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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI033493-18
Application #
8013322
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hiltke, Thomas J
Project Start
1994-05-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
18
Fiscal Year
2011
Total Cost
$383,834
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Château, Alice; Seifert, H Steven (2016) Neisseria gonorrhoeae survives within and modulates apoptosis and inflammatory cytokine production of human macrophages. Cell Microbiol 18:546-60
Stohl, Elizabeth A; Lenz, Jonathan D; Dillard, Joseph P et al. (2016) The Gonococcal NlpD Protein Facilitates Cell Separation by Activating Peptidoglycan Cleavage by AmiC. J Bacteriol 198:615-22
Palmer, Guy H; Bankhead, Troy; Seifert, H Steven (2016) Antigenic Variation in Bacterial Pathogens. Microbiol Spectr 4:
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
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; Seifert, H Steven (2015) Neisseria gonorrhoeae MutS affects pilin antigenic variation through mismatch correction and not by pilE guanine quartet binding. J Bacteriol 197:1828-38
Obergfell, Kyle P; Seifert, H Steven (2015) Mobile DNA in the pathogenic Neisseria. Microbiol Spectr 3:
Obergfell, Kyle P; Seifert, H Steven (2015) Mobile DNA in the Pathogenic Neisseria. Microbiol Spectr 3:MDNA3-0015-2014
Zhang, Yan; Rajan, Rakhi; Seifert, H Steven et al. (2015) DNase H Activity of Neisseria meningitidis Cas9. Mol Cell 60:242-55
Gault, Joseph; Ferber, Mathias; Machata, Silke et al. (2015) Neisseria meningitidis Type IV Pili Composed of Sequence Invariable Pilins Are Masked by Multisite Glycosylation. PLoS Pathog 11:e1005162

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