PT  - JOURNAL ARTICLE
AU  - Jason Girkin
AU  - Su-Ling Loo
AU  - Camille Esneau
AU  - Steven Maltby
AU  - Francesca Mercuri
AU  - Brendon Chua
AU  - Andrew T. Reid
AU  - Punnam Chander Veerati
AU  - Chris L. Grainge
AU  - Peter A.B. Wark
AU  - Darryl Knight
AU  - David Jackson
AU  - Christophe Demaison
AU  - Nathan W. Bartlett
TI  - TLR2-mediated innate immune priming boosts lung anti-viral immunity
AID  - 10.1183/13993003.01584-2020
DP  - 2020 Jan 01
TA  - European Respiratory Journal
PG  - 2001584
4099  - http://erj.ersjournals.com/content/early/2020/11/26/13993003.01584-2020.short
4100  - http://erj.ersjournals.com/content/early/2020/11/26/13993003.01584-2020.full
AB  - Research question Assessment of whether TLR2 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 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 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Girkin reports grants, personal fees and non-financial support from Ena Therapeutics Pty Ltd, during the conduct of the study; In addition, Dr. Girkin has a patent PCT/AU2018/050295 issued.Conflict of interest: Dr. Loo reports grants from Ena Therapeutics, during the conduct of the study.Conflict of interest: Dr. Esneau has nothing to disclose.Conflict of interest: Dr. Maltby has nothing to disclose.Conflict of interest: Dr. Mercuri reports personal fees from Ena Therapeutics, outside the submitted work; In addition, Dr. Mercuri has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued.Conflict of interest: Dr. Chua is a co-founder and shareholder of Ena Therapeutics Pty Ltd.Conflict of interest: Dr. Reid has nothing to disclose.Conflict of interest: Dr. Veerati has nothing to disclose.Conflict of interest: Dr. Grainge has nothing to disclose.Conflict of interest: Dr. Wark has nothing to disclose.Conflict of interest: Dr. Knight reports grants from Boehringer Ingelheim, outside the submitted work.Conflict of interest: Dr. Jackson reports other from Ena Therapeutics Pty. Ltd., outside the submitted work; In addition, Dr. Jackson has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued.Conflict of interest: Dr. Demaison reports personal fees from Ena Therapeutics, outside the submitted work; In addition, Dr. Demaison has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued.Conflict of interest: Dr. Bartlett reports grants, personal fees and other from Ena Therapeutics, during the conduct of the study; In addition, Dr. Bartlett has a patent PCT/AU2018/050295 issued.