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Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity.

ABSTRACT: Ocular bacterial keratitis, often associated with Pseudomonas aeruginosa bacterial infection, commonly occurs in contact lens wearers and may lead to vision impairment. In this study, we analyzed the contribution of neutrophil extracellular traps (NETs) to the mediation of protection during ocular keratitis. Both invasive and cytotoxic P. aeruginosa clinical isolates induced NET release by neutrophils. NETs carried the characteristic histone proteins, elastase, lysozyme, myeloperoxidase, and metabolic enzymes. While the invasive P. aeruginosa strains PAO1 (serogroup O5) and 6294 (serogroup O6) were trapped by NETs, the cytotoxic P. aeruginosa strains 6077, 6206 (serogroup O11), and PA14 (serogroup 010) were less sensitive to NET capture. The mechanism of escape by the cytotoxic strains from adhesion to NETs involved the shedding of outer membrane vesicles (OMVs) that outcompeted the cytotoxic P. aeruginosa strains for NET binding. When ocular infection was caused by an invasive strain in vivo, NETs were released at the ocular surface to capture bacteria, limiting their spread. Treatment with MNase I had a dose-dependent effect, with low doses of MNase speeding up bacterial clearance and high doses of MNase having toxic consequences. Cumulatively, our data suggest that NET-mediated immunity is a two-step process. Initially, pathogens attach to NET fragments; subsequently, upon nuclease activity, active serine proteases, which proteolytically degrade NET-associated proteins and promote DNase activity, are released. Therefore, a balance between NET production and NET degradation is needed to achieve maximal NET immunity.

SUBMITTER: Shan Q

PROVIDER: S-EPMC4187885 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity.

Shan Qiang Q Dwyer Markryan M Rahman Samir S Gadjeva Mihaela M

Infection and immunity 20140721 10

Ocular bacterial keratitis, often associated with Pseudomonas aeruginosa bacterial infection, commonly occurs in contact lens wearers and may lead to vision impairment. In this study, we analyzed the contribution of neutrophil extracellular traps (NETs) to the mediation of protection during ocular keratitis. Both invasive and cytotoxic P. aeruginosa clinical isolates induced NET release by neutrophils. NETs carried the characteristic histone proteins, elastase, lysozyme, myeloperoxidase, and met ...[more]

PMID: 25047845

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Project description:BackgroundNeutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed.MethodsWe systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups.ResultsA gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs.ConclusionNETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.

Dataset Information

Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity.

Publications

Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity.

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