Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

项目总结 立克次体属细菌是专性的胞内共生体和许多重要的病原体。 人类和动物感染。这些细菌通过食血节肢动物传播给人类。致病 立克次体寄生于循环系统内皮细胞，导致血管渗漏 发病率和死亡率。立克次体是历史上最重要的病原体之一，有数百万人 与这些感染相关的死亡人数。 补体系统是哺乳动物免疫系统的一种众所周知的药剂，经典的 被认为是血管系统细胞外空间的秘密守护员。直到最近，人们还认为这不太可能 像补体系统这样的细胞外免疫成分会遇到像这样的细胞内病原体 更不用说进化会将这些系统推向敌对关系。因此，我们是 人们才开始意识到补体如何控制细胞内的细菌感染。来自以下方面的新兴数据 立克次体和其他生物已经开始识别补体的一些分子和细胞机制 对抗细胞内病原体的功效。随着“细胞内补体”这一新概念的迅速发展 牵引，这项提案中概述的实验将是重新定义一种先天免疫成分的核心， 在一个多世纪前被发现。 根据临床和实验证据，我们假设补体激活是必不可少的。 对专性细胞内立克次体感染的有效免疫反应。然而，实验数据表明， 补体的功效并不直接来自补体的抗菌成分。相反， 补体对立克次体的疗效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)评估补体的促炎成分对抗立克次体的作用 免疫反应，以及2)定义补体诱导的免疫系统中特定靶向的组件 细胞内的病原体。通过研究补体和临床相关病原体之间的相互作用， 所取得的成果将促进我们对基本补体生物学的集体理解，进一步明确具体的 对立克次体感染的免疫应答，直接影响抗立克次体疫苗的设计，为预防和预防立克次体感染提供依据。 未来研究分析补体操作作为预防或治疗性干预的前提 细胞内细菌病原体。

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.