Age shapes the myeloid cell antiviral response to RSV infection in a human airway tissue model 4051

Abstract Description Respiratory syncytial virus (RSV) infection causes significant morbidity in elderly adults. To determine how advanced age impacts myeloid cell (MC) antiviral responses, we developed a 3D human lung model (HLM) to recapitulate the small airway. The HLM is composed of layered primary differentiated small airway epithelial cells at air-liquid interface, fibroblasts embedded in collagen, and endothelial cells. Introduced blood MC (monocytes and dendritic cells) from 36-40yo (Adult) or 69-88yo (Elderly) donors migrated throughout the HLM. Recovered MC were assessed using flow cytometry, microscopy, and transcriptional profiling. MC acquired phenotypes and morphology of tissue-resident cells, indicating adaptation to the airway environment and differentiation into tissue-resident macrophages. However, prior to infection, sorted Elderly MCs showed reduced expression of genes promoting macrophage differentiation and function, e.g. PPARG, MARCO, INHBA, yet showed higher basal expression of pro-inflammatory genes, e.g. IL18, CDKN1A, TLR9, compared to sorted Adult MCs. After RSV challenge, HLM built with Elderly MC harbored significantly more RSV RNA, consistent with poor induction of genes in IFN signaling, viral sensing, and macrophage activation pathways. Thus, diminished expression of canonical macrophage genes, increased baseline inflammation, and reduced ability to build up antiviral IFN responses contribute to the impaired viral clearance in HLM bearing Elderly MC. Funding Sources Funded by NIH R01 EB025596 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)