Transforming Growth Factor β Enhances Respiratory Syncytial Virus Replication and Tumor Necrosis Factor Alpha Induction in Human Epithelial Cells

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Abstract
Asthma is characterized as a chronic inflammatory disease associated with significant tissue remodeling. Patients with asthma are more susceptible to virus-induced exacerbation, which subsequently can lead to increased rates of hospitalization and mortality. While the most common cause of asthma-related deaths is respiratory viral infections, the underlying factors in the lung environment which render asthmatic subjects more susceptible to viral exacerbation are not yet identified. Since transforming growth factor β (TGF-β) is a critical cytokine for lung tissue remodeling and asthma phenotype, we have focused on the effects of TGF-β on viral replication and virus-induced inflammation. Treatment of human epithelial cells with TGF-β increased respiratory syncytial virus (RSV) replication by approximately fourfold. Tumor necrosis factor alpha (TNF-α) mRNA and protein expression were also significantly increased above levels with RSV infection alone. The increase in RSV replication and TNF-α expression after TGF-β treatment was concomitant with an increase in virus-induced p38 mitogen-activated protein kinase activation. Our data reveal a novel effect for TGF-β on RSV replication and provide a potential mechanism for the exaggerated inflammatory response observed in asthmatic subjects during respiratory viral infections.