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
2961-2973
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
eba99148-620c-452a-a334-c1a52ba94078
Kurukulaaratchy, Ramesh J
9c7b8105-2892-49f2-8775-54d4961e3e74
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Wilkinson, Tom M A
9c51b529-00ce-45d2-b6e0-b623f61fdf82
Staples, Karl J
e0e9d80f-0aed-435f-bd75-0c8818491fee
WATCH study investigators
October 2022
Ackland, Jodie
dba59510-7535-47f8-b2ba-2d49dfa7fbd8
Barber, Clair
ff31b460-34c3-466c-90e4-f70b3e954c82
Heinson, Ashley
822775d1-9379-4bde-99c3-3c031c3100fb
Azim, Adnan
87c31e0e-c9bf-4258-9ae9-889e2382e7ba
Cleary, David W
f4079c6d-d54b-4108-b346-b0069035bec0
Christodoulides, Myron
eba99148-620c-452a-a334-c1a52ba94078
Kurukulaaratchy, Ramesh J
9c7b8105-2892-49f2-8775-54d4961e3e74
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Wilkinson, Tom M A
9c51b529-00ce-45d2-b6e0-b623f61fdf82
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), .
(doi:10.1111/all.15375).
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
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Allergy - 2022 - Ackland - Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic (1)
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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
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Local EPrints ID: 456946
URI: http://eprints.soton.ac.uk/id/eprint/456946
ISSN: 0105-4538
PURE UUID: c77949b5-88e0-4466-a7a7-169efd4dfe2f
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Date deposited: 17 May 2022 17:08
Last modified: 10 Dec 2024 18:18
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Author:
Clair Barber
Author:
Ashley Heinson
Author:
Adnan Azim
Author:
Tom M A Wilkinson
Corporate Author: WATCH study investigators
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