A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

White, Brandon; Komalo, Ben; Nicolaisen, Lauren; Donne, Matt; Marsh, Charlie; DeVay, Rachel M.; Nguyen, An M.; Cousin, Wendy; Heinrich, Jarred; Van Trump, William J.; Plott, Tempest; Fuller, Colin J.; Nguyen, Dat; Chen, Daniel; Bucher, Delia; Tyrra, Sabine; Haynes, Laura; Kuchel, George; Goronzy, Jorg; Larbi, Anis; Fulop, Tamas; Heiser, Diane; Schwandner, Ralf; Elabd, Christian; Kamens, Ben

Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.