Mapping Protein Interaction Networks Essential for Gonococcal Pathogenesis

绘制淋球菌发病机制所必需的蛋白质相互作用网络

基本信息

批准号：
10814526
负责人：
Andrew EMILI
金额：
$ 59.46万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2021-05-06 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10814526
关键词：
Address Animal Model Antibiotic Resistance Antibiotics Architecture Automobile Driving Awareness Bacteria Biological Biological Assay Biology Biomedical Research Cell Adhesion Cells Clinical Communicable Diseases Communities Comparative Genomic Analysis Computer Models Dependence Development Disease Drug resistance Environment Escherichia coli Etiology Female genitalia Foundations Future Gene Expression Profiling Generations Genetic Screening Genital Genitalia Genome Genomic approach Genomics Goals Gonorrhea Grant Growth Health Host resistance Human Immune Evasion In Vitro Incidence Infection Interdisciplinary Study Intervention Invaded Investigation Knowledge Knowledge acquisition Label Life Male Genital Organs Maps Mass Spectrum Analysis Mediating Metabolic Metabolism Methods Microbe Modeling Molecular Morbidity - disease rate Mucous Membrane Mutagenesis Neisseria gonorrhoeae Nutrient Outcome Pathogenesis Pathologic Pathway Analysis Phenotype Physiological Physiology Population Process Proteins Proteome Proteomics Recording of previous events Resistance Resistance to infection Resources Role Sexually Transmitted Agents Sexually Transmitted Diseases Stress Superbug System Systems Biology Technology Therapeutic Therapeutic Intervention Transgenic Mice Validation Variant Work chronic infection clinically relevant combat commensal bacteria comparative comparative genomics drug development drug discovery experimental study fitness follow-up frailty gene complementation human pathogen humanized mouse improved in vivo innovation insight macromolecule microbiome mouse model pathogen pharmacologic protein complex protein protein interaction reproductive tract research study resistant strain trend validation studies

项目摘要

Neisseria gonorrhoeae (Ngo) is the etiological agent of the sexually transmitted infection (STI) gonorrhea, a high morbidity disease with ~100 million cases worldwide each year. Alarmingly, therapeutic and pharmacologic approaches to treat gonorrhea are under threat by the global emergence of `superbug' strains resistant to all clinically useful antibiotics. Gonococci are exquisitely adapted to life in humans, to the extent that they have shed much of the metabolic capacity typical of other bacteria and depend upon unique strategies that allow for replication and immune evasion while colonizing human mucosal tissues. Reflecting this specialization, Ngo genomes encode less than half the number of proteins observed in more prototypical bacteria such as E. coli. A biological enigma then is how the neisserial genome has evolved to exploit a variety of mucosal niches and how strain variation contributes to pathogenesis. Our hypothesis is that this depends on specialized protein-protein interaction networks, and that acquiring this knowledge will have major clinical value because it would reveal protein complexes and processes uniquely required by gonococci but not commensal species, either because they have distinct functional capabilities or because the smaller neisserial genome lacks functional redundancy that allow other bacteria to overcome environmental or other stresses. The core goal of our multidisciplinary research strategy is the generation of global protein interaction networks of gonococci that offer a detailed systems-based understanding of the specialized cellular apparatus used by Ngo during infection. While population genomic, transcriptional profiling and genetic screens have provided valuable insights into Ngo biology, these studies would gain significant benefit through their integration with comprehensive roadmaps detailing the organization of protein complexes that support growth and infection phenotypes. Key to the clinical relevance of this project is a focus on the impact of strain variation through investigations of infectious clinical isolates of Ngo, supported by complementary investigations of the population genomics of Ngo. We will combine quantitative mass spectrometry, network analysis, comparative genomics and targeted mutagenesis with in vitro and in vivo phenotype analysis to illuminate macromolecular protein assemblies that are critical to infection and clinical persistence within the genital mucosa. By the end of this grant, we will have identified key conserved components of the physical circuitry driving gonococcal growth, infection and adaptation to human mucosal tissues, providing mechanistic insights into its unique pathobiology, and laying the foundation for future clinical intervention strategies to combat infectious disease.

Neisseria Gonorrhoeae（NGO）是性传播感染（STI）淋病的病因学药每年在全球范围内约有1亿例病例发病疾病。令人震惊的是，治疗和药理学促淋病治疗的方法受到“超级咬合”菌株对所有人的抗性的威胁临床上有用的抗生素。淋球菌非常适应人类的生命，以至于他们脱落了其他细菌典型的代谢能力大部分，并依赖于允许的独特策略复制和免疫逃避，同时定居于人粘膜组织。反映这种专业，非政府组织基因组编码在更原型细菌（例如大肠杆菌）中观察到的蛋白质数量的一半。一个然后，生物元素是奈瑟氏基因组如何进化以利用多种粘膜壁ni的发展以及如何发展菌株变异有助于发病机理。我们的假设是这取决于专用蛋白质蛋白质交互网络，而获取这些知识将具有主要的临床价值，因为它会揭示蛋白质复合物和过程是淋球菌所要求的，而不是共生物种，也不是因为它们具有独特的功能能力，或者因为较小的奈瑟氏基因组缺乏功能冗余这允许其他细菌克服环境或其他压力。我们多学科的核心目标研究策略是淋球菌的全球蛋白质相互作用网络的产生，该网络提供了详细的非政府组织在感染过程中使用的专门细胞设备的基于系统的理解。尽管人口基因组，转录分析和遗传筛选为非政府组织提供了宝贵的见解生物学，这些研究将通过与全面路线图的整合而获得可观的好处详细介绍支持生长和感染表型的蛋白质复合物的组织。临床的关键该项目的相关性是通过调查感染性临床的菌株变异的影响非政府组织的分离株，得到对非政府组织人群基因组学的补充研究的支持。我们将结合定量质谱法，网络分析，比较基因组学和靶向诱变，并在体外和体内表型分析，以阐明对感染至关重要的大分子蛋白质组件生殖器粘膜内的临床持久性。在这笔赠款的结束时，我们将确定保存密钥物理电路的组成部分驱动淋球菌生长，感染和对人粘膜的适应组织，为其独特的病理生物学提供机械洞察力，并为将来的临床奠定基础打击传染病的干预策略。