Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program

Anna Sintsova; Helen Sarantis; Epshita A Islam; Chun Xiang Sun; Mohsen Amin; Carlos H F Chan; Clifford P Stanners; Michael Glogauer; Scott D Gray-Owen

doi:10.1371/journal.ppat.1004341

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Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program

Journal article

Open access

Peer reviewed

Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program

Anna Sintsova, Helen Sarantis, Epshita A Islam, Chun Xiang Sun, Mohsen Amin, Carlos H F Chan, Clifford P Stanners, Michael Glogauer and Scott D Gray-Owen

PLoS pathogens, Vol.10(9), e1004341

09/2014

DOI: 10.1371/journal.ppat.1004341

PMCID: PMC4154863

PMID: 25188454

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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.

Oxidative Stress

Signal Transduction

Inflammation - pathology

Oligonucleotide Array Sequence Analysis

Protein-Tyrosine Kinases - metabolism

Humans

Carcinoembryonic Antigen - genetics

Gene Expression Profiling

Intracellular Signaling Peptides and Proteins - metabolism

Carcinoembryonic Antigen - metabolism

Inflammation - metabolism

Inflammation Mediators - metabolism

Neisseria gonorrhoeae - immunology

Neutrophils - microbiology

Neisseria gonorrhoeae - pathogenicity

Syk Kinase

Biomarkers - metabolism

Gonorrhea - microbiology

Cytokines - metabolism

Enzyme-Linked Immunosorbent Assay

Gonorrhea - immunology

Neutrophils - immunology

Phagocytosis - physiology

Mice, Transgenic

Inflammation - etiology

Bacterial Adhesion

Gonorrhea - metabolism

Animals

Mice

Details

Title: Subtitle: Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program
Creators: Anna Sintsova - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Helen Sarantis - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Epshita A Islam - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Chun Xiang Sun - Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
Mohsen Amin - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Carlos H F Chan - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
Clifford P Stanners - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
Michael Glogauer - Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
Scott D Gray-Owen - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.10(9), e1004341
DOI: 10.1371/journal.ppat.1004341
PMID: 25188454
PMCID: PMC4154863
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Publisher: Public Library of Science; United States
Grant note: MOP-15499 / Canadian Institutes of Health Research
Language: English
Date published: 09/2014
Academic Unit: Surgery; Radiation Oncology
Record Identifier: 9984047852002771

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