Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection gonorrhea. Genital gonorrhea is common in both genders, but has significant morbidity for women who are more frequently asymptomatically infected. Gonococcal infection in women has a range of symptoms that starts with dysuria and discharge and can end in conditions including pelvic inflammatory disease, internal abscess, ectopic pregnancy, or infertility. Infected individuals do not develop protective immunity, and the bacteria are rapidly developing antibiotic resistance. It is conceivable that soon we will not have an effective way to treat gonococcal infection. This issue has resulted in an increased incentive to develop a vaccine to prevent gonococcal disease. This study seeks to add to the field by exploring gonococcal properties that can be exploited for human vaccines or therapies. Interestingly, this pathogen has evolved to exclusively infect humans. In so doing, it has adapted unique methods of obtaining nutrients, including hijacking human proteins to acquire the essential nutrient iron. The gonococcal transferrin-iron acquisition system is composed of an integral, outer-membrane, TonB dependent transporter (TbpA), and a surface exposed lipo-protein (TbpB). This system is an ideal target for vaccine and drug development because it is plays a role in bacterial essential nutrient uptake, it is surface exposed, and the protein sequences are well conserved across strains. Previous studies have shown that gonococci lacking the transferrin iron acquisition system are incapable of initiating infection in human males. In addition, whole protein and epitope specific vaccine formulations derived from these proteins have shown growth inhibitory and bactericidal properties. Recently, crystal structures have been solved for TbpA and TbpB from the closely related pathogen Neisseria meningitidis. With a high level of sequence conservation between these two species, these crystals have been used to predict the three dimensional structure for the gonococcal proteins. This new information dramatically enhances the ability to target Tbp functional domains, which has significantly moved this field forward. This study will employ site specific mutagenesis of surface exposed loops of TbpA to assess key structure- function relationships in its interactions with human transferrin. In addition, several surface exposed loop peptides will be synthesized and will be used to immunize mice. The original peptides and the resulting sera will independently be characterized for their ability to interfere with TbpA-transferrin interactions. The goals of this study are to contribute to the understanding of how this receptor complex functions and to determine optimal targets for vaccine and drug development, such that new therapies can be developed for gonococcal infection before current treatments are rendered obsolete by acquired antibiotic resistance.

Public Health Relevance

Gonorrhea is a common sexually transmitted infection that can have severe long term consequences, especially for women. This project's goals are to better understand how the bacteria that cause this infection acquire the essential nutrient iron from the human protein transferrin and to explore ways we might be able to block the bacteria from doing so. Information we gain in this study will be applied to vaccine and drug development efforts, so that new options become available as the pathogen becomes resistant to old treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Hiltke, Thomas J
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Virginia Commonwealth University
Schools of Medicine
United States
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Kandler, Justin L; Acevedo, Rosuany VĂ©lez; Dickinson, Mary Kathryne et al. (2016) The genes that encode the gonococcal transferrin binding proteins, TbpB and TbpA, are differentially regulated by MisR under iron-replete and iron-depleted conditions. Mol Microbiol 102:137-51
Booth, Laurence; Roberts, Jane L; Cash, Devin R et al. (2015) GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease. J Cell Physiol 230:1661-76
Cash, Devin R; Noinaj, Nicholas; Buchanan, Susan K et al. (2015) Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae. Infect Immun 83:4438-49