The Impact of Aging on Antiviral Pathways and Immune Functions

Résumé du livre

As global populations shift into higher age demographics there is a significant global public health challenge caused by increased morbidity and mortality associated with age. These aging associated morbidities and mortalities can be partially attributed to a condition of chronically enhanced basal inflammatory levels and immune system dysregulation known as immunosenescence. This phenomenon is suspected to decrease vaccine efficacy and natural immunity against multiple infections including coronavirus disease of 2019 (COVID-19). It is well documented that older individuals have severe COVID-19 complications including pneumonia, respiratory failure, or acute respiratory distress syndrome (ARDS). We have previously demonstrated older donors have delayed and defective induction of type I interferons, T-cell and B-cell helper cytokines in response to TLR/RLR ligands when compared to those from younger adult subjects. However, the underlying intracellular mechanisms defining these defects are not well described. We investigated these impairments in the aging immune system within the context of COVID- 19 vaccination status and COVID-19 infection. We hypothesized that the anti-viral signaling alterations that we observe in healthy older individuals have lasting impacts on how they respond to mRNA vaccination, and SARS-CoV-2 infection. We show that type I IFN production, including the phosphorylation of IRF7 and TBK-1 in the TLR 7/8, RIG-I or cGAS-STING pathways and phagocytosis is dysregulated in innate immune cells (i.e., cDC1s, cDC2s, and CD14dimCD16+ monocytes) from healthy aged individuals (>65yrs old). Anti-viral signaling deficits are also highlighted after application of lipid nanoparticles that are devoid of mRNA (eLNP). Accordingly, application of eLNP resulted in maturation and activation of monocytes and dendritic cells as well as increased phagocytosis. Germinal center dendritic cells (cDC2) display altered anti-inflammatory capacity characterized by increased frequency of PD-L1 and production of TGF-B2 and TGF-B3 when treated with eLNP, suggesting eLNP-mediated immunomodulation is differential across age groups. These findings have been expanded upon in a COVID-19 cohort to similar affect. Taken together, these studies and results discussed herein highlight the importance of antiviral target identification that is considerate of immunosenescent defects and subsequently will enhance vaccine induced immune responses in >65 individuals.