) Seasonal influenza A viruses (IAV) are responsible for considerable human morbidity and mortality throughout the world. The risk for respiratory complications and hospitalization is highest among the elderly, young children, and anyone with certain underlying or previous medical conditions, such as being born preterm. Since preterm infants are often exposed to high oxygen, the parent grant uses mice to investigate how an aberrant oxygen environment at birth alters lung development and the host response to influenza A virus infection later in life. Our research has shown how young adult (8 week old) mice exposed to 100% oxygen for the first 4 days of life have simplified alveoli that are deficient in alveolar epithelial type II (AECIIs), an innate immune privileged and alveolar stem cell. They also exhibit greater inflammation and fibrotic lung disease when infected with IAV (HKx31, H3N2) than infected siblings birthed into room air. Neonatal hyperoxia does not impair production of virus specific antibodies, cytolytic functions of CD8+T cells, or the ability to effectively clear virus. Instead, genetic depletion studies using diphtheria A toxin (DTA) support the idea that the oxygen-dependent loss of AECIIs is responsible for enhancing primary infection of distal alveolar cells, thereby increasing the severity of epithelial injury, inflammation, and fibrotic lung disease. Given that AECIIs protect the lung against infection, their loss as the lung naturally ages could contribute to the heightened respiratory morbidity seen in animal models and elderly humans infected with IAV. Hence, this Revision Supplement tests the hypothesis that the loss of AECIIs in aged mice will enhance primary infection to IAV similar to that of a young adult mouse exposed to high oxygen at birth. The proposed studies will map the loss of AECIIs as mice age and determine how aging enhances primary infection of distal alveolar cells, thereby resulting in greater epithelial injury, inflammation, and fibrotic lung disease. Understanding how the loss of AECIIs influences host-pathogen interactions in mice is important because it could lead to new therapies that reduce severity of lung diseases in susceptible individuals.
/ RELEVANCE TO PUBLIC HEALTH Aging is considered a consequence of accumulated oxygen-induced damage. This proposal tests the hypothesis that the heightened response of aged mice to influenza A virus infection reflects that of a young adult mouse exposed to high oxygen at birth. Confirmation of this hypothesis could help predict risk and develop new therapies for improving health of elderly individuals with a respiratory viral infection.
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