Airway IRF7hi versus IRF7lo molecular response patterns determine clinical phenotypes in children with acute wheezing

Khoo, K.; Read, J.; Franks, K.; Zhang, G.; Bizzintino, J.; Coleman, L.; McCrae, C.; Oberg, L.; Troy, N.; Prastanti, F.; Everard, J.; Oo, S.; Borland, M.; Maciewicz, R.; Le Seouf, P.; Laing, I.; Bosco, A.

doi:10.1101/222950

bioRxiv · 10.1101/222950

Airway IRF7hi versus IRF7lo molecular response patterns determine clinical phenotypes in children with acute wheezing

Khoo, K.·Read, J.·Franks, K.·Zhang, G.·Bizzintino, J.·Coleman, L.·McCrae, C.·Oberg, L.·Troy, N.·Prastanti, F.·Everard, J.·Oo, S.·Borland, M.·Maciewicz, R.·Le Seouf, P.·Laing, I.·Bosco, A.

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Abstract

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I interferon responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signalling and downregulation of interferon gamma. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo versus IRF7hi: symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p=0.011) and nearly three times as long for cough (p<0.001); the odds ratio of admission to hospital was increased more than four-fold (p=0.018); and time to recurrence was shorter (p=0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes.\n\nAbbreviationsAHR, airway hyperresponsiveness; ARG1, Arginase 1, CSF3, Colony Stimulating Factor 3; CD38, Cluster of Differentiation 38; CD163, Cluster of Differentiation 163; cDCs, conventional (or myeloid) dendritic cells; DDX60, DExD/H-Box Helicase 60; ED, Emergency Department; EGF, Epidermal Growth Factor; ERK, Extracellular signal-Regulated Kinase; FCER1G, Fc Fragment Of IgE Receptor Ig; HMBS, Hydroxymethylbilane Synthase; IFNg, Interferon Gamma; IFNL1, Interferon Lambda 1; IL-1R2, Interleukin 1 Receptor Type 2; IRF7, Interferon Regulatory Factor 7; ISG15, Interferon-stimulated gene 15; MDA5, Melanoma Differentiation-Associated protein 5; MX1, Myxovirus Resistance Protein 1; NAD, nicotinamide adenine dinucleotide; NCR1, Natural cytotoxicity triggering receptor 1; OSM, Oncostatin M; PD-L1, Programmed Death-Ligand 1; PPIA, Peptidylprolyl Isomerase A; PPIB Peptidylprolyl Isomerase B; RSAD2, Radical S-adenosyl methionine domain-containing protein 2; RSV, respiratory syncytial virus; RT-qPCR, quantitative reverse transcription PCR; RV, rhinovirus; sPLA2, secretory Phospholipase A2; TGFb, Transforming Growth Factor beta; THBS1, Thrombospondin 1; TNF, Tumor Necrosis Factor; TLR2, Toll-like Receptor 2.

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Khoo, K., Read, J., Franks, K., Zhang, G., Bizzintino, J., Coleman, L., McCrae, C., Oberg, L., Troy, N., Prastanti, F., Everard, J., Oo, S., Borland, M., Maciewicz, R., Le Seouf, P., Laing, I., Bosco, A.. 2017-11-21. Airway IRF7hi versus IRF7lo molecular response patterns determine clinical phenotypes in children with acute wheezing. https://doi.org/10.1101/222950

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