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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.

淋病奈瑟菌（Neisseria gonorrhoeae, Ngo）是性传播感染（STI）淋病的病原，发病率高