Deciphering ubiquitin-regulated host responses to the intracellular pathogen Legi

破译泛素调节的宿主对细胞内病原体 Legi 的反应

• 批准号: 8226935
• 负责人: Craig R. Roy
• 金额: $ 22.04万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226935
• 关键词: Animal Model; Bacteria; Bacterial Typing; Binding; Biochemical; Biogenesis; Biological; Breathing; Cell Proliferation; Cell physiology; Cell surface; Cells; Cellular Stress Response; Computer Simulation; Cues; Cytosol; Data; Detection; Disease Outbreaks; Engineering; Enzymes; Evolution; Fresh Water; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Infection; Inflammatory; Invaded; Knowledge; Legionella; Legionella pneumophila; Legionnaires' Disease; Lipids; Maps; Methodology; Microbe; Modification; Molecular; Molecular Profiling; Monitor; Outcome; Pathway interactions; Process; Proteins; Proteomics; Protozoa; Regulation; Sensory; Signal Transduction; Site; Source; Staging; Stimulus; Stress Response Signaling; Swimming; Systems Biology; Translations; Type IV Secretion System Pathway; Ubiquitin; Ubiquitination; Vacuole; Virulent; Water; aerosolized; antimicrobial; base; combat; cytokine; design; human FRAP1 protein; in vivo; interest; macrophage; mutant; novel; pathogen; pathogenic bacteria; respiratory; response; surveillance network; trafficking; ubiquitin ligase

DESCRIPTION (provided by applicant): Distinguishing pathogenic from non-pathogenic microbes presents an interesting challenge to the host immune system and is critical for eliciting the appropriate immune response to combat the invading pathogen. Vacuolar pathogens have evolved multiple strategies to manipulate host functions to promote intracellular survival, necessitating co-evolution of immune molecular sensory networks that detect the pathogen attempts at subversion. To dissect how this process occurs at the molecular level we have developed methodology that monitors modifications on host proteins to reverse-engineer the host response networks to pathogenic infection in silico. To this end, we are using the respiratory pathogen Legionella pneumophila as a model organism to decipher specific regulation of host cellular pathways to pathogenic challenge. The overall goal of the project is to use biochemical and molecular approaches to characterize how cellular pathways in macrophages utilize regulatory molecular modifications, such as ubiquitin, to specifically alter the outcome of signaling cascades in response pathogenic infection. Specific emphasis is placed on the cellular cascades that coordinate the cytokine response of innate immune cells. PUBLIC HEALTH RELEVANCE: Deciphering the molecular interactions between the respiratory bacterial pathogen Legionella pneumophila and cells of the innate immune system will uncover how the host distinguishes virulent from avirulent microbes to initiate appropriate antimicrobial responses. This knowledge will ultimately aid in the design of more effective antimicrobial therapies.

描述（由申请人提供）：区分致病性和非致病性微生物对宿主免疫系统提出了一个有趣的挑战，并且对于引发适当的免疫应答以对抗入侵的病原体至关重要。嗜酸性病原体已经进化出多种策略来操纵宿主功能以促进细胞内存活，这使得检测病原体颠覆企图的免疫分子感觉网络的共同进化成为必要。为了剖析这一过程如何在分子水平上发生，我们开发了一种方法，该方法监测宿主蛋白质的修饰，以通过计算机对病原体感染的宿主反应网络进行反向工程。为此，我们正在使用呼吸道病原体嗜肺军团菌作为模式生物，以破译宿主细胞途径对病原体挑战的特异性调节。该项目的总体目标是使用生物化学和分子方法来表征巨噬细胞中的细胞通路如何利用调节分子修饰，如泛素，以特异性地改变响应病原性感染的信号级联的结果。特别强调的是放在协调先天免疫细胞的细胞因子反应的细胞级联。 公共卫生相关性：破译呼吸道细菌病原体嗜肺军团菌和先天免疫系统细胞之间的分子相互作用，将揭示宿主如何区分有毒和无毒的微生物，以启动适当的抗菌反应。这些知识最终将有助于设计更有效的抗菌疗法。