The COVID-19 pandemic highlighted the need for human tissue models of infection to study host-pathogen interactions, rapidly screen potential therapeutic interventions, and study fundamental pathogenic mechanisms. We have developed a novel 3D culture platform enabling long-term ex vivo culture of healthy primary human peripheral lung microtissues to study the fundamental mechanisms of viral transport, infection, progression, and treatment of SARS-CoV-2. The 3D microtissue system uses controlled perfusion of fresh media through soft granular PAAm microgels in which human lung microtissues are suspended in place and kept viable for the extended duration of the study. The ultralow yield stress (&lt; 2 Pa) property of the microgels allows intrinsic virus-host interaction and the corresponding evolution of infected microtissues. The cultured lung microtissues maintained greater than 90% viability and contained heterogeneous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. In addition, samples were readily infectible with HCoV-OC43 and SARS-CoV-2 coronavirus strains, and demonstrated comparable susceptibility to infection. Treatment of tissues with different therapeutic compounds revealed suppressed viral growth with some compounds, while others suppressed viral replication in tissues from a subset of donors. The existing 2D cell lines do not recapitulate in vivo complexities, and the absence of inter-individual heterogeneity of host response to SARS-CoV-2 infection from lab-grown organoids makes them a less ideal in vitro model. Although animal models may reproduce a virus-host interaction and the associated systemic symptoms from whole body response to infection, intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to SARS-CoV-2 basic research. This platform may offer an alternative in vitro model for understanding the virus and contributing to therapeutic strategies for prevention and/or intervention.

3D lung microtissue models of SARS-CoV-2 infection and progression

ACS Fall 2021

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