Programa del congreso

The COVID-19 pandemic showed the need for novel preclinical models that accurately replicate human physiology and immune responses. Conventional in vitro systems lack tissue complexity and physiologically relevant microenvironments, while animal models differ from humans in respiratory anatomy, cellular composition, and immune function, severely limiting the translation of results. To address these limitations, we developed a hybrid human lung organoid model by integrating lung epithelial cells, stromal cells, macrophages, and NK cells. Progenitor cells were isolated from human lung resections, expanded as organoids, and combined with tissue-resident stromal cells and peripheral blood immune cells isolated via magnetic cell sorting, in a three-dimensional architecture via Matrigel domes. The co-culture system was able to sustain cell viability and promoted self-organization, enabling cell–cell communication within the three-dimensional architecture of the model. Upon infection with SARS-CoV-2, viral RNA and infectious titers peaked at 24 hours post-infection, followed by a gradual decline. Quantification of subgenomic viral RNA confirmed active viral replication. Infection induced expression of transcripts compatible with an innate immune response, with significant upregulation of IL-6, CXCL10, TNF-α, IFN-β, CCL5, and interferon-stimulated genes ISG15 and MX1. This hybrid organoid model overcomes critical limitations of classical systems by integrating multiple human lung cell types in a physiologically relevant environment. It supports productive SARS-CoV-2 infection and recapitulates early innate immune responses, providing a robust platform for investigating viral pathogenesis and evaluating therapeutic interventions for COVID-19 and other respiratory diseases.