Abstract
The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-κB pathway. In this study, we investigated the effects of the NF-κB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2α dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection.
Highlights
Respiratory syncytial virus (RSV) is a negative-stranded RNA virus in the genus Pneumovirus, family Paramyxoviridae and is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children [1]
We investigated whether other nuclear factor kappa B (NF-kB) inhibitors, curcumin and pyrollidine dithiocarbamate (PDTC), could prevent replication of RSV compared to IMD0354
When human nasal epithelial cells (HNECs) were pretreated with IMD0354, curcumin and PDTC at 1 and 10 mg/ml 30 min before infection with RSV at an multiplicity of infection (MOI) of 1 for 24 h, 1 and 10 mg/ml IMD0354 and 10 mg/ml curcumin, but not PDTC, prevented production of RSV/G- and M2-1-proteins, which indicated the replication of RSV, together with a decrease of phospho-NF-kB in Western blotting (Figure 1)
Summary
Respiratory syncytial virus (RSV) is a negative-stranded RNA virus in the genus Pneumovirus, family Paramyxoviridae and is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children [1]. There is no effective vaccine, and the use of passive RSV-specific antibodies is limited to high-risk patients [2]. The envelope of RSV contains three transmembrane surface proteins, the fusion F glycoprotein, attachment G glycoprotein and small hydrophobic protein (SH protein) [3,4]. The fusion envelope glycoprotein of RSV was reported to bind to nucleolin at the apical cell surface for entering through the hostcell and nucleolin was found to be a functional cellular receptor for RSV [5]. RSV induces and activates protein kinase R (PKR), a cellular kinase relevant to limiting viral replication, which regulates the activation of a translation initiation factor, the a subunit of eukaryotic translation initiation factor 2 (eIF-2a) [8,9,10]
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