Global Analysis of Neutrophil Responses to Neisseria gonorrhoeae Reveals a Self-Propagating Inflammatory Program

PLoS Pathogens

Clifford P. Stanners¹  Carlos H. F. Chan¹  Scott D. Gray-Owen²  Helen Sarantis²  Mohsen Amin²  Anna Sintsova²  Epshita A. Islam²  Chun Xiang Sun³  Michael Glogauer³ 

[1] Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada;Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

关键词: Neutrophils;    Neisseria gonorrhoeae;    Cytokines;    Inflammation;    Respiratory burst;    Transcription factors;    Gonorrhea;    Phagocytosis;   

DOI  :  10.1371/journal.ppat.1004341

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY