Crucial role for iron metabolism in mediating influenza A virus infection and associated disease

Rationale and ObjectivesIron availability and metabolism are important in the pathogenesis of bacterial infections. More recently, links have been reported between iron and the severity of viral infections. In this study, we characterize a crucial relationship between iron metabolism and IAV infection and disease. MethodsIron-related gene expression was assessed in human airway epithelial cells (AEC) infected with IAV. AECs were cultured with ferric iron, iron-loaded transferrin, or iron chelator, deferoxamine (DFO), prior to infection with IAV. Mice were placed on a high iron diet for 8 weeks prior to infection with IAV or treated with anti-transferrin receptor-1 (TFR1) antibody during IAV infection. The effects of iron modulation and depletion of TFR1-mediated responses on IAV infection were assessed. Measurements and main resultsIron-related gene expression and metabolism are altered systemically and in lung tissues and AECs during IAV infections. Increasing iron availability increases viral titer in AECs, while DFO protects against iron-induced increased susceptibility to infection. Increasing systemic iron loading, which increases iron levels in the lung, increases viral titer, proinflammatory responses, airway inflammation, and worsens IAV-induced disease in terms of lung function and weight loss in vivo. Inhibition of TFR1 protects against IAV-induced disease in vivo. ConclusionIAV infections remain a major threat to human health and global economies. Strategies that boost protective, or reduce pathogenic, host responses may provide broadly effective, long-term therapeutic options. We have identified a key role for iron metabolism in modifying host responses to IAV that can be harnessed to protect against disease. Key MessagesO_LIIron metabolism is altered systemically, and in airway epithelial cells and lung tissues, during IAV infection. C_LIO_LIIncreased iron availability increases viral titer both in vitro and in vivo C_LIO_LISystemic iron loading worsens IAV-induced inflammation and disease outcomes in vivo, highlighting iron as a crucial factor for modulating IAV infections and disease. C_LIO_LIHost epithelial cells and lung tissues reduce TFRC gene expression, whilst the number and proportion of TFR1hi expressing cells increase, in response to IAV infection. Neutralising TFR1 protects against IAV-induced disease in vivo, highlighting TFR1 as a potential therapeutic target for IAV infections. C_LI