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* Department of Medicine, Division of Infectious Diseases,
Curriculum in Oral Biology,
Department of Microbiology and Immunology,
Lineberger Comprehensive Cancer Center,
¶ Curriculum in Genetics and Molecular Biology, and
|| Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and
# Department of Laboratory Medicine, University of California at San Francisco, CA 94121
Neisseria gonorrhoeae is a common sexually transmitted pathogen that significantly impacts female fertility, neonatal health, and transmission of HIV worldwide. N. gonorrhoeae usually causes localized inflammation of the urethra and cervix by inducing production of IL-1β and other inflammatory cytokines. Several NLR (nucleotide-binding domain, leucine-rich repeat) proteins are implicated in the formation of pro-IL-1β-processing complexes called inflammasomes in response to pathogens. We demonstrate that NLRP3 (cryopyrin, NALP3) is the primary NLR required for IL-1β/IL-18 secretion in response to N. gonorrhoeae in monocytes. We also show that N. gonorrhoeae infection promotes NLRP3-dependent monocytic cell death via pyronecrosis, a recently described pathway with morphological features of necrosis, including release of the strong inflammatory mediator HMBG1. Additionally, N. gonorrhoeae activates the cysteine protease cathepsin B as measured by the breakdown of a cathepsin B substrate. Inhibition of cathepsin B shows that this protease is an apical controlling step in the downstream activities of NLRP3 including IL-1β production, pyronecrosis, and HMGB1 release. Nonpathogenic Neisseria strains (Neisseria cinerea and Neisseria flavescens) do not activate NLRP3 as robustly as N. gonorrhoeae. Conditioned medium from N. gonorrhoeae contains factors capable of initiating the NLRP3-mediated signaling events. Isolated N. gonorrhoeae lipooligosaccharide, a known virulence factor from this bacterium that is elaborated from the bacterium in the form of outer membrane blebs, activates both NLRP3-induced IL-1β secretion and pyronecrosis. Our findings indicate that activation of NLRP3-mediated inflammatory response pathways is an important venue associated with host response and pathogenesis of N. gonorrhoeae.
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1 This work was supported by the University of North Carolina Multidisciplinary Clinical Research Career Development Award (National Institutes of Health Grant RR023248) and the Developmental Awards Program of the National Institutes of Health-National Institute of Allergy and Infectious Diseases Sexually Transmitted Infections and Topical Microbicide Cooperative Research Centers grants to the University of Washington (Grant AI 31448) and the University of North Carolina (Grant AI031496 to J.A.D.). Additional support for this project was provided by the National Institutes of Health: Grant AI63031 to J.P.-Y.T., Grant AI031496 to P.F.S. and C.E.T., and Grant AI063927 to G.A.J. The Lineberger Postdoctoral Training Programs supported D.T.B. B.P.O. is supported by the Irvington Institute Fellowship.
2 Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, University of North Carolina at Chapel Hill, Campus Box 7295, Chapel Hill, NC 27499. E-mail address: jenny_ting{at}med.unc.edu
3 Abbreviations used in this paper: CLR, C-lectin receptor; LOS, lipooligosaccharide; PARP, poly(ADP-ribose) polymerase; GC, gonococci; shRNA, small hairpin RNA; MOI, multiplicity of infection; LDH, lactate dehydrogenase; PMN, polymorphonuclear; GCB, gonococcal media base; ASC, apoptotic speck protein-containing a caspase recruitment domain.
4 The online version of this article contains supplemental material.
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