Mapping Proteostasis in the Lung
Seasonal influenza A virus infection causes at least 20,000–50,000 deaths in the United States each year; during the 2009 pandemic, infection with IAV rose to the 9th leading cause of death overall. Infection results in epithelial damage and the exudation of fluid and protein into the alveolar space threatening gas exchange. Severe infection results in Acute Respiratory Distress Syndrome (ARDS), which is the primary cause of death in patients with IAV infection. Seasonal and pandemic IAV infection causes disproportionate morbidity and mortality in older individuals. We, and others, have found similarly disproportionate mortality in aged mice infected with influenza A. It is now well established in C. elegans and other models that proteostasis protection declines during “normal” aging. Our preliminary data using novel luminescence- and mass spectroscopy–based techniques to measure proteostasis in the aging lung suggest that influenza A infection is associated with transient collapse of the lung epithelial proteostasis network. Therefore, we use influenza A virus as a validated model that directly mirrors a clinically important problem in human aging to probe the frailty and resilience of the proteostasis networks in the normal aged lung. By applying this model, our experiments will establish causal links between aging, proteostasis, and lung function in mouse models, which are likely to be relevant for human aging.
GR Scott Budinger, MD