Discovery of novel, ubiquitin-regulated mechanisms of TB control by macrophages

发现巨噬细胞控制结核病的新型泛素调节机制

基本信息

批准号：
9228923
负责人：
JEFFERY S COX
金额：
$ 72.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2015-08-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228923
关键词：
Acetylation Affect Anti-Bacterial Agents Antibiotics Area Autophagocytosis Bacteria Bacterial Infections Bioinformatics Biological Biology Cell Death Cell Survival Cell physiology Cells Chemicals Chronic Data Set Event Gene Expression Genetic Genetic Screening Genetic Transcription Genetic study Global Change Glycine Goals Growth Human Genetics Immune Immune system Immunologic Receptors Individual Infection Innate Immune Response Innate Immune System Integration Host Factors Interferons Lead Mass Spectrum Analysis Measures Mediating Metabolic Pathway Metabolism Methods Modification Molecular Monitor Mycobacterium tuberculosis Nature Outcome Pathogenesis Pathogenicity Pathway interactions Phagocytes Phosphorylation Pilot Projects Play Post-Translational Protein Processing Process Proteins Proteome Proteomics Reaction Resistance Role Shapes Signal Transduction Site-Directed Mutagenesis System TRAF6 gene Technology Therapeutic Time Tissues Tuberculosis Ubiquitin Work design experimental study global health human morbidity human mortality in vivo inhibitor/antagonist macrophage microorganism novel novel therapeutics overexpression pathogen protein degradation protein function public health relevance response targeted treatment tool trafficking transcription factor ubiquitin ligase ubiquitin-protein ligase virtual

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, remains a major cause of human morbidity and mortality, particularly in the developing world. Chronic M. tuberculosis infection requires long- term interactions between the bacterium and host immune system, and tissue macrophages play key roles in the outcome of infection. Although technologies to monitor global changes in host gene expression have catalyzed our understanding of the important roles for TLR activation and interferon during TB infection, modulation of transcription represents only one of many cellular responses to bacterial infection. Post- translational modification of proteins, such as ubiquitylation, phosphorylation, and acetylation play a role in regulating virtually every cellular process. How these signaling events lead to observed changes in metabolic pathways, autophagy, and vesicular trafficking during bacterial infection remain unknown. Furthermore, how these processes may be manipulated by pathogens is crucial for understanding the pathogenic strategies of microorganisms. This proposal seeks to use powerful new proteomic technologies to globally quantify changes in ubiquitylation in order to identify novel functional macrophage responses to M. tuberculosis infection. Our preliminary experiments utilizing this approach have uncovered profound changes in host protein ubiquitylation in response to intracellular pathogens. These studies have provided the first glimpse into a vast unknown of post-translational modifications during innate immune responses. Our hypothesis is that these changes play fundamental roles in shaping the subsequent innate responses to infection by controlling autophagy, metabolism, protein degradation, and signaling, and may be manipulated by pathogens for their own benefit. Our preliminary genetic work indicates that novel pathways are controlled by ubiquitylation during infection and are capable of restricting M. tuberculosis growth in macrophages, further validating the power of this approach to uncover new biology. Ultimately, our long-term goal is to harness these powerful immune mechanisms for therapeutic purposes.

描述（由应用提供）：结核病（TB）是由结核分枝杆菌感染引起的，仍然是人类发病率和死亡率的主要原因，尤其是在发展中国家。慢性结核病感染需要细菌与宿主免疫系统之间的长期相互作用，组织巨噬细胞在感染结果中起关键作用。尽管监测宿主基因表达的全局变化的技术已经催化了我们对TB感染期间TLR激活和干扰素重要作用的理解，但转录的调节仅代表了许多细胞对细菌感染的反应之一。蛋白质的翻译后修饰，例如泛素化，磷酸化和乙酰化，在控制几乎每个细胞中都起作用过程。这些信号事件如何导致在细菌感染期间观察到代谢途径，自噬和囊泡运输的变化仍然未知。此外，如何通过病原体操纵这些过程对于理解微生物的致病策略至关重要。该提案试图使用强大的新蛋白质组学技术来量化泛素化的变化，以鉴定对结核分枝杆菌感染的新型功能性巨噬细胞反应。我们利用这种方法的初步实验发现了响应细胞内病原体的宿主蛋白泛素化的深刻变化。这些研究为先天免疫反应期间的巨大翻译后修饰提供了第一个瞥见。我们的假设是，这些变化在通过控制自噬，代谢，蛋白质降解和信号传导来塑造随后对感染的先天反应中起着基本作用，并且可以通过病原体来为自己的利益而操纵。我们的初步遗传工作表明，新的途径是通过感染过程中泛素化控制的，并且能够限制巨噬细胞中结核分枝杆菌的生长，进一步验证这种方法的能力以发现新的生物学。最终，我们的长期目标是利用这些强大的免疫机制用于治疗目的。