Abstract
Introduction Interferon (IFN) responses have been reported to be defective in rhinovirus (RV)-induced asthma. The heterodimeric receptor of type I IFN (IFN-α/β) is composed of IFN-αR1 and IFN-αR2. Ligand binding to the IFN-α/β receptor complex activates signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2 intracellularly. Although type III IFN (IFN-λ) binds to a different receptor containing IFN-λR1 and interleukin-10R2, its triggering leads to activation of the same downstream transcription factors. Here, we analysed the effects of RV on IFN type I and III receptors, and asked about possible Toll-like receptor 7/8 (TLR7/8) agonist R848-mediated IFN-αR1 and IFN-λR1 regulation.
Methods We measured IFN-α, IFN-β and IFN-λ and their receptor levels in peripheral blood mononuclear cell (PBMC) supernatants and cell pellets stimulated with RV1b and R848 in two cohorts of children with and without asthma recruited at pre-school age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice.
Results We observed that R848 induced IFN-λR mRNA expression in PBMCs of healthy and asthmatic children, but suppressed IFN-αR mRNA levels. In murine lung cells, RV1b alone and together with R848 suppressed IFN-αR protein in T-cells compared with controls and in total lung IFN-λR mRNA compared with RV1b infection alone.
Conclusions In PBMCs from pre-school age children, IFN-αR mRNA was reduced and IFN-λR1 mRNA was induced upon treatment with the TLR7/8 agonist R848, thus suggesting new avenues for induction of antiviral immune responses in paediatric asthma.
Abstract
TLR7/8 agonist reduced IFN-αR1 but induced IFN-λR1 in PBMCs of pre-school age children. This induction of IFN-λR1 offers a new mechanism for therapy of children with RV1b-exacerbated asthma. https://bit.ly/2QWnoTp
Footnotes
This article has supplementary material available from erj.ersjournals.com
Data sharing: All data reported in the figures and as supplementary will be shared upon request to collaborate with the corresponding author.
Author contributions: J. Krug generated the laboratory results, correlated, analysed and interpreted all of the data, and generated all of the figures, tables and supplementary material. She wrote the introduction, methods, results and the discussion sections. She was involved in drafting and editing the manuscript, and contributed to the revision of the manuscript. A. Kiefer recruited, analysed and diagnosed the children from the PreDicta WP1 cohort in Erlangen and the AGENDAS cohort. J. Koelle helped with the murine data recruitment. T. Vuorinen provided the respiratory virus analysis for PreDicta and AGENDAS. M. Akdis and B. Stanic provided the multiplex cytokine data for the PreDicta WP1 cohort in Erlangen that are reported and correlated in figures 1c and 2b–d. N.G. Papadopoulos was the coordinator of the PreDicta studies and P. Xepapadaki helped N.G. Papadopoulos to establish the different European cohorts in PreDicta. M.T. Chiriac helped generating the laboratory results regarding the IFN-λR qPCR. T. Zimmermann was involved in the recruitment and analysis of the PreDicta studies. S. Finotto contributed to the design of the study, writing the first draft and editing the manuscript, analysed and mentored all of the studies for the PreDicta and AGENDAS part in Erlangen, and contributed to the revision of the manuscript.
Conflict of interest: J. Krug has nothing to disclose.
Conflict of interest: A. Kiefer has nothing to disclose.
Conflict of interest: J. Koelle has nothing to disclose.
Conflict of interest: T. Vuorinen has nothing to disclose.
Conflict of interest: P. Xepapadaki reports personal fees for advisory board work from Uriach, Novartis, Nestle and Nutricia, outside the submitted work.
Conflict of interest: B. Stanic has nothing to disclose.
Conflict of interest: M.T. Chiriac reports grants from the DFG (grant CH1428/2-1), during the conduct of the study.
Conflict of interest: M. Akdis has nothing to disclose.
Conflict of interest: T. Zimmermann has nothing to disclose.
Conflict of interest: N.G. Papadopoulos reports personal fees for advisory board work and lectures from Novartis, Nutricia, HAL, Menarini/Faes Farma and Mylan/Meda, personal fees for lectures from Sanofi, Biomay, MSD, Asit Biotech and Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and GSK, grants from Gerolymatos International SA and Capricare, outside the submitted work.
Conflict of interest: S. Finotto has nothing to disclose.
Support statement: The present work was performed in fulfilment of the requirements for obtaining the degree “Dr med.” for Jasmin Krug. This work was supported by the European grant PreDicta (Post-infectious immune reprogramming and its association with persistence and chronicity of respiratory allergic diseases) awarded to S. Finotto in Erlangen (Germany) and in the other European centres to N.G. Papadopoulos in Athens (Greece) and to M. Akdis in Davos (Switzerland); by the Dept of Molecular Pneumology in Erlangen and by a DFG grant (CRC1181/TP 08) in Erlangen awarded to S. Finotto. J. Krug was supported by a SFB grant in the CRC1181 grant awarded to S. Finotto in Erlangen and by the Dept of Molecular Pneumology in Erlangen. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received May 5, 2020.
- Accepted November 5, 2020.
- Copyright ©ERS 2021