Cystic fibrosis (CF) is an inherited life-shortening condition and the CF lung is particularly prone to chronic infection with Pseudomonas aeruginosa. This infection is associated with significant lung damage and decreased lung function, increased treatment costs, decreased quality of life and increased mortality. It is, therefore, clear that new therapeutic strategies are needed to treat these infections.
P. aeruginosa persistence in the CF lung is largely attributed to it ‘hiding’ from antibiotics and host immune cells in a biofilm. To coordinate biofilm growth, as well as the production of host lung-damaging virulence molecules, P. aeruginosa produces acyl-homoserine lactone (AHL) signalling molecules. Additionally, bacterial AHLs are able to freely enter human cells and interfere with normal cellular functions, ultimately resulting in further inflammation and lung damage. Therefore, an AHL-degrading therapy could render P. aeruginosa more susceptible to antibiotics and immune clearance and prevent the bacteria negatively effecting host inflammatory pathways.
PON2 is a human enzyme able to inactivate AHLs and is normally present in lung epithelial cells. PON2 has extremely limited ability to protect the lungs from infection as it resides inside the cells rather than outside where it would be in direct contact with the P. aeruginosa‐produced AHL. When P. aeruginosa cultures are treated with recombinant human PON2 (rhPON2) AHL accumulation is prevented, cultures have significantly increased susceptibility to tobramycin, expression of many genes associated with virulence and biofilm formation are decreased and biofilm formation is inhibited. Additionally, the upregulation of inflammatory pathways is prevented when cultured human respiratory epithelial cells are co-treated with AHL and rhPON2, and when mice are co-infected with P. aeruginosa and rhPON2.
In summary, our preliminary data supports the use of rhPON2 to prevent AHL accumulation, attenuate P. aeruginosa virulence, increase P. aeruginosa susceptibility to tobramycin, and protect host cells from infection and modulation of inflammatory pathways.