Neisseria gonorrhoeae is a human pathogen that can persists on the mucosa for lengthy periods without causing overt symptoms of disease. Clinical and basic findings suggest that the onset of sympomatic infection may be due to a shift in the delicate balance between quiescence and virulence. The N. gonorrhoeae Type IV pilus (Tfp) plays a major role in the early stages of attachment. Tfp initiates a multi-dimensional communication system between the bacterium and the host, activating signaling pathways that reduce host cell toxicity and enhance host cell survival. N. gonorrhoeae produces a glycoprotease, Gcp, that affects Tfp dynamics and invasion. The gcp mutant produces Tfp fibers that bundle together in great numbers, and these bundles retract with higher force than the wt strain. The mutant is more invasive, implying that Gcp normally reduces virulence. We will test the hypothesis that these phenotypes are mechanistically related, and that they have their basis in Gcp processing/modification of pilin (the Tfp structural subunit) and host cell proteins. The overall goal of this study is to understand the factors that affect the cell biology and biophysics of Tfp-mediated infection, as they have the potential to disturb this balance between host and pathogen. Project Narrative Neisseria gonorrhoeae, a sexually transmitted pathogen of humans, can persist on the mucosal surface for lengthy periods without causing overt disease. Several findings suggest that symptomatic gonococcal infection may be due to a shift in the delicate balance between quiescence and virulence that had been established early in infection.
The aim of this proposal is to determine how the neisserial glycoprotease, Gcp, affects this balance through its activity on bacterial and host cell proteins.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Hiltke, Thomas J
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University of Arizona
Schools of Medicine
United States
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Baker, Joseph L; Biais, Nicolas; Tama, Florence (2013) Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition. PLoS Comput Biol 9:e1003032
Biais, Nicolas; Higashi, Dustin; So, Magdalene et al. (2012) Techniques to measure pilus retraction forces. Methods Mol Biol 799:197-216
Lynch, Christopher D; Gauthier, Nils C; Biais, Nicolas et al. (2011) Filamin depletion blocks endoplasmic spreading and destabilizes force-bearing adhesions. Mol Biol Cell 22:1263-73
Biais, Nicolas; Higashi, Dustin L; Brujic, Jasna et al. (2010) Force-dependent polymorphism in type IV pili reveals hidden epitopes. Proc Natl Acad Sci U S A 107:11358-63
Moore, Simon W; Biais, Nicolas; Sheetz, Michael P (2009) Traction on immobilized netrin-1 is sufficient to reorient axons. Science 325:166