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A4715 - Enhanced Interferon Response Genes in Bronchial Epithelial Cells After In Vivo Rhinovirus Challenge of Asthma Patients
Author Block: A. Ravi1, J. Koster2, A. Dijkhuis3, Y. S. Sabogal Piñeros4, S. Bal4, P. J. Sterk5, R. Lutter6; 1Respiratory Medicine and Experimental Immunology, Acamedic Medical Center, Amsterdam, Netherlands, 2Oncogenomics, Acamedic Medical Center, Amsterdam, Netherlands, 3Experimental Immunology, Acamedic Medical Center, Amsterdam, Netherlands, 4Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands, 5Academic Medical Center, Amsterdam, Netherlands, 6Respiratory Medicine, Academic Medical Center, Amsterdam, Netherlands.
Rationale: Rhinovirus (RV) induces acute worsening of asthma symptoms. Bronchial epithelial cells (PBECs) are primary targets of RV and direct inflammatory and immune responses. PBECs from asthmatics compared to those from healthy controls have been reported to display a deficient anti-viral response to RV in vitro. The aim of this study is to determine the anti-viral response by PBECs from asthma patients in vivo.
Methods: Mild asthma patients (n=15) and healthy controls (n=4) were challenged with RV16. PBECs were obtained by bronchial brushes before and 6 days post-infection. The transcriptome was determined by RNA sequencing and was correlated with clinical outcomes.
Results: Anti-viral interferon response genes (n=21) were upregulated (>3-fold) in asthmatics after RV16, but not in healthy controls. The interferon response genes correlate positively with bronchoalveolar lavage (BAL) cells viral load (R2=0.47 ; p=0.003). Interferon response genes, particularly IFI6 (Interferon alpha inducible protein 6) and IFITM1/3 (Interferon induced transmembrane protein 1/3) correlated (R2=0.28 ; p=0.04) with the virus-induced drop in FEV1 after RV16. BALF eosinophil cationic protein (ECP) increased (p=0.009) after RV16 in asthmatics and correlated, like percentage BALF eosinophils, with interferon response genes (R2=0.47 ; p= 0.004 and R2=0.66 ; p= 0.0002, respectively). Interestingly, the neutrophils and myeloperoxidase (MPO) did not increase after RV16, and importantly, did not correlate with interferon response genes before and after exposure. Interferon-inducible nitric oxide synthase (iNOS) is the major source of fraction exhaled nitric oxide (FeNO). In line herewith, iNOS in PBECs strongly correlated with FeNO before (R2=0.68 ; p=0.0001) and after RV16 (R2=0.69 ; p=0.0001). However, IFN response genes correlated with FeNO (R2=0.41 ; p=0.009) only after RV16 challenge in asthmatics. Ingenuity pathway analysis showed that both type I and II interferons underlie the interferon response by PBECs after RV16 in asthma.
Conclusion: In asthma there are exaggerated rather than impaired innate and adaptive interferon responses in vivo after RV16 infection. Importantly, the enhanced interferon response genes after RV16 correlated with the viral load and strongly correlated with inflammation and loss of asthma control in mild asthma patients.