Feared Pathogen Turns Our Lung Defenses Against Ourselves

lung cells infected by P. aeruginosa bacteria / photo by Laventie Benoit-Joseph, University of Basel
Lung cells infected by P. aeruginosa bacteria. Photo by Laventie Benoit-Joseph, University of Basel. CC-BY-NC-ND.

The “superbug” Pseudomonas aeruginosa is an especially dangerous bacterium, resists many antibiotics, and often causes intractable pneumonia and death when it infiltrates the lungs. 

A new study from Sebastián Riquelme and Alice Prince at the Vagelos College of Physicians and Surgeons at Columbia University Irving Medical Center now reveals how P. aeruginosa use our own immune defenses to multiply and persist in our lungs. 

Superbug eats our antibacterial defenses

Our immune system should fight off P. aeruginosa as it does other bacteria. A succession of anti-bacterial defenses is usually activated once the immune system senses toxins and sugars that coat many bacteria cells, including P. aeruginosa.

But P. aeruginosa often resist these defenses and becomes entrenched in the lungs inside an impenetrable biofilm.

The new research shows that P. aeruginosa, unlike other opportunistic bacteria, can sidestep an antibacterial substance — called itaconate — that normally helps in the fight against pathogens. (Itaconate has been recently characterized as a major immune suppressor molecule produced in mitochondria of immune cells, and its synthesis is induced by the protein IRG1).

The bacteria sidestep itaconate by making a series of adaptations, including using itaconate as food to fuel its own growth.  P. aeruginosa also produce extracellular polysaccharides in response to itaconate to create a biofilm that shields the bacteria. 

Unfortunately, the extracellular polysaccharides produced by the pathogenic bacteria, in turn, induces our immune cells to produce even more IRG1 and itaconate.

In sum, the pathogen’s adaptations generate a self-perpetuating bacterial community in our lungs. 

Lab vs. patient strains

The discovery was surprising, because previous laboratory strains of P. aeruginosa did not behave in the same way. 

“In this new work, we used strains isolated from the airways of cystic fibrosis patients and from subjects in intensive care units, which gave us unexpected but relevant results,” Riquelme says.

“We need to take P. aeruginosa’s tremendous metabolic ability to adapt into account when looking for new therapeutics,” Riquelme adds. “Also, we need to define what our immune cells are producing during infection, as certain secreted molecules might provide pathogens with advantages instead of providing protection for us.”

“But by identifying the mechanisms by which these organisms adapt and exploit our defenses, it is conceivable that targeting these very adaptations may allow us to combat such infectious agents and prevent the devastating diseases they cause.”

References

More information

Sebastián Riquelme, PhD, is an instructor of pediatrics at Columbia University Vagelos College of Physicians and Surgeons.

Alice Prince, MD, is the John M. Driscoll Jr, MD, and Yvonne Driscoll, MD, Professor of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons.

The research was published in a paper titled “Pseudomonas Aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation” in the June 2020 issue of Cell Metabolism. 

Other authors: Kalle Liimatta (Columbia University Irving Medical Center), Tania Wong Fok Lung (CUIMC), Blanche Fields (CUIMC), Danielle Ahn (CUIMC), David Chen (CUIMC), Carmen Lozano and Yolanda Sáenz(Centro de Investigación Biomédica de la Rioja, Logroño, Spain), Anne-Catrin Uhlemann (CUIMC), Barbara C Kahl (University Hospital Münster, Münster, Germany), Clemente J Britto (Yale University School of Medicine) and  Emily DiMango (CUIMC).