Transforming Growth Factor-Beta-Mediated Enhanced Lung Virus Infection and Modulation by Pirfenidone.

Abstract

Introduction/Aim. Virus infections in patients with pre-existing lung conditions such as asthma and chronic obstructive pulmonary disease often have devastating consequences. Transforming growth factor beta (TGFB) is upregulated in these diseases and its immune-suppressive actions may be pertinent to the vulnerability of patients to damaging infections. We explored influenza A virus (IAV) infection in models of acute and chronic TGFB over-expression and evaluated benefits of pirfenidone, a TGFB antagonist in clinical use for lung fibrosis. Methods. We utilised a transgenic mouse model of TGFB overexpression in the lung. Following IAV infection, tissue and bronchoalveolar lavage (BAL) fluid were assessed for IAV replication, disease severity, inflammation and immune responses. Treatment with pirfenidone was given by gavage and responses compared. Results. In both acute and chronic models mice with elevated TGFB developed more severe bronchitis and pneumonia (P < 0.05). IAV replication was increased (P < 0.001), the result of blunted innate immune responses (P < 0.001). TGFB also mediated significant elevations of inflammatory cytokines, chemokines and inflammatory cell populations in BAL. Administration of pirfenidone during infection reduced disease severity by dampening inflammatory responses and reducing IAV replication. Conclusion. Our findings demonstrate profound immune suppression mediated by TGFB leading to amplified virus infection and intensified lung inflammation. Pirfenidone opposed the detrimental effects of TGFB by reducing inflammation, thus diminishing the extent of infection. Collectively, these data reveal the damaging activities of TGFB during virus infections in lung diseases characterised by TGFB over-production. We further provide proof-of-concept evidence that repurposing pirfenidone can oppose TGFB activities and attenuate virus infections in a susceptible patient population.