Alveolus on a chip model of non-tuberculous mycobacteria infection

Project Summary Nontuberculous mycobacteria (NTM) infections have emerged as a significant public health concern, particularly in individuals with compromised immune systems and those with underlying pulmonary conditions. The intricacies of NTM pathogenesis and the limited availability of appropriate in vitro and in vivo models for studying NTM infections have hindered our understanding of the disease and the development of effective therapeutic interventions. This project aims to address this critical gap by using a cutting-edge humanized lung-on-a-chip model to investigate NTM infections in a physiologically relevant environment. Our research leverages the innovative lung-on-a-chip technology, which mimics the structural and functional complexity of the human lung alveolus, to provide a platform for studying NTM infection. This model is a fully human system built with primary cells including human lung alveolar cells, pulmonary vascular cells and immune cells, and incorporates a dynamic microenvironment that closely replicates the physiological conditions of the lung. By introducing a variety of NTM strains into this humanized alveolus, we will gain insights into the key steps of NTM pathogenesis, host-pathogen interactions, and identify potential therapeutic targets. We will pursue the following Specific Aims: 1. We will take advantage of the system we successfully established with Mycobacterium fortuitum to determine the transcriptional response of airway cells to NTM infection, and the impact of airway immune responses to NTM survival. 2. We will use the alveolus-on-a-chip system to study innate immune mechanisms controlling NTM infection in the alveolus, and the role airway NTM infection plays in triggering recruitment of myeloid cells from the vasculature. The proposed work is expected to identify how model human airways respond to NTM infection along with discovering common and unique responses to the panel of NTM species tested.