Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

重新定义细胞外免疫机制与细胞内立克次体感染之间的相互作用

基本信息

批准号：
10410561
负责人：
Sean Phillip Riley
金额：
$ 23.18万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-25 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410561
关键词：
Anaphylatoxins Animals Anti-Bacterial Agents Arthropods Bacteria Bacterial Infections Biology Blood Vessels Cardiovascular system Cells Clinical Collection Complement Complement Activation Complement Membrane Attack Complex Complex Data Deposition Development Dose Effectiveness Endothelial Cells Evolution Extracellular Space Extravasation Foundations Future Gram-Negative Bacteria Human Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes In Vitro Infection Infection prevention Inflammatory Innate Immune Response Investigation Liquid substance Logic Lytic Mammalian Cell Molecular Molecular Conformation Morbidity - disease rate Mus National Institute of Allergy and Infectious Disease Natural Immunity Organism Parasites Pathogenicity Patients Peptides Phenotype Predisposition Proteins Proteolysis Recording of previous events Reproducibility Rickettsia Rickettsia Infections Rickettsia conorii Rickettsia prowazekii Rickettsia rickettsii Rickettsia typhi Rickettsial Vaccines Signal Transduction System Therapeutic Therapeutic Intervention Traction adaptive immune response antimicrobial arm base clinically relevant complement deficiency complement system defined contribution design endosymbiont experimental study extracellular fitness human disease macromolecular assembly molecular marker molecular recognition mortality pathogen pathogenic bacteria preventive intervention priority pathogen response tool vaccine development vaccine-induced immunity

项目摘要

PROJECT SUMMARY Bacteria of the genus Rickettsia are obligate intracellular endosymbionts and the causative agents of many significant human and animal infections. These bacteria are transmitted to humans by hematophagous arthropods. Pathogenic Rickettsia species parasitize endothelial cells of the circulatory system, causing vascular leakage with significant morbidity and mortality. Rickettsia species are amongst the most important pathogens in history, with millions of human fatalities associated with these infections. The complement system is a well-known potion of the mammalian immune system that has classically been considered a secreted patroller of the extracellular spaces of the vasculature. Until recently it was considered unlikely that extracellular immune components like the complement system would encounter intracellular pathogens like Rickettsia; let alone that evolution would drive these systems into an adversarial relationship. Consequently, we are only beginning to appreciate how complement can control intracellular bacterial infections. Emerging data from Rickettsia and other organisms has begun to identify some of the molecular and cellular mechanisms of complement efficacy against intracellular pathogens. As the newly-emerging concept of “intracellular complement” is rapidly gaining traction, the experiments outlined in this proposal will be central to redefining an innate immune component that was discovered over a century ago. Based on both clinical and experimental evidence, we have hypothesized that complement activation is essential for the effective immune response to obligate intracellular Rickettsia infections. However, experimental data suggests that complement efficacy does not result directly from the antibacterial components of complement. Instead, complement efficacy against Rickettsia is derived from secondary interaction with other portions of the immune system. We therefore aim to 1) assess the contribution of the proinflammatory components of complement to the anti-Rickettsia immune response, and 2) define complement-induced components of the immune system that specifically target intracellular pathogens. By studying the interaction between complement and clinically relevant pathogens, the achieved results will advance our collective understanding of basic complement biology, further define the specific immune response to Rickettsia infection, directly influence the design of anti-Rickettsia vaccines, and provide the premise for future studies to analyze complement manipulation as a preventative or therapeutic intervention for intracellular bacterial pathogens.

项目摘要立克属的细菌是债务内内共生体和许多显着的属性剂人类和动物感染。这些细菌是通过血型节肢动物传播给人类的。致病性立克物种使电路系统的寄生细胞寄生，导致血管泄漏显着发病率和死亡率。人力病物种是历史上最重要的病原体之一，有数百万人类与这些感染有关的死亡。完成系统是哺乳动物免疫系统的众所周知的药水，在经典上被认为是脉管系统细胞外空间的分泌巡逻。直到最近它被认为是出乎意料的诸如完成系统之类的细胞外免疫成分会遇到像立克;更不用说这种进化会将这些系统带入对抗关系。因此，我们是才开始欣赏完成如何控制细胞内细菌感染。来自新兴数据立克和其他生物已经开始确定一些分子和细胞的完成机制针对细胞内病原体的功效。随着新出现的“细胞内完成”概念正在迅速获得牵引力，该提案中概述的实验将是重新定义先天免疫成分的核心发现一个多世纪前。基于临床和实验证据，我们假设完成是必不可少的为了有效地免疫反应，以履行细胞内人力体感染。但是，实验数据表明完成效率并非直接来自完成的抗菌成分。反而，针对立克的补体效率来自与免疫系统其他部分的二次相互作用。因此，我们的目标是1）评估完成的促炎成分对反雷克西亚的贡献免疫反应，以及2）定义免疫系统的完整诱导的成分，该组件专门针对细胞内病原体。通过研究完整和临床相关病原体之间的相互作用，实现的结果将提高我们对基本完成生物学的集体理解，进一步定义特定对立克感染的免疫反应，直接影响抗瑞克疫苗的设计，并提供将来研究的前提，以分析完成操作作为预防或治疗干预措施细胞内细菌病原体。