Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection

Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E 2 (PGE 2 ), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE 2 within the aged lung. PGE 2 impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE 2 receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults. Ageing has been associated with impaired function of alveolar macrophages and increased susceptibility, mortality and complications as a result of viral infection. Here, the authors show that prostaglandin E 2 is one of the factors responsible for impairing immune defences against influenza during ageing.