Introduction: The interplay between iron availability, immune responses and microbes is important in the pathogenesis of bacterial infections. However, the relationship between respiratory viral infections and iron metabolism is largely unknown. Here we investigated the relationship between iron levels, iron metabolism and the pathogenesis of influenza A virus (IAV) infections.

Methods: Human bronchial epithelial cells (BECs) were cultured with ferric ammonium citrate (FAC) prior to infection with IAV (H1N1) to assess the effects of increased iron on infection in human airway cells. BALB/c mice were intranasally infected with IAV (PR8/H1N1) and expression of iron regulatory genes assessed in lung tissue. Groups of mice were placed on a high iron diet for 8 weeks prior to infection or treated with anti-transferrin receptor (TFR)1 antibody during infection to assess the effects of increased iron levels and depletion of TFR1-mediated cellular iron uptake on infection, respectively.

Results: IAV infection reduces the expression of genes for iron uptake proteins, TFR1 and divalent metal transporter (DMT)1, in BECs and murine lung tissue and decreases expression of genes for iron storage proteins, ferritin light (FTL) and heavy (FTH) chains, in BECs. Increasing iron levels both in BEC cultures and systemically in mice increases IAV titre. Increasing systemic iron levels in vivo increases airway inflammation and airflow obstruction, while depleting TFR1+ cells decreases inflammation and airflow obstruction, during IAV infection.

Conclusions: IAV infections alter iron metabolism in the airways and lungs. Iron levels and metabolism play an important role in IAV-induced disease and may be targeted therapeutically.