Pseudomonas aeruginosa is a nosocomial pathogen that causes severe and life-threatening pneumonia. According to the WHO, it is one of the world’s most dangerous bacterial pathogens that are resistant to multiple antibiotics. Now, using human lung microtissues, researchers at the Biozentrum of the University of Basel have uncovered P. aeruginosa‘s strategy to infect human lung tissue.

The findings are published in Nature Microbiology in an article titled, “Goblet cell invasion promotes breaching of respiratory epithelia by an opportunistic human pathogen.”

Pseudomonas aeruginosa, a leading cause of severe hospital-acquired pneumonia, causes infections with up to 50% mortality rates in mechanically ventilated patients,” the researchers wrote. “Despite some knowledge of virulence factors involved, it remains unclear how P. aeruginosa disseminates on mucosal surfaces and invades the tissue barrier. Using infection of human respiratory epithelium organoids, here we observed that P. aeruginosa colonization of apical surfaces is promoted by cyclic di-GMP-dependent asymmetric division.”

Researchers led by Urs Jenal, PhD, a professor at the Biozentrum, University of Basel, gained novel insights into the infection process using lab-grown lung microtissues generated from human stem cells.

Our lungs are lined by a thin layer of tightly packed cells that protects the deeper layers of lung tissue. The surface is covered with mucus. However, Pseudomonas bacteria have found a way to breach it. But how the pathogen crosses the tissue barrier has not been fully understood until now.

“We have grown human lung microtissues that realistically mimic the infection process inside a patient’s body,” explained Jenal. “These lung models enabled us to uncover the pathogen’s infection strategy. It uses the mucus-producing goblet cells as Trojan horses to invade and cross the barrier tissue. By targeting the goblet cells, which make up only a small part of the lung mucosa, the bacteria can breach the defense line and open the gate.”

Using human lung organoids, the researchers have been able to elucidate the infection strategies of Pseudomonas. However, it remains unclear how the pathogens adapt their behavior during the infection process.

Jenal’s team developed a biosensor to measure and track a small signaling molecule called c-di-GMP in individual bacteria. The method was recently described in Nature Communications. “This is a technological breakthrough,” said Jenal. “Now we can monitor in real time and with high resolution how this signaling molecule is regulated during infection and how it controls the pathogen’s virulence. We now have a detailed view on when and where individual bacterial cells activate certain programs to regulate their behavior. This method enables us to investigate lung infections in more detail.”

The organoids have uncovered a better understanding of how pathogens behave in human tissue. The findings may lead to the development of new therapeutics against pathogens that are resistant and pose a threat to human health.

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