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

• 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
• 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

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.

淋病奈瑟菌 (Ngo) 是性传播感染 (STI) 淋病的病原体，是一种高度 全球每年约有 1 亿例发病。令人震惊的是，治疗和药理学 全球出现对所有淋病均具有耐药性的“超级细菌”菌株，导致治疗淋病的方法受到威胁 临床上有用的抗生素。淋球菌非常适应人类的生活，以至于它们已经排出了 大部分其他细菌的典型代谢能力取决于独特的策略 定植于人体粘膜组织时进行复制和免疫逃避。反映这种专业化，Ngo 基因组编码的蛋白质数量不到在更典型的细菌（例如大肠杆菌）中观察到的蛋白质数量的一半。一个 生物学之谜是奈瑟氏球菌基因组如何进化以利用各种粘膜生态位以及如何进化 菌株变异有助于发病机制。我们的假设是，这取决于专门的蛋白质-蛋白质 交互网络，并且获得这些知识将具有重大的临床价值，因为它将揭示 淋球菌独特需要的蛋白质复合物和过程，但共生物种则不然，因为 它们具有独特的功能能力，或者因为较小的奈瑟氏菌基因组缺乏功能冗余 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 研究策略是生成淋球菌的全局蛋白质相互作用网络，提供详细的 对 Ngo 在感染过程中使用的专门细胞装置进行基于系统的理解。尽管 群体基因组、转录谱和遗传筛选为非政府组织提供了宝贵的见解 生物学，这些研究将通过与综合路线图的整合获得显着的好处 详细描述支持生长和感染表型的蛋白质复合物的组织。临床关键 该项目的相关性是通过感染性临床调查来关注菌株变异的影响 Ngo 的分离株，得到 Ngo 群体基因组学补充研究的支持。我们将结合 定量质谱、网络分析、比较基因组学和体外靶向诱变 和体内表型分析，以阐明对感染和感染至关重要的大分子蛋白质组装体 临床上在生殖器粘膜内持续存在。到本次拨款结束时，我们将确定关键的保守 驱动淋球菌生长、感染和适应人类粘膜的物理回路的组成部分 组织，为其独特的病理生物学提供机制见解，并为未来的临床奠定基础 对抗传染病的干预策略。