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Endocervical and Neutrophil Lipoxygenases Coordinate Neutrophil Transepithelial Migration to Neisseria gonorrhoeae.

ABSTRACT: Background:Infection with Neisseria gonorrhoeae (GC) is characterized by robust neutrophil influx that is insufficient to clear the bacteria. Sustained neutrophilic inflammation contributes to serious clinical sequelae that particularly affect women, including pelvic inflammatory disease and infertility. Methods:We established a 3-component system using GC, End1 polarized human endocervical cells, and primary human neutrophils to investigate neutrophil transepithelial migration following infection. Results:Neutrophil migration across endocervical monolayers increased with the infectious dose and required GC-epithelial cell contact. Epithelial protein kinase C, cytosolic phospholipase A2, 12R-lipoxygenase (LOX), and eLOX3 hepoxilin synthase were required for neutrophil transmigration to GC, and migration was abrogated by blocking the MRP2 efflux pump and by adding recombinant soluble epoxide hydrolase. These results are all consistent with epithelial cell production of the neutrophil chemoattractant hepoxilin A3 (HXA3). Neutrophil transmigration was also accompanied by increasing apical concentrations of leukotriene B4 (LTB4). Neutrophil 5-lipoxygenase and active BLT1 receptor were required for apical LTB4 and neutrophil migration. Conclusions:Our data support a model in which GC-endocervical cell contact infection stimulates HXA3 production, driving neutrophil migration that is amplified by neutrophil-derived LTB4. Therapeutic targeting of these pathways could limit inflammation and deleterious clinical sequelae in women with gonorrhea.

SUBMITTER: Stevens JS

PROVIDER: S-EPMC6173577 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Endocervical and Neutrophil Lipoxygenases Coordinate Neutrophil Transepithelial Migration to Neisseria gonorrhoeae.

Stevens Jacqueline S JS Gray Mary C MC Morisseau Christophe C Criss Alison K AK

The Journal of infectious diseases 20181001 10

<h4>Background</h4>Infection with Neisseria gonorrhoeae (GC) is characterized by robust neutrophil influx that is insufficient to clear the bacteria. Sustained neutrophilic inflammation contributes to serious clinical sequelae that particularly affect women, including pelvic inflammatory disease and infertility.<h4>Methods</h4>We established a 3-component system using GC, End1 polarized human endocervical cells, and primary human neutrophils to investigate neutrophil transepithelial migration fo ...[more]

PMID: 29905822

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Project description:UnlabelledNeisseria gonorrhoeae (the gonococcus) causes gonorrhea and is uniquely adapted to survive within the human reproductive tract. Gonococci evade host immune surveillance in part by varying their pili and opacity-associated proteins. These variable surface antigens influence interactions with host epithelial and immune cells. A potent polymorphonuclear leukocyte (PMN) response is a hallmark of symptomatic gonococcal infection, with vast numbers of PMNs recruited to the site of infection. A large body of literature describes gonococcus-PMN interactions, but the factors driving the outcome of infection are not fully understood. Gonococci have been described to both induce and suppress the PMN oxidative burst, but we determined that gonococci differentially affect induction of the PMN oxidative burst depending on the multiplicity of infection (MOI). Infecting PMN at an MOI of <20 gonococci elicits an oxidative burst, while an MOI of >20 suppresses the burst. Oxidative burst in response to gonococci is enhanced by, but does not require, expression of pili or opacity proteins. Neutrophil extracellular traps (NETs) were observed in gonococcus-infected PMNs, a process which requires an oxidative burst, yet gonococci induced NETs under suppressing conditions. The NETs were unable to kill gonococci despite killing the common vaginal bacterium Lactobacillus crispatus. Thus, gonococci influence PMN biology to promote their own survival by suppressing the oxidative burst of PMNs and stimulating the formation of NETs, which do not effectively kill gonococci, illustrating how N. gonorrhoeae has evolved to modulate PMN responses to promote infection.ImportanceNeisseria gonorrhoeae, the gonococcus, is the only causative agent of gonorrhea and is exclusively found within the human host. Gonococci stochastically vary the composition of antigens on their surface to evade immune surveillance. We used gonococcal mutants which stably express different surface antigens to dissect interactions between gonococci and primary human polymorphonuclear leukocytes (PMNs). We found that gonococci, depending on the number of bacteria present, either induce or suppress the oxidative burst of PMNs regardless of other stimuli. Gonococci also cause PMNs to release DNA, forming neutrophil extracellular traps (NETs) independently of the oxidative burst. The NETs were unable to kill gonococci but were able to kill commensal bacteria, suggesting that NET production can help gonococci outcompete other bacterial species. We propose that gonococci have evolved to manipulate PMN responses to promote their own survival during infection.

Dataset Information

Endocervical and Neutrophil Lipoxygenases Coordinate Neutrophil Transepithelial Migration to Neisseria gonorrhoeae.

Publications

Endocervical and Neutrophil Lipoxygenases Coordinate Neutrophil Transepithelial Migration to Neisseria gonorrhoeae.

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