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Myeloperoxidase: a front-line defender against phagocytosed microorganisms.

ABSTRACT: Successful immune defense requires integration of multiple effector systems to match the diverse virulence properties that members of the microbial world might express as they initiate and promote infection. Human neutrophils--the first cellular responders to invading microbes--exert most of their antimicrobial activity in phagosomes, specialized membrane-bound intracellular compartments formed by ingestion of microorganisms. The toxins generated de novo by the phagocyte NADPH oxidase and delivered by fusion of neutrophil granules with nascent phagosomes create conditions that kill and degrade ingested microbes. Antimicrobial activity reflects multiple and complex synergies among the phagosomal contents, and optimal action relies on oxidants generated in the presence of MPO. The absence of life-threatening infectious complications in individuals with MPO deficiency is frequently offered as evidence that the MPO oxidant system is ancillary rather than essential for neutrophil-mediated antimicrobial activity. However, that argument fails to consider observations from humans and KO mice that demonstrate that microbial killing by MPO-deficient cells is less efficient than that of normal neutrophils. We present evidence in support of MPO as a major arm of oxidative killing by neutrophils and propose that the essential contribution of MPO to normal innate host defense is manifest only when exposure to pathogens overwhelms the capacity of other host defense mechanisms.

SUBMITTER: Klebanoff SJ

PROVIDER: S-EPMC3545676 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Myeloperoxidase: a front-line defender against phagocytosed microorganisms.

Klebanoff Seymour J SJ Kettle Anthony J AJ Rosen Henry H Winterbourn Christine C CC Nauseef William M WM

Journal of leukocyte biology 20121011 2

Successful immune defense requires integration of multiple effector systems to match the diverse virulence properties that members of the microbial world might express as they initiate and promote infection. Human neutrophils--the first cellular responders to invading microbes--exert most of their antimicrobial activity in phagosomes, specialized membrane-bound intracellular compartments formed by ingestion of microorganisms. The toxins generated de novo by the phagocyte NADPH oxidase and delive ...[more]

PMID: 23066164

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Project description:OBJECTIVES:Develop a standardized simulation method to assess clinical skills of ICU providers. DESIGN:Simulation assessment. SETTING:Simulation laboratory. SUBJECTS:Residents, Critical Care Medicine fellows, acute care nurse practitioner students. INTERVENTIONS:Performance scoring in scenarios from multiple Critical Care Medicine competency domains. MEASUREMENTS AND MAIN RESULTS:Three-hundred eighty-four performances by 48 participants were scored using checklists (% correct) and holistic "global" ratings (1 [unprepared] to 9 [expert]). One-hundred eighty were scored by two raters. Mean checklist and global scores (± SD) ranged from 65.0% (± 16.3%) to 84.5% (± 17.3%) and 4.7 (± 1.4) to 7.2 (± 1.2). Checklist and global scores for Critical Care Medicine fellows and senior acute care nurse practitioner students (Experienced group, n = 26) were significantly higher than those for the Novice acute care nurse practitioner students (Novice group, n = 14) (75.6% ± 15.6% vs 68.8% ± 21.0% and 6.1?±?1.6 vs 5.4?±?1.5, respectively; p < 0.05). Residents (Intermediate group, n = 8) scored between the two (75.4% ± 18.3% and 5.7?±?1.7). 38.5% of the Experienced group scored in the top quartile for mean global score, compared with 12.5% of the Intermediate and 7.1% of the Novice groups. Conversely, 50% of the Novice group scored in the lower quartile (< 5.3), compared with 37.5% of the Intermediate and 11.5% of the Experienced groups. Psychometric analyses yielded discrimination values greater than 0.3 for most scenarios and reliability for the eight-scenario assessments of 0.51 and 0.60, with interrater reliability of 0.71 and 0.75, for checklist and global scoring, respectively. CONCLUSIONS:The simulation assessments yielded reasonably reliable measures of Critical Care Medicine decision-making skills. Despite a wide range of performance, those with more ICU training and experience performed better, providing evidence to support the validity of the scores. Simulation-based assessments may ultimately prove useful to determine readiness to assume decision-making roles in the ICU.

Project description:The neutrophil enzyme myeloperoxidase (MPO) is a major enzyme made by neutrophils to generate antimicrobial and immunomodulatory compounds, notably hypochlorous acid (HOCl), amplifying their capacity for destroying pathogens and regulating inflammation. Despite its roles in innate immunity, the importance of MPO in preventing infection is unclear, as individuals with MPO deficiency are asymptomatic with the exception of an increased risk of candidiasis. Dysregulation of MPO activity is also linked with inflammatory conditions such as atherosclerosis, emphasising a need to understand the roles of the enzyme in greater detail. Consequently, new tools for investigating granular dynamics in vivo can provide useful insights into how MPO localises within neutrophils, aiding understanding of its role in preventing and exacerbating disease. The zebrafish is a powerful model for investigating the immune system in vivo, as it is genetically tractable, and optically transparent. To visualise MPO activity within zebrafish neutrophils, we created a genetic construct that expresses human MPO as a fusion protein with a C-terminal fluorescent tag, driven by the neutrophil-specific promoter lyz. After introducing the construct into the zebrafish genome by Tol2 transgenesis, we established the Tg(lyz:Hsa.MPO-mEmerald,cmlc2:EGFP)sh496 line, and confirmed transgene expression in zebrafish neutrophils. We observed localisation of MPO-mEmerald within a subcellular location resembling neutrophil granules, mirroring MPO in human neutrophils. In Spotless (mpxNL144) larvae-which express a non-functional zebrafish myeloperoxidase-the MPO-mEmerald transgene does not disrupt neutrophil migration to sites of infection or inflammation, suggesting that it is a suitable line for the study of neutrophil granule function. We present a new transgenic line that can be used to investigate neutrophil granule dynamics in vivo without disrupting neutrophil behaviour, with potential applications in studying processing and maturation of MPO during development.

Dataset Information

Myeloperoxidase: a front-line defender against phagocytosed microorganisms.

Publications

Myeloperoxidase: a front-line defender against phagocytosed microorganisms.

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