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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Anderson, Mark T; Dewenter, Lena; Maier, Berenike et al. (2014) Seminal plasma initiates a Neisseria gonorrhoeae transmission state. MBio 5:e01004-13
Chen, Adrienne; Seifert, H Steven (2014) Saturating mutagenesis of an essential gene: a majority of the Neisseria gonorrhoeae major outer membrane porin (PorB) is mutable. J Bacteriol 196:540-7
Chen, Adrienne; Seifert, H Steven (2013) Structure-function studies of the Neisseria gonorrhoeae major outer membrane porin. Infect Immun 81:4383-91
Anderson, Mark T; Seifert, H Steven (2013) Phase variation leads to the misidentification of a Neisseria gonorrhoeae virulence gene. PLoS One 8:e72183
Cahoon, Laty A; Manthei, Kelly A; Rotman, Ella et al. (2013) Neisseria gonorrhoeae RecQ helicase HRDC domains are essential for efficient binding and unwinding of the pilE guanine quartet structure required for pilin antigenic variation. J Bacteriol 195:2255-61
Cahoon, Laty A; Seifert, H Steven (2013) Transcription of a cis-acting, noncoding, small RNA is required for pilin antigenic variation in Neisseria gonorrhoeae. PLoS Pathog 9:e1003074
Stohl, Elizabeth A; Dale, Erin M; Criss, Alison K et al. (2013) Neisseria gonorrhoeae metalloprotease NGO1686 is required for full piliation, and piliation is required for resistance to H2O2- and neutrophil-mediated killing. MBio 4:
Stohl, Elizabeth A; Chan, Yolande A; Hackett, Kathleen T et al. (2012) Neisseria gonorrhoeae virulence factor NG1686 is a bifunctional M23B family metallopeptidase that influences resistance to hydrogen peroxide and colony morphology. J Biol Chem 287:11222-33
Criss, Alison K; Seifert, H Steven (2012) A bacterial siren song: intimate interactions between Neisseria and neutrophils. Nat Rev Microbiol 10:178-90
Cahoon, Laty A; Seifert, H Steven (2011) Focusing homologous recombination: pilin antigenic variation in the pathogenic Neisseria. Mol Microbiol 81:1136-43

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