Respiratory viruses induce ferroptosis-like features in lung epithelial cells.

During infection, viruses can modulate various regulated cell death (RCD) mechanisms to evade host immunity and enhance replication. However, less is known about how viruses alter the recently discovered RCD ferroptosis, which is characterized by an iron-dependent accumulation of lipid peroxidation and mitochondrial fragmentation. Influenza A virus (IAV) H1N1 and human adenovirus type C5 (HAdV-C5) are two common causes of respiratory infections of the upper and lower respiratory tracts and can lead to severe illness. While IAV has been shown to induce ferroptosis to support its replication, less is known about whether this is also true for HAdV-C5. Here, we perform a comparative study investigating ferroptosis features during IAV H1N1 and HAdV-C5 infections using alveolar (A549) and bronchial (BEAS-2B) epithelial cells. Our data reveal that HAdV-C5, similar to H1N1, induces lipid peroxidation in a time-dependent manner, which is partially suppressed in the presence of the ferroptosis inhibitor ferrostatin-1. Strikingly, HAdV-C5 infections only lead to changes in ferritin protein levels, which is responsible for iron storage, during late stages of infection. Furthermore, both H1N1 and HAdV-C5 infections trigger a profound mitochondrial network remodeling in A549, BEAS-2B, and primary human epithelial cells, comparable to that induced by the ferroptosis inducer RSL3, with effects varying by cell type and infection stage. These findings suggest that HAdV-C5, just like H1N1, can activate ferroptosis-like processes, highlighting a potential role for lipid peroxidation and mitochondrial alterations in adenoviral infection. IMPORTANCE: The findings presented here contribute to a deeper understanding of the molecular mechanisms involved in viral infections of the lung epithelium, particularly in the context of virus-induced lung epithelial cell death, a topic of significant relevance to the area of early viral response mechanisms. By elucidating the role of ferroptosis-like hallmarks encompassing lipid peroxidation and mitochondrial dysfunction, our work may inform the development of new therapeutic strategies aimed at enhancing lung epithelial integrity and barrier function, representing the first layer of defense against human pathogens. The topic is of particular importance given the increasing prevalence of antimicrobial resistance. We believe that our research offers significant insights into the field of viral infections and lung disease and would be of great interest to readers in the field of viral biology and respiratory infections.