Neisseria gonorrhoeas is the only causative agent of the sexually transmitted infection, gonorrhea. One of the hallmarks of gonococcal infection is the lack of immunity to reinfection, even after repeated expose to the organism. We are studying the process of pilin antigenic variation (Av), which is one of the important facets of gonococcal (Gc) pathogenesis. First, it allows immune evasion by the bacterium and continual retransmission through the high risk/core group of infected people. Second, it controls the expression of one of the primary virulence factors of this bacterium (the pilus). Third, the functional properties of the pilus can be altered by pilin Av, and the pilus functions in the initiating events of colonization. We have been determining how this human specific pathogen mediates the high frequency genomic rearrangements that are the basis of pilin Av. We have made outstanding progress on this project as outlined in this document and have developed a leadership position in understanding the molecular mechanisms behind any Av system. We have published 13 peer-reviewed papers with the support of this grant in the past 3.5 years, nine of which are directly related to the goals of this project in determining the mechanisms behind pilin Av. We will pursue four major areas during the extension period of this MERIT Award. First, we will determine how a new gene product we have identified functions in pilin Av. Second, we will define a c/s- acting site we have defined as being essential for pilin Av. Third, we will define the recombination intermediates of pilin Av using strain we have isolated which accumulate intermediate structures that interfere with growth of the organism. Forth, we will investigate why inactivation of two genes in the threonine biosynthesis pathway interfere with pilin Av. Understanding the mechanisms used to direct and control pilin Av is essential to understanding this aspect of the pathogenesis of gonococcal disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Hiltke, Thomas J
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Northwestern University at Chicago
Schools of Medicine
United States
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Obergfell, Kyle P; Schaub, Ryan E; Priniski, Lauren L et al. (2018) The low-molecular-mass, penicillin-binding proteins DacB and DacC combine to modify peptidoglycan cross-linking and allow stable Type IV pilus expression in Neisseria gonorrhoeae. Mol Microbiol :
Quillin, Sarah J; Hockenberry, Adam J; Jewett, Michael C et al. (2018) Neisseria gonorrhoeae Exposed to Sublethal Levels of Hydrogen Peroxide Mounts a Complex Transcriptional Response. mSystems 3:
Quillin, Sarah Jane; Seifert, H Steven (2018) Neisseria gonorrhoeae host adaptation and pathogenesis. Nat Rev Microbiol 16:226-240
Xu, Jing; Seifert, H Steven (2018) Analysis of Pilin Antigenic Variation in Neisseria meningitidis by Next-Generation Sequencing. J Bacteriol 200:
Seifert, H Steven (2017) Haemophilus spills its guts to make a biofilm. Proc Natl Acad Sci U S A 114:8444-8446
Lenz, Jonathan D; Stohl, Elizabeth A; Robertson, Rosanna M et al. (2016) Amidase Activity of AmiC Controls Cell Separation and Stem Peptide Release and Is Enhanced by NlpD in Neisseria gonorrhoeae. J Biol Chem 291:10916-33
Rotman, Ella; Webber, David M; Seifert, H Steven (2016) Analyzing Neisseria gonorrhoeae Pilin Antigenic Variation Using 454 Sequencing Technology. J Bacteriol 198:2470-82
Peak, Ian R; Chen, Adrienne; Jen, Freda E-C et al. (2016) Neisseria meningitidis Lacking the Major Porins PorA and PorB Is Viable and Modulates Apoptosis and the Oxidative Burst of Neutrophils. J Proteome Res 15:2356-65
Anderson, Mark T; Byerly, Luke; Apicella, Michael A et al. (2016) Seminal Plasma Promotes Neisseria gonorrhoeae Aggregation and Biofilm Formation. J Bacteriol 198:2228-35
Palmer, Guy H; Bankhead, Troy; Seifert, H Steven (2016) Antigenic Variation in Bacterial Pathogens. Microbiol Spectr 4:

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