Mapping Protein Interaction Networks Essential for Gonococcal Pathogenesis

淋病奈瑟菌（Neisseria gonorrhoeae，Ngo）是性传播感染（sexually transmitted infection，STI）淋病的病原体， 全球每年约有1亿例发病。令人担忧的是，治疗和药理学 治疗淋病的方法正受到全球出现的对所有细菌都有抗药性的“超级细菌”菌株的威胁。 临床上有用的抗生素。淋球菌非常适应人类的生活， 大部分的代谢能力典型的其他细菌，并取决于独特的战略，允许 复制和免疫逃避，同时定殖人类粘膜组织。为了反映这种专业化，Ngo 基因组编码的蛋白质数量不到在更典型的细菌如大肠杆菌中观察到的蛋白质数量的一半。杆菌一 生物学上的一个谜就是奈瑟菌基因组是如何进化到利用各种粘膜小生境的， 菌株变异有助于致病。我们的假设是，这取决于专门的蛋白质-蛋白质 交互网络，获得这些知识将具有重大的临床价值，因为它将揭示 蛋白复合物和过程是淋球菌而不是淋病菌种所特有的， 或者因为较小的奈瑟球菌基因组缺乏功能冗余 使其他细菌能够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球蛋白质相互作用网络， 系统为基础的理解Ngo在感染过程中使用的专门细胞装置。而 群体基因组、转录谱分析和遗传筛选为Ngo提供了有价值的见解 生物学，这些研究将通过与综合路线图的整合获得显着利益， 详细描述了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研究关注菌株变异的影响。 Ngo的分离物，由Ngo的群体基因组学的补充调查支持。我们将联合收割机 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，以阐明对感染至关重要的大分子蛋白质组装， 在生殖器粘膜内的临床持久性。到本补助金结束时，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电路组件 组织，提供其独特的病理生物学机制的见解，并奠定了未来的临床基础， 防治传染病的干预战略。

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.