Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets

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.

Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration

“…However, our knowledge of the potential role of host ceramidases in viral pathology remains elusive. It was reported that the overall inhibition of ceramidase activity in host peripheral blood lymphocytes using Ceranib 1 and Ceranib 2 significantly reduces the replication of the rhinovirus and measles virus, respectively [ 110 , 111 ]. Furthermore, the inhibition of ACDase activity in macrophages significantly increases the propagation of herpes simplex virus-1, which, in turn, elevates the mortality rate in Asah1 −/− mice [ 112 ].…”

<p>Lipid metabolism in chronic obstructive pulmonary disease</p>

“…Viral infections can provoke acute worsening of disease in patients with COPD 53. Study showed that the activity of FAS was enhanced when infected with rhinovirus in bronchial epithelial cells, and that inhibition of FAS reduced the rhinoviral infections 54. Therefore, FAS might be a potential target for exacerbation of COPD.…”

In vivo experimental models of infection and disease

“…With the development of inhaled IFN as a therapy option for asthma, the role of IFN in COPD requires urgent further investigation. Other areas of future research include the effects of virus infection on novel pathways such as lipidomics 131 and metabolomics 121 in asthma and COPD.…”