Innate immune-mediated control of pulmonary Legionella pneumophila infection

先天免疫介导控制肺部嗜肺军团菌感染

基本信息

批准号：
10867793
负责人：
Sunny Shin
金额：
$ 8.15万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-11-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10867793
关键词：
Ablation Acetyl Coenzyme A Address Alveolar Macrophages Anti-Bacterial Agents Antibiotic Resistance Automobile Driving Bacterial Infections Bacterial Pneumonia Cell physiology Cells Collaborations Communities Cytokine Signaling Data Defense Mechanisms Development Enzymes Epigenetic Process Epithelial Cells Funding Future Generations Genetic Transcription Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Histone Acetylation Hospitals Host Defense Host Defense Mechanism Immune In Vitro Infection Infection Control Inflammatory Inflammatory Response Innate Immune System Interleukin-1 Interleukin-1 Receptors Interleukin-1 alpha Interleukin-1 beta Interleukin-12 Interleukin-6 JAK2 gene Knowledge Lactate Dehydrogenase Legionella Legionella pneumophila Legionnaires&apos Disease Licensing Lung Mediating Metabolic Morbidity - disease rate Myeloid Cells Nosocomial pneumonia Production Protein Biosynthesis Publishing Receptor Signaling Research Role Signal Transduction Source Stat5 protein TNF gene Testing Therapeutic Time Transcriptional Activation Translations Type IV Secretion System Pathway Vaccines Virulence Virulence Factors aerobic glycolysis alveolar epithelium antimicrobial cell type community acquired pneumonia cytokine defined contribution design epigenetic marker immune clearance improved in vivo innate immune mechanisms insight monocyte mortality mouse model novel pathogen pathogenic bacteria pathogenic microbe programs response therapeutically effective

项目摘要

Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to promote cytokine production. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.

项目摘要细胞内细菌病原体，例如肺炎军团菌，这是社区和社区的重要原因医院可获得的肺炎，在全球范围内负责大量发病率和死亡率。随着传播细菌病原体中广谱抗生素的耐药性正在升级，发现新颖的先天性免疫防御机制可能是未来治疗方法的关键，以应对这种增加威胁。细胞内病原体部署毒力因子以禁用许多免疫细胞功能。赢得这个战斗，主人必须通过尚未定义的机制来克服这种颠覆。解决这个问题知识的关键差距，我们试图定义成功的先天免疫清除的参数军团菌。军团菌通过使用其IV型分泌系统在肺泡巨噬细胞内复制细菌效应子，其中几种抑制宿主蛋白的合成。几个效应子抑制宿主蛋白合成。尽管在宿主翻译中进行了这种阻滞，但军团菌感染矛盾地增强了生产炎症细胞因子。在上一个资金期间，我们证明了军团菌感染的肺泡巨噬细胞能够合成并释放IL-1；此外，需要IL-1受体（IL-1R）信号传导为了通过旁观者髓样细胞强大地产生TNF和IL-12。有趣的是，我们新发表的研究表演肺泡上皮细胞中的IL-1R信号传导首次诱导粒细胞巨噬细胞的产生菌落刺激因子（GM-CSF），这是旁观者细胞因子产生和细菌所必需的清除。有趣的是，尽管GM-CSF充当宿主防御的有效炎症细胞因子，以防止广泛病原体的光谱，我们的发现首次表明GM-CSF代谢重新编程单核细胞进行有氧糖酵解，从而促进细胞因子的产生。我们将检验肺泡的假设上皮衍生的GM-CSF代谢重新编程单核细胞以扩大表观遗传变化，从而增强 TLR驱动的细胞因子产生和感染的控制。在此续约中，我们提出三个目标首先：定义哪种细胞类型会产生和响应GM-CSF，其次：了解GM-CSF介导的作用在宿主防御中的代谢重编程，第三：定义GM-CSF和TLR信号如何合作促进细胞因子产生。这些研究将共同定义使用的新型先天免疫机制由宿主克服病原体编码的毒力活性。因此，拟议的研究将提供对针对广泛的微生物病原体使用的宿主防御机制的重要洞察力并有助于开发改进的抗微生物治疗剂和疫苗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Listening In: Plasmacytoid DC, Monocyte-Derived DC, and Neutrophil Crosstalk in Antifungal Defense.

DOI：
10.1016/j.chom.2020.06.015
发表时间：
2020-07-08
期刊：
CELL HOST & MICROBE
影响因子：
30.3
作者：
Liu, Xin;Shin, Sunny
通讯作者：
Shin, Sunny

Viewing Legionella pneumophila Pathogenesis through an Immunological Lens.

DOI：
10.1016/j.jmb.2019.07.028
发表时间：
2019-10-04
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Liu, Xin;Shin, Sunny
通讯作者：
Shin, Sunny

TNF and type I IFN induction of the IRG1-itaconate pathway restricts Coxiella burnetii replication within mouse macrophages.

IRG1-衣康酸途径的 TNF 和 I 型 IFN 诱导限制了小鼠巨噬细胞内伯氏柯克斯体的复制。

DOI：
10.1101/2023.07.07.548079
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Boyer,MarkA;Fischer,NatashaLopes;Shin,Sunny
通讯作者：
Shin,Sunny

Legionella-Infected Macrophages Engage the Alveolar Epithelium to Metabolically Reprogram Myeloid Cells and Promote Antibacterial Inflammation.

DOI：
10.1016/j.chom.2020.07.019
发表时间：
2020-11-11
期刊：
CELL HOST & MICROBE
影响因子：
30.3
作者：
Liu, Xin;Boyer, Mark A.;Holmgren, Alicia M.;Shin, Sunny
通讯作者：
Shin, Sunny

Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity.

DOI：
10.1371/journal.ppat.1006785
发表时间：
2017-12
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Mantegazza AR;Wynosky-Dolfi MA;Casson CN;Lefkovith AJ;Shin S;Brodsky IE;Marks MS
通讯作者：
Marks MS