3D tissue-engineered lung models to study immune responses following viral infections of the small airways

Small airway infections caused by respiratory viruses are some of the most prevalent causes of illness and death. With the recent worldwide pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is currently a push in developing models to better understand respiratory diseases. Recent advancements have made it possible to create three-dimensional (3D) tissue-engineered models of different organs. The 3D environment is crucial to study physiological, pathophysiological, and immunomodulatory responses against different respiratory conditions. A 3D human tissue-engineered lung model that exhibits a normal immunological response against infectious agents could elucidate viral and host determinants. To create 3D small airway lung models in vitro, resident epithelial cells at the air-liquid interface are co-cultured with fibroblasts, myeloid cells, and endothelial cells. The air-liquid interface is a key culture condition to develop and differentiate airway epithelial cells in vitro. Primary human epithelial and myeloid cells are considered the best 3D model for studying viral immune responses including migration, differentiation, and the release of cytokines. Future studies may focus on utilizing bioreactors to scale up the production of 3D human tissue-engineered lung models. This review outlines the use of various cell types, scaffolds, and culture conditions for creating 3D human tissue-engineered lung models. Further, several models used to study immune responses against respiratory viruses, such as the respiratory syncytial virus, are analyzed, showing how the microenvironment aids in understanding immune responses elicited after viral infections.