Cathelicidin "fire alarm" paper out

Cathelicidin "fire alarm" paper out

NEW PAPER

Our latest paper is now out in PLoS Pathogens, available fully Open Access for everybody to read.

Lung infections are a very common cause of death worldwide. As the threat of antibiotic-resistance grows, new approaches are urgently needed to treat disease-causing bacteria, such as the multidrug-resistant Pseudomonas aeruginosa. Treatments that could enhance the body’s most effective natural defences might overcome antibiotic-resistance problems and/or be used together with existing therapies.

Antimicrobial Host Defense Peptides are a vital part of the natural defences that prevent infection from occurring in animals, insects and even plants. Peptides, such as the human LL-37, are produced naturally by the body and can kill bacteria and viruses. Some of these peptides can also boost the numbers and functions of cells that can remove harmful infections. Understanding “immunomodulatory” activities like these can help us design new treatments in the future, based on Antimicrobial Host Defense Peptides.

Airway lining cells have important roles as a barrier to keep harmful bacteria out. However, if they become infected, with bacteria getting inside those cells, then they need to be removed. Otherwise harmful infections can establish a protected site and grow there. Infected cells also need to send signals to inform other cells of the danger and start an appropriate defence response.

We show that when Pseudomonas aeruginosa infects airway lining cells, the human peptide LL-37 can provide a signal, acting like a fire alarm. This instructs the compromised, infected cells to send out their own danger signals, to call in other cells to the defend the site. It also instructs these infected to kill themselves before the infection gets a foothold. We demonstrate the mechanism of this process, from bacterial and lung cell perspectives. This occurs by activating a signalling system (called the NLRP3 inflammasome) inside the cell, with a previously unknown ability to respond differently when the cells experience the combination of infection and the LL-37.

This discovery reveals a new mechanism for defending the lung against infections, and has potential implications for innovative new approaches to treat multi-drug resistant infections in the future.

Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa.

McHugh BJ, Wang R, Li HN, Beaumont PE, Kells R, Stevens H, Young L, Rossi AG, Gray RD, Dorin JR, Gwyer Findlay EL, Brough D, Davidson DJ.

PLoS Pathog. 2019 Apr 12;15(4):e1007694

Link to paper online

Davidson Lab funded by the Medical Research Council