Age-Associated Determinants of Alveolar Macrophage-Mediated Antiviral and Inflammatory Responses
Influenza A virus (IAV) causes a highly infectious upper respiratory tract disease in humans that, despite the availability of vaccines, still results in 300,000 to 500,000 deaths annually worldwide. Individuals aged 65 years of age or older are especially susceptible, accounting for ~90% of the deaths and ~70% of influenza-related hospitalizations annually. Past studies suggest that age-associated impairment of the immune system leads to dysregulated and prolonged inflammatory responses can contribute to severe influenza. However, the mechanism(s) by which the immune system is affected during aging has not been fully elucidated. The insulin-like growth factor 1 and mechanistic target of rapamycin (mTOR) axis is an intracellular signaling network involved in regulating the molecular aging process and the immune system.
Separately, the IGF-1 and mTOR signaling pathway are associated with regulating the lifespan of organisms. The IGF-1 signaling pathway is an evolutionary ancient and conserved pathway found in Caenorhabditis elegans and in humans that promotes cell growth and survival, maturation and proliferation. Data suggest IGF-1 signaling activity inversely correlates with lifespan in certain cell types through the regulation of the metabolic state. Similarly, data show that the mTOR pathway is a negative regulator of an organism lifespan. The activity of both pathways is also involved in governing the functions of innate immune cells, such as alveolar macrophages (AMj). IGF-1 produced by AMj were found to inhibit phagocytosis mediated by alveolar epithelial cells and subsequently exacerbate inflammation and obstruct lung tissue repair. The mTOR pathway has role in controlling the polarization of macrophages.
We previously demonstrated that protection against influenza provided by broadly-reactive antibodies require Fc-engagement and cell-mediated cytolytic activity. We also showed that murine AMj are responsible for antibody-mediated protection. By contrast, antibody-dependent cell-mediated effector activity against IAV are less dependent on natural killer cells (NK) and neutrophils in our animal model. Here, we will investigate the role of the IGF-1/mTOR signaling axis in the aged mouse model and human AM (in collaboration with Dr. Gordon Yung at University of California San Diego), to determine their impact on influenza disease severity. Our central hypothesis posits that the IGF-1/mTOR signaling pathway of AMj plays a crucial role in initiating the antiviral response and in the resolution of the inflammatory response following viral clearance. In aged systems, our hypothesis predicts that genetic and epigenetic changes in the IGF-1/mTOR pathway and related signaling networks result in molecular alterations that lead to impaired immunity and dysregulated inflammation. Identifying genetic and molecular determinants governing antiviral activity and inflammation mediated by AMj will provide novel therapeutic targets and provide a deeper understanding of influenza pathogenesis in older individuals.