Mechanisms of the Age-Associated Dysregulation of the Immune Response to Influenza Infections
Chen, Judy
2023
Abstract
Aging impairs the immune response to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the mechanisms that lead to this age-related dysregulation of lung immunity are largely unknown. The goal of this dissertation is to enhance our understanding of how aging leads to a dysregulated immune response against IAV infection. Prostaglandin E2 (PGE2) is an immune-modulating lipid produced downstream of cycloogenase-1 (COX-1) and COX-2. Using murine models and human bronchoalveolar lavage fluid (BALF) samples, we show that PGE2 levels within the lung airways and airspaces increase with aging. Our work reveals that PGE2 in the aged lungs limits the mitochondrial health and proliferation of alveolar macrophages (AMs), the frontline immune defense against respiratory pathogens. We show that deletion of the PGE2 receptor EP2 rescues the ability of AMs to proliferate in the aged lung and blocking EP2 improved the survival of age mice to a lethal IAV infection. Aged mice that receive the EP2 blockade also show reduced levels of lung damage, viral load, and lung inflammation. Through transcriptomic analysis and ex vivo culture methods, we identified type II alveolar epithelial cells (AECs) as a primary cellular source of the PGE2 in the aged lung. Type II AECs isolated from aged mice secrete about two-times more PGE2 than type II AECs isolated from young mice. We hypothesized that senescence, a hallmark of aging, is a cellular mechanism that drives the increased production of PGE2 by type II AECs with age. We show that irradiation-induced senescence in type II AECs isolated from young mice leads to increased production of PGE2. Likewise, the use of senolytics to deplete senescent cells in ex vivo culture of type II AECs isolated from aged mice leads to a decrease in PGE2 levels. Overall, our study reveals that age-associated overproduction of PGE¬2 in the lung, largely by senescent type II alveolar epithelial cells, impairs AM mitochondrial function, cellular proliferation, and total AM cell numbers. This limits the ability of AMs in an aged lung to defend against IAV infections. Mitophagy is the autophagic degradation of old and damaged mitochondria. Mitophagy is critical for maintaining a healthy mitochondrial pool and is known to become dysregulated with aging. Mitophagy machinery is targeted to damaged mitochondria by the accumulation of Parkin, an E3 ubiquitin ligase, on the outer mitochondrial membrane. We show that Parkin knockout (KO) mice experience higher levels of lung pathology, inflammation, and viral load compared to wildtype (WT) mice. Importantly, a deficiency in Parkin leads to an impairment in the IAV-specific CD4+ T cell response and an impairment in CD4+ T cell activation. Overall, this thesis introduces new potential therapeutic targets - namely senescent type II AECs, their production of PGE2, EP2 signaling in AMs, and impaired mitophagy- to reduce the burden of IAV, and possibly other respiratory viruses such as coronaviruses, in older adults.Deep Blue DOI
Subjects
Aging Influenza Senescence Mitophagy
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