title: Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program.
abstract: An overwhelming neutrophil-driven response causes both acute symptoms and the lasting sequelae that result from infection with Neisseria gonorrhoeae. Neutrophils undergo an aggressive opsonin-independent response to N. gonorrhoeae, driven by the innate decoy receptor CEACAM3. CEACAM3 is exclusively expressed by human neutrophils, and drives a potent binding, phagocytic engulfment and oxidative killing of Opa-expressing bacteria. In this study, we sought to explore the contribution of neutrophils to the pathogenic inflammatory process that typifies gonorrhea. Genome-wide microarray and biochemical profiling of gonococcal-infected neutrophils revealed that CEACAM3 engagement triggers a Syk-, PKCδ- and Tak1-dependent signaling cascade that results in the activation of an NF-κB-dependent transcriptional response, with consequent production of pro-inflammatory cytokines. Using an in vivo model of N. gonorrhoeae infection, we show that human CEACAM-expressing neutrophils have heightened migration toward the site of the infection where they may be further activated upon Opa-dependent binding. Together, this study establishes that the role of CEACAM3 is not restricted to the direct opsonin-independent killing by neutrophils, since it also drives the vigorous inflammatory response that typifies gonorrhea. By carrying the potential to mobilize increasing numbers of neutrophils, CEACAM3 thereby represents the tipping point between protective and pathogenic outcomes of N. gonorrhoeae infection.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Sintsova
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Sarantis
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Epshita A
authors.initials: EA
authors.lastname: Islam
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chun Xiang
authors.initials: CX
authors.lastname: Sun
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amin
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Carlos H F
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Clifford P
authors.initials: CP
authors.lastname: Stanners
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D015415:Biomarkers / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006069:Gonorrhea / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009344:Neisseria gonorrhoeae / Q000276:immunology / Q000472:pathogenicity*; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010587:Phagocytosis / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D015415:Biomarkers; C075729:CEACAM3 protein, human; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse