Understanding the role of Ngo1049 in subverting host-mediated metal starvation in Neisseria gonorrhoeae

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Abstract Neisseria gonorrhoeae (Ngo) is an obligate human bacterial pathogen that causes the sexually transmitted infection gonorrhea. Due to increasing rates of gonorrhea and increased antibiotic resistance, vaccines and new therapeutics are urgently needed. A promising strategy is targeting nutrient metal acquisition systems since they are usually conserved, expressed during infection, and essential for bacterial survival in vivo. Ngo undermines host metal restriction mechanisms by expressing outer membrane transporters to acquire essential metals from human metal-sequestering proteins such zinc from calprotectin and psoriasin and iron from lactoferrin and transferrin. However, many gene products that support Ngo growth in metal-limiting conditions remain uncharacterized. We found that the product of the ngo1049 gene is highly expressed in Ngo grown under zinc- limiting conditions. Ngo1049 is conserved among pathogenic Neisseria, and bioinformatic analysis predicts that Ngo1049 is a metal-binding transferase localized in the periplasm. A Zur binding motif was identified upstream of ngo1049, suggesting expression is regulated by Zur (zinc uptake regulator), which represses expression in high zinc concentrations. ngo1049 transcripts are highly induced during Ngo infection of human endocervical cells, indicating a potential role for Ngo1049 in Ngo pathogenesis. Based on these findings, I hypothesize Ngo1049 is a Zur-regulated protein that facilitates zinc acquisition in metal-limited conditions at inflamed epithelial surfaces. To test this hypothesis, in this F31-Diversity submission I propose to determine the localization and regulation mechanism(s) of Ngo1049. Second, I will examine the contribution of Ngo1049 to zinc acquisition in metal-limiting conditions. Lastly, I will define how Ngo1049 enables Ngo survival at inflamed mucosal surfaces after exposure to epithelial cells and human immune cells that contain metal chelating proteins. By defining this new member of the Ngo metal regulon, my work will potentially point to new therapies for this antibiotic-resistant bacterium. Through its combination of bacterial physiology and genetics, biochemistry, and cellular microbiology, as well as the professional development opportunities available to me during my graduate training, this project will provide me with the background and expertise to pursue a career as the leader of an academic research laboratory in host-pathogen interactions.