Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

项目摘要 立克次氏体属细菌是专性细胞内共生菌，是许多重要疾病的病原体。 人类和动物感染。这些细菌通过吸血节肢动物传播给人类。致病 立克次体寄生于循环系统的内皮细胞，引起血管渗漏， 发病率和死亡率。立克次体是历史上最重要的病原体之一，数百万人感染立克次体。 与这些感染有关的死亡。 补体系统是哺乳动物免疫系统的一个众所周知的组成部分， 被认为是血管系统细胞外空间的分泌巡逻者。直到最近， 像补体系统这样的细胞外免疫成分会遇到细胞内病原体， 立克次体;更不用说进化会驱使这些系统进入敌对关系。因此，我们 才刚刚开始了解补体是如何控制细胞内细菌感染的。新兴数据来自 立克次氏体和其他生物已经开始确定一些分子和细胞机制的补体 对细胞内病原体的功效。随着“细胞内补体”这一新兴概念的迅速普及， 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， 发现于世纪前。 基于临床和实验证据，我们假设补体激活是必需的 用于对专性细胞内立克次体感染的有效免疫应答。然而，实验数据表明， 补体功效不是直接由补体的抗菌成分产生的。相反地， 补体对立克次体的效力来源于与免疫系统其它部分的次级相互作用。 因此，我们的目的是1）评估补体的促炎成分对抗立克次体的贡献， 免疫应答，和2）定义特异性靶向免疫系统的补体诱导的组分 胞内病原体通过研究补体与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，进一步确定特定的补体分子。 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，并提供 未来研究分析补体操纵作为预防或治疗干预的前提 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.