Editors' ChoiceCystic Fibrosis

Cracking the Code of Pseudomonas Longevity: Unveiling the PAMPs!

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Science Translational Medicine  20 Jan 2010:
Vol. 2, Issue 15, pp. 15ec8
DOI: 10.1126/scitranslmed.3000834

The genetic disease cystic fibrosis causes a progressive decline of lung function and eventual death, which is often accompanied by years of chronic lung infection with Pseudomonas aeruginosa. The mechanisms by which these bacteria escape host defenses and resist treatment are unknown. In a recent article, Cigana et al., report that P. aeruginosa that are resident for long times in the human lung may acquire mutations that help them persist. These adaptations involve products of microbial metabolism called pathogen-associated molecular patterns (PAMPs), which are recognized by host immune cells to initiate immune responses. Lipid A, part of the lipopolysaccharide produced by P. aeruginosa, is a PAMP that is modified during adaptation to chronic infection, but these modifications have not been characterized in actual clinical samples. Now, the authors isolated three clonal strains of P. aeruginosa from a patient with cystic fibrosis, one at the onset of infection and two after years of chronic colonization. Using mass spectrometry, they determined the chemical structure of lipid A and peptidoglycan, another PAMP, from the three strains and evaluated their biological activities. Both the lipid A and the peptidoglycan isolated from the chronic colonizing strain of bacteria had significant structural modifications. Characterization of the bacterial genes that modify lipid A revealed that the pagL gene was mutated in the strain obtained at the later stage of cystic fibrosis. Both of the PAMPs made by these later-stage bacteria induced attenuated inflammation in human cells and in mouse lungs as compared with those made by early-stage bacteria. These results suggest that the inferior inflammatory response induced by chronic colonizing bacterial strains is responsible for the impaired ability of the host to mount an immune response adequate to eradicate the infection. This insight will point to new approaches for the treatment of chronic lung infections in cystic fibrosis and, if such adaptations also occur in other chronic bacterial infections, to broader applications as well.

C. Cigana et al., Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PLoS ONE 4, e8439 (2009). [Full Text]

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