Pregnancy Zone Protein is Associated with Airway Infection, Neutrophil Extracellular Trap Formation and Disease Severity in Bronchiectasis

Simon Finch, Amelia Shoemark, Alison J. Dicker, Holly R Keir, Alexandria Smith, Samantha Ong, Brandon Tan, Jean-yu Choi, Thomas C Fardon, Diane Cassidy, Jeffrey T. J. Huang, James D. Chalmers

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Abstract

Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.

Original languageEnglish
Pages (from-to)992-1001
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume200
Issue number8
Early online date2 Jul 2019
DOIs
Publication statusPublished - 15 Oct 2019

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Pregnancy Proteins
Bronchiectasis
Infection
Sputum
Fluorescence Microscopy
Pseudomonas aeruginosa
Pseudomonas Infections
Neutrophils
Liquid Chromatography
Extracellular Traps
Mass Spectrometry
Electron Microscopy
Enzyme-Linked Immunosorbent Assay
16S Ribosomal RNA
RNA Sequence Analysis
Proteobacteria
Bacterial Load
Validation Studies
Tetradecanoylphorbol Acetate
Immunosuppressive Agents

Keywords

  • bronchiectasis
  • exacerbations
  • microbiome
  • neutrophils

Cite this

@article{cb187648318f46e99a8a860dc3ae21e6,
title = "Pregnancy Zone Protein is Associated with Airway Infection, Neutrophil Extracellular Trap Formation and Disease Severity in Bronchiectasis",
abstract = "Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.",
keywords = "bronchiectasis, exacerbations, microbiome, neutrophils",
author = "Simon Finch and Amelia Shoemark and Dicker, {Alison J.} and Keir, {Holly R} and Alexandria Smith and Samantha Ong and Brandon Tan and Jean-yu Choi and Fardon, {Thomas C} and Diane Cassidy and Huang, {Jeffrey T. J.} and Chalmers, {James D.}",
year = "2019",
month = "10",
day = "15",
doi = "10.1164/rccm.201812-2351OC",
language = "English",
volume = "200",
pages = "992--1001",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "8",

}

TY - JOUR

T1 - Pregnancy Zone Protein is Associated with Airway Infection, Neutrophil Extracellular Trap Formation and Disease Severity in Bronchiectasis

AU - Finch, Simon

AU - Shoemark, Amelia

AU - Dicker, Alison J.

AU - Keir, Holly R

AU - Smith, Alexandria

AU - Ong, Samantha

AU - Tan, Brandon

AU - Choi, Jean-yu

AU - Fardon, Thomas C

AU - Cassidy, Diane

AU - Huang, Jeffrey T. J.

AU - Chalmers, James D.

PY - 2019/10/15

Y1 - 2019/10/15

N2 - Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.

AB - Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.

KW - bronchiectasis

KW - exacerbations

KW - microbiome

KW - neutrophils

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U2 - 10.1164/rccm.201812-2351OC

DO - 10.1164/rccm.201812-2351OC

M3 - Article

C2 - 31264895

VL - 200

SP - 992

EP - 1001

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 8

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