Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), impose a significant burden on the Australian health care system. Chronic inflammation is associated with increased scarring and fibrosis, resulting in gradual decrements in lung function, and patients are inclined to develop recurrent viral or bacterial infections. The molecule central to this pathology is transforming growth factor-β (TGFβ), a pleiotropic cytokine well known for its role in cellular proliferation, induction of tissue remodelling and fibrosis. Previous work within our laboratory has demonstrated that addition of clinically relevant concentrations of TGFβ resulted in enhanced virus replication and suppression of innate immune responses in primary lung fibroblasts.
To investigate the effects of TGFβ in vivo, we have utilised a transgenic mouse model that over-expresses biologically active TGFβ in the lung following doxycycline administration, at levels similar to that seen clinically, to examine TGFβ-associated tissue events and function following influenza A virus (IAV) infection.
Mice over-expressing TGFβ (Tg-TGFβ) lost significantly more weight and developed more severe pneumonic disease over a 5 day period following IAV infection compared to those with normal TGFβ levels. Analysis of the bronchoalveolar lavage (BAL) fluid demonstrated that following IAV infection Tg-TGFβ mice had significantly higher total cell numbers and elevated levels of IL-6 and MCP-1. In contrast, the expression of type I and III interferons and interferon regulated genes (IRGs) were significantly reduced in the Tg-TGFβ mice compared to the normal mice following IAV infection.
Our data indicate that expression of TGFβ at clinically relevant concentrations in the lungs results in more severe disease following IAV infection. Targeting of TGFβ or components of its signalling pathway may be a viable therapeutic option to counteract the adverse effects of TGFβ over-expression following viral infection.