Mapping Protein Interaction Networks Essential for Gonococcal Pathogenesis

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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.