Sensormechanismen für mikrobielle Viabilität und Regulation der Immunantwort in Antigenpräsentierenden Zellen
微生物活力和抗原呈递细胞免疫反应调节的传感器机制
- 批准号:
86606927 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Research Fellowships
相似国自然基金
内源性蛋白酶抑制剂SerpinA3N对缺血性脑卒中后血脑屏障的保护作用及其表达调控机制
- 批准号:82371317
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
相似海外基金
Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia
建立肺炎期间LOX-1依赖性免疫调节机制
- 批准号:
10526202 - 财政年份:2022
- 资助金额:
-- - 项目类别:
HDAC9 nuclear/cytoplasmic shuttling in pulmonary vascular endothelial barrier regulation
HDAC9核/细胞质穿梭在肺血管内皮屏障调节中的作用
- 批准号:
10597538 - 财政年份:2022
- 资助金额:
-- - 项目类别:
HDAC9 nuclear/cytoplasmic shuttling in pulmonary vascular endothelial barrier regulation
HDAC9核/细胞质穿梭在肺血管内皮屏障调节中的作用
- 批准号:
10446078 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Defining the role of the nuclear lamina in the mechanical regulation of lung fibrosis
定义核层在肺纤维化机械调节中的作用
- 批准号:
10672169 - 财政年份:2022
- 资助金额:
-- - 项目类别:
TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation
脓毒症和急性炎症中内源性酰基多巴胺的 TRPV1 依赖性神经免疫调节和调节
- 批准号:
10634744 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Defining the role of the nuclear lamina in the mechanical regulation of lung fibrosis
定义核层在肺纤维化机械调节中的作用
- 批准号:
10387049 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia
建立肺炎期间LOX-1依赖性免疫调节机制
- 批准号:
10674622 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Regulation of phosphodiesterases and cAMP signaling during the host-pathogen interaction in the pulmonary endothelium
肺内皮宿主-病原体相互作用过程中磷酸二酯酶和 cAMP 信号传导的调节
- 批准号:
9901604 - 财政年份:2018
- 资助金额:
-- - 项目类别: