Molecular basis for Pseudomonas aeruginosa persistent infections in CF patients

March 12, 2010

New research reveals Small Colony Variants (SCVs) of P. aeruginosa to be a hallmark of chronic infection in cystic fibrosis (CF) patients. Results, published March 12th in the open-access journal PLoS Pathogens, suggest that SCV-mediated persistence might be a good target for antimicrobial chemotherapy.

Cystic fibrosis is a widespread genetic disease that leads to progressive disability and early death. The principal cause of and in CF patients is a progressive deterioration of the respiratory system caused by a chronic infection of the patients' lungs, mainly by the opportunistic bacterial pathogen . CF lung infections can be treated with antibiotics, however full clearance is not possible due to the protective environment of the CF lung and the adaptation of infective species to a persistent lifestyle. This presents serious challenges for the long-term chemotherapy of CF patients.

Adaptive P. aeruginosa morphotypes include SCVs, slow-growing and strongly adherent variants that frequently arise in chronic lung infections. Because the appearance of SCVs correlates with poor lung function and , they have long been suspected of mediating the P. aeruginosa persistence phenotype in CF infections.

In this study, the researchers characterized a signaling system in P. aeruginosa called YfiBNR, mutations in which lead to the generation of SCV variants. Activation of YfiBNR resulted in increased levels of the signaling molecule c-di-GMP, which in turn triggered massive production of exopolysaccharides and drastically reduced growth rates, two hallmarks of SCV behavior. YfiN-mediated SCVs were shown to be highly resistant to macrophage phagocytosis, suggesting a role for the SCV phenotype in immune system evasion. Consistent with this, activation of YfiN significantly increased the persistence of P. aeruginosa in long-term infections in a mouse model, establishing a firm causal link between SCV and persistence in chronic P. aeruginosa infections.

The authors conclude that 'c-di-GMP has long been a key suspect in chronic behavior of bacterial pathogens. The finding that the c-di-GMP-mediated SCV phenotype confers a persistent advantage in mice provides the first direct evidence in favor of such a model. This study thus opens up new avenues to specifically counteract persistent infections.'

More information: Malone JG, Jaeger T, Spangler C, Ritz D, Spang A, et al. (2010) YfiBNR Mediates Cyclic di-GMP Dependent Small Colony Variant Formation and Persistence in Pseudomonas aeruginosa. PLoS Pathog 6(3): e1000804. doi:10.1371/journal.ppat.1000804

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