title: Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation.
abstract: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS‑2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro‑inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease.
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Qiuqin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Zhonglan
authors.initials: Z
authors.lastname: Su
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Song
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Χu
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yi
authors.affiliation: Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated with Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.
authors.forename: Man
authors.initials: M
authors.lastname: Tian
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D005260:Female; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000502:physiology; D012137:Respiratory System / Q000187:drug effects / Q000473:pathology / Q000821:virology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C012589:trichostatin A; D000077337:Vorinostat; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D056464:Histone Deacetylase 2