Lung-on-chip uncovered new insight on response to early TB infection

The findings reveal the early events that take place during tuberculosis infection and provide a model for future research into respiratory and other infections.

EPFL scientists have developed a lung-on-chip model to examine how the body responds to early tuberculosis (TB) infection. The model uncovered what happens during initial TB infection and may explain in part why those who smoke or have compromised surfactant functionality have a higher risk of contracting primary or recurrent infection.

The model reveals that respiratory system cells, called alveolar epithelial cells, play an essential role in controlling early TB infection. They do this by producing a surfactant substance – a mixture of molecules (lipids and proteins) that reduce the surface tension where air and liquid meet in the lung.

Lead author Vivek Thacker, a postdoctoral researcher at the McKinney Lab, École Polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland, said, “We created the lung-on-chip model as a way of studying some of these early events. Previous studies have shown that components of surfactant produced by alveolar epithelial cells can impair bacterial growth, but that the alveolar epithelial cells themselves can allow intracellular bacterial growth.”

“The roles of these cells in early infection are therefore not completely understood. We used our model to observe where the sites of the first contact are, how M. tuberculosis grows in alveolar epithelial cells compared to bacteria-killing cells called macrophages, and how the production of surfactant affects growth, all while maintaining these cells at the air-liquid interface found in the lung.”

Using the model, scientists recreated a deficiency in surfactant produced by alveolar epithelial cells. They later observed how the lung cells respond to early TB infection.

The technology is optically transparent, meaning they could use an imaging technique called time-lapse microscopy to follow the growth of single M. tuberculosis bacteria in either macrophages or alveolar epithelial cells over multiple days.

The findings uncovered that a lack of surfactant results in uncontrolled and rapid bacterial growth in macrophages and alveolar epithelial cells. On the other hand, the presence of surfactant significantly reduces this growth in both cells and, in some cases, prevents it altogether.

Senior author John McKinney, Head of the Laboratory of Microbiology and Microtechnology at EPFL, said“Our work shines a light on the early events that take place during TB infection and provides a model for scientists to build on for future research into other respiratory infections. It also paves the way for experiments that increase the complexity of our model to help understand why some TB lesions progress while others heal, which can occur simultaneously in the same patient. This knowledge could one day be harnessed to develop effective new interventions against TB and other diseases.”

Journal Reference:
  1. Vivek V. Thacker, Neeraj Dhar, Kunal Sharma, Riccardo Barrile, Katia Karalis, John D. McKinney. A lung-on-chip model of early M. tuberculosis infection reveals an essential role for alveolar epithelial cells in controlling bacterial growth. eLife 2020;9:e59961. DOI: 10.7554/eLife.59961

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