Mini human lung chip reveals early tuberculosis events

Researchers have struggled to build laboratory models that faithfully reproduce the human alveolus — the tiny air sacs deep in the lung where many respiratory infections begin — while keeping the immune components that shape disease. Chak Hon Luk and colleagues addressed that gap by creating an autologous, single donor platform derived from human induced pluripotent stem cells (iPSC). They built a Lung-on-Chip, called iLoC, that combines the major cell types of the distal lung including Type II and I alveolar epithelial cells, vascular endothelial cells and macrophages within a microfluidic device. The device recreates two key physical features of the lung environment: a true air-liquid interface and 3D mechanical stretching that mimics breathing. Because all cell types come from the same donor source, the system is “autologous” and avoids mismatches between tissues and immune cells. Imaging along with single-cell RNA sequencing (scRNA-seq) showed that the cellular profiles in the iLoC resemble those found in the human distal lung, suggesting the model can reproduce important aspects of lung biology that are missing from simpler laboratory systems.

To test whether the iLoC could model infection, the team exposed it to the human pathogen Mycobacterium tuberculosis (Mtb). Using imaging and the cellular readouts available in the device, they found that both macrophages and epithelial cells became infected. Overall bacterial growth was limited in most cases, but in some experiments the infection behaved stochastically: large clusters of macrophages formed that included necrotic core-like structures and foci where Mtb replication was evident. The researchers also made a genetically engineered, autophagy deficient iLoC to probe host mechanisms. This autophagy-deficient model, created by targeting ATG14, showed higher macrophage necrosis after Mtb infection yet did not show increased bacterial replication. These findings came from a single-donor, genetically tractable human alveolar platform that combines iPSC-derived cells, microfluidic engineering, imaging and scRNA-seq to observe early events after Mtb exposure.

The iLoC described by Chak Hon Luk and collaborators provides a new way to study the earliest pathological events in human lung infection in a system that keeps immune cells and lung cells together under realistic physical conditions. Because it is autologous and derived from iPSC, the model is genetically tractable: researchers can introduce specific mutations or deficits such as ATG14 deficiency to see how human lung cells and macrophages respond. That ability to combine human genetics, immune biology and realistic tissue mechanics could help scientists dissect why some infections remain contained while others lead to cell death and tissue damage. Importantly, the platform is presented explicitly as a tool to study lung diseases and therapies, suggesting it could be used to test candidate drugs, probe mechanisms of necrosis and bacterial control, and to compare responses across human genetic backgrounds without relying only on animal models.