Peroxisome proliferator‐activated receptor gamma ligands inhibit the replication of respiratory syncytial virus

Abstract

Respiratory syncytial virus (RSV) is worldwide the major cause of morbidity and life-threatining lower respiratory tract disease in infants. However, there exist no promising antiviral treatment. Recently, peroxisome proliferator-activated receptor-γ (PPARγ) has been shown to modulate the virus growth of HIV. We hypothesized, therefore, that activation of PPARγ might interfere with the replication of RSV in human lung epithelial cells (A549), the target for RSV infection. Specific activation of PPARγ was induced with the endogenous agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), the synthetic thiazolidinedione compounds ciglitazone and troglitazone, and Fmoc-Leu, respectively. All PPARγ agonists under study subsequently added to RSV-infection reduced the virus-induced cytotoxicity. However, only the PPARγ agonists ciglitazone, troglitazone, and Fmoc-Leu, respectively, totally abolished the cytopathic cell damage up to 72 h postinfection. Simultaneously, all PPARγ agonists markedly inibited the cell surface expression of the viral G and F protein on RSV-infected A549 cells. The reduced viral G protein expression correlated with a diminished G protein mRNA amount determined by RT-PCR. Simultaneously, a diminished RSV N gene expression was demonstrated by real-time RT-PCR. Theses changes led to a 1000fold reduced release of infectious progeny virus. Our in vitro data suggest that especially the synthetic PPARγ agonists Fmoc-Leu and the thiazolidinediones ciglitazone and troglitazone may have a significantly protective impact on human lung epithelial cells in the course of RSV infection.