Jason Girkin1,2,3, Su-Ling Loo1,2,3, Camille Esneau1,2, Steven Maltby1,2, Francesca Mercuri4, Brendon Chua5, Andrew T Reid1,2, Punnam Chander Veerati1,2, Chris L Grainge2,6, Peter A B Wark2,6, Darryl Knight2, David Jackson5, Christophe Demaison4, Nathan W Bartlett7,2. 1. Viral Immunology and Respiratory Disease group, University of Newcastle, Newcastle, Australia. 2. Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia. 3. These authors contributed equally. 4. Ena Respiratory Pty Ltd, Melbourne, Australia. 5. Dept of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. 6. Dept of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, Australia. 7. Viral Immunology and Respiratory Disease group, University of Newcastle, Newcastle, Australia nathan.bartlett@newcastle.edu.au.
Abstract
BACKGROUND: We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases. METHODS: We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome. RESULTS: We show, in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response. CONCLUSION: Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.
BACKGROUND: We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases. METHODS: We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome. RESULTS: We show, in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response. CONCLUSION: Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.
Authors: Teresa C Williams; Su-Ling Loo; Kristy S Nichol; Andrew T Reid; Punnam C Veerati; Camille Esneau; Peter A B Wark; Christopher L Grainge; Darryl A Knight; Thomas Vincent; Crystal L Jackson; Kirby Alton; Richard A Shimkets; Jason L Girkin; Nathan W Bartlett Journal: Commun Biol Date: 2022-05-04
Authors: Georgia Deliyannis; Chinn Yi Wong; Hayley A McQuilten; Annabell Bachem; Michele Clarke; Xiaoxiao Jia; Kylie Horrocks; Weiguang Zeng; Jason Girkin; Nichollas E Scott; Sarah L Londrigan; Patrick C Reading; Nathan W Bartlett; Katherine Kedzierska; Lorena E Brown; Francesca Mercuri; Christophe Demaison; David C Jackson; Brendon Y Chua Journal: JCI Insight Date: 2021-03-08