Abstract
In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine changes in 493 distinct lipid species. Through pathway and network analysis, we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted FA synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609, and C75 were the most potent inhibitors, which confirmed that FAS and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.
Highlights
In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist
To quantify changes in the lipidome of a relevant host cell during infection with the RV-A1b strain of RV, we established conditions where cultures of primary human bronchial epithelial cell (HBEC) were synchronously infected with RV-1Ab
Using a high multiplicity of infection (MOI) of 20 and monitoring viral replication by expression of the viral 2C protein by confocal microscopy (Fig. 1), we showed that a time course up to 6 h post infection produced a consistent high-percentage (>80%) infection of HBECs without a substantial cytopathic effect
Summary
In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Additional support was provided by the National Heart and Lung Institute (student funding to A.G.) and Medical Research Council Centre Grant G10000758 (to the Medical Research Council and Asthma United Kingdom Centre in Allergic Mechanisms of Asthma of which A.M., A.G., D.S., and R.S. were members). Oxysterol binding protein (OSBP) [4,5,6], and protein kinase D (PKD) [7]; inhibitors of these targets inhibit replication of a number of picornaviruses. This suggests that membrane remodeling is important for picornaviral replication and represents potential for the discovery of novel anti-viral targets
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