Abstract
Pseudomonas aeruginosa is the predominant microorganism in chronic lung infection of cystic fibrosis patients. The chronic lung infection is preceded by intermittent colonization. When the chronic infection becomes established, it is well accepted that the isolated strains differ phenotypically from the intermittent strains. Dominating changes are the switch to mucoidity (alginate overproduction) and loss of epigenetic regulation of virulence such as the Quorum Sensing (QS). To elucidate the dynamics of P. aeruginosa QS systems during long term infection of the CF lung, we have investigated 238 isolates obtained from 152 CF patients at different stages of infection ranging from intermittent to late chronic. Isolates were characterized with regard to QS signal molecules, alginate, rhamnolipid and elastase production and mutant frequency. The genetic basis for change in QS regulation were investigated and identified by sequence analysis of lasR, rhlR, lasI and rhlI. The first QS system to be lost was the one encoded by las system 12 years (median value) after the onset of the lung infection with subsequent loss of the rhl encoded system after 17 years (median value) shown as deficiencies in production of the 3-oxo-C12-HSL and C4-HSL QS signal molecules respectively. The concomitant development of QS malfunction significantly correlated with the reduced production of rhamnolipids and elastase and with the occurrence of mutations in the regulatory genes lasR and rhlR. Accumulation of mutations in both lasR and rhlR correlated with development of hypermutability. Interestingly, a higher number of mucoid isolates were found to produce C4-HSL signal molecules and rhamnolipids compared to the non-mucoid isolates. As seen from the present data, we can conclude that P. aeruginosa and particularly the mucoid strains do not lose the QS regulation or the ability to produce rhamnolipids until the late stage of the chronic infection.
Highlights
The onset of the chronic lung infection with Pseudomonas aeruginosa in CF patients is preceded by intermittent colonization [1] usually with environmental strains [2]
We have demonstrated that rhamnolipid plays a major role in the defense against the cellular components of the immune system, especially against the polymorphonuclear neutrophilic leukocytes (PMNs) which dominate the immune response in the CF lung [7,8,9]
The majority of the CF isolates (63) were not producing 3-oxo-C12-HSL after 12 years of infection while only a small proportion (16 isolates) were 3-oxo-C12-HSL producers but lost the ability to produce C4-HSL. The lost of both Quorum Sensing (QS) molecules was found first after 17 years of infection. This shows that the abilities to produce 3-oxo-C12-HSL and C4-HSL signal molecules are lost at different time points during the chronic lung infection and interesting is the finding of C4-HSL molecules in isolates from the late stages of the infection
Summary
The onset of the chronic lung infection with Pseudomonas aeruginosa in CF patients is preceded by intermittent colonization [1] usually with environmental strains [2]. P. aeruginosa employ two dominating QS system the las and the rhl encoded system Both systems feature specific signal molecules for separation of the processes, 3-oxo-C12-HSL and C4-HSL respectively. The signal molecule binding region, which is located in the N-terminal portion of the protein and a helix-turn-helix motif (HTH) located in the Cterminal, which is responsible for the protein binding to the target promoters [13,14,15]. Within these systems a third analogous receptor, the QscR operates with 3-oxo-C(12)-HSL to modulate gene expression of a specific regulon which overlaps with the two other las and rhl regulons [16]. This was further substantiated in a recent paper, where the authors provided evidence that rhl system is able to overcome the absence of the las system by activating specific LasR-controlled functions, including production of 3-oxo-C(12)HSL and PQS [19]
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