The impact of lipid nanoparticles (LNP) on anti-viral pathways and immune function in aged individuals

Abstract

Abstract Aging leads to increased morbidity and mortality posing a big challenge to societies as the world population shifts to an increased proportion of aged individuals. Immunosenescence, a condition of chronic increased level of basal inflammation and immune system dysregulation, is suspected to decrease vaccine efficacy and enhance COVID-19 complications in older individuals. Current vaccination efforts like mRNA vaccines utilize lipid nanoparticle (LNP) platforms that elicit the immune response however, little is known about how LNP adjuvantation affects anti-viral pathways and immune function in aged individuals. We have previously shown 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 older adults (n=11). Our preliminary data utilizing LNP show that in response to LNP stimulus at 4 and 24 hours, older adults have decreased IFNy output. Thus, we further hypothesize that cDC1, cDC2, and CD14dim CD16+ monocytes from healthy, older adults (n=11) will have dysregulated anti-viral signaling and antigen presentation in response to LNP stimulation as measured by the defect in type I IFN production, phosphorylation of IRF7, TBK-1, and immune function like phagocytosis and antigen presentation via flow cytometry. These data support our previous reports of a delayed/decreased proinflammatory output following stimulation and demonstrate potential targets of antiviral pathways that can resolve dysfunctions of the aging immune system for an effective vaccination response. Supported by NIH (U19 AI128910-04S1)