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Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma

Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma
Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma
Background: Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Methods: Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi-infected monocyte-derived macrophages to identify transcriptomic networks associated with NTHi infection. Results: NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p =.0436) and higher sputum neutrophil proportion (67% vs 25%, p =.0462). WGCNA identified a transcriptomic network of immune-related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p <.05). Macrophage network genes SGPP2 (p =.0221), IL1B (p =.0014) and GBP1 (p =.0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration (IL1B; rho = 0.41, p =.041) and lower prebronchodilator FEV1/FVC% (GBP1; rho = −0.43, p =.046 and IL1B; rho = −0.42, p =.055). Conclusions: NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes.
NTHi, T17 responses, asthma, inflammation, macrophage, neutrophil
0105-4538
2961-2973
Ackland, Jodie
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Barber, Clair
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Heinson, Ashley
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Azim, Adnan
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Cleary, David W
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Christodoulides, Myron
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Kurukulaaratchy, Ramesh J
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Howarth, Peter
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Wilkinson, Tom M A
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Staples, Karl J
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WATCH study investigators
Ackland, Jodie
dba59510-7535-47f8-b2ba-2d49dfa7fbd8
Barber, Clair
ff31b460-34c3-466c-90e4-f70b3e954c82
Heinson, Ashley
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Azim, Adnan
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Cleary, David W
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Christodoulides, Myron
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Kurukulaaratchy, Ramesh J
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Howarth, Peter
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Wilkinson, Tom M A
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Staples, Karl J
e0e9d80f-0aed-435f-bd75-0c8818491fee

Ackland, Jodie, Barber, Clair, Heinson, Ashley and Azim, Adnan , WATCH study investigators (2022) Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Allergy: European Journal of Allergy and Clinical Immunology, 77 (10), 2961-2973. (doi:10.1111/all.15375).

Record type: Article

Abstract

Background: Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Methods: Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi-infected monocyte-derived macrophages to identify transcriptomic networks associated with NTHi infection. Results: NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p =.0436) and higher sputum neutrophil proportion (67% vs 25%, p =.0462). WGCNA identified a transcriptomic network of immune-related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p <.05). Macrophage network genes SGPP2 (p =.0221), IL1B (p =.0014) and GBP1 (p =.0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration (IL1B; rho = 0.41, p =.041) and lower prebronchodilator FEV1/FVC% (GBP1; rho = −0.43, p =.046 and IL1B; rho = −0.42, p =.055). Conclusions: NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes.

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NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma resubmission CLEAN 2022-04-20 - Accepted Manuscript
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Accepted/In Press date: 13 April 2022
e-pub ahead of print date: 16 May 2022
Published date: October 2022
Additional Information: Funding Information: This work was primarily funded by an Asthma UK studentship award (AUK‐PHD‐2016‐363). We also gratefully acknowledge the support of the Southampton AAIR charity in funding this work. The WATCH study also received funding support from Novartis and the AAIR Charity. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding information GBP1 IL1B Haemophilus influenzae SGPP2 Funding Information: The authors wish to acknowledge the contributions of the wider WATCH study team including Matthew Harvey, Mae Felongco, Helen Wheeler, June Law, Yvette Thirlwall, Kim Bentley, Laura Presland, Frances Mitchell, Deborah Knight, Colin Newell, Yueqing Cheng, Josune Olza Meneses, Paddy Dennison, Heena Mistry, Anna Freeman, Hans Michael Haitchi, Kerry Day, David Hill and Ratko Djukanovic. The authors also wish to acknowledge the support of the Southampton NIHR BRC and Clinical Research Facility. The Clinical Research Facility and BRC are funded by NIHR Southampton and are a partnership between the University of Southampton and University Hospital Southampton NHS Foundation Trust. We would also like to thank and acknowledge Sruthymol Lukose and Elaine Ho (University of Southampton) for their assistance with image analysis and Dr Alastair Watson for his help in preparing the manuscript for submission. Publisher Copyright: © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Keywords: NTHi, T17 responses, asthma, inflammation, macrophage, neutrophil

Identifiers

Local EPrints ID: 456946
URI: http://eprints.soton.ac.uk/id/eprint/456946
ISSN: 0105-4538
PURE UUID: c77949b5-88e0-4466-a7a7-169efd4dfe2f
ORCID for Jodie Ackland: ORCID iD orcid.org/0000-0003-3120-3620
ORCID for Clair Barber: ORCID iD orcid.org/0000-0001-5335-5129
ORCID for Ashley Heinson: ORCID iD orcid.org/0000-0001-8695-6203
ORCID for David W Cleary: ORCID iD orcid.org/0000-0003-4533-0700
ORCID for Myron Christodoulides: ORCID iD orcid.org/0000-0002-9663-4731
ORCID for Ramesh J Kurukulaaratchy: ORCID iD orcid.org/0000-0002-1588-2400
ORCID for Karl J Staples: ORCID iD orcid.org/0000-0003-3844-6457

Catalogue record

Date deposited: 17 May 2022 17:08
Last modified: 31 Jan 2023 03:04

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Contributors

Author: Jodie Ackland ORCID iD
Author: Clair Barber ORCID iD
Author: Ashley Heinson ORCID iD
Author: Adnan Azim
Author: David W Cleary ORCID iD
Author: Peter Howarth
Author: Tom M A Wilkinson
Author: Karl J Staples ORCID iD
Corporate Author: WATCH study investigators

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