Cystic fibrosis, better known by the name of mucoviscidosis, is a pernicious hereditary disease. Due to a metabolic disorder, the bodily secretions of the patients contain too little water. One of the corollaries is that the mucus in the bronchi of the patients is overly viscous. They suffer from chronic cough and recurrent severe infections of the lung. This is caused by pathogens such as Pseudomonas aeruginosa persistently colonising the viscous mucus where they form resistant biofilms. More than 90% of the patients die as a result of this chronic lung infection. Some forms of P. aeruginosa has adapted particular well to the conditions in the viscous mucus of the lung - they form very compact colonies that are often resistant to antibiotics and tend to adhere closely to each other. Scientists from the TWINCORE recently discovered the difference between these pathogens specialised on cystic fibrosis patients and their relatives - and thus laid the foundation for new therapeutic approaches.
These special strains of P. aeruginosa get their name from their appearance on culture dishes in the laboratory. They form particularly compact, small colonies and are therefore called "Small Colony Variance", or SCV. There are different types of SCVs - but it is common to all that there are specialised on the conditions in the lungs of cystic fibrosis patients. "They form very strong biofilms and thus contribute significantly to the chronic course of the lung infection," says Andrea Blanka, who is a scientist at the Institute for Molecular Bacteriology. Once the bacteria agglomerate into a Biofilm, they are difficult to recognise by the immune system and antibiotics do not penetrate into the mucous matrix of the biofilm. "We wanted to know which factors in our clinical P. aeruginosa isolate is responsible for these changes and the ensuing adaptation to the ill lung of cystic fibrosis patients."
In order to elucidate the special features of the compact colonies, the TWINCORE scientists and their colleagues from the Helmholtz Centre for Infection Research in Braunschweig and the Hannover Medical School compared the genes of these bacteria and the appearance of this special variant to common P. aeruginosa strains.
"We then found out that the SCV strain we investigated has a mutated Gene that is responsible for the production of long-chain fatty acids," says Andrea Blanka. "As a result of this mutation, fewer long-chain fatty acids are produced and incorporated into the membrane by the bacteria." This is the crucial piece of the puzzle since the length of the fatty acids of which the enveloping membrane of the bacteria is composed affects a so-called chemo-sensory system of P. aeruginosa that is located in the membrane. This controls, in addition to other regulators, how much of the messenger substance, cyclic di-guanosine monophosphate, or c-di-GMP, is produced in the cells. If the bacteria produce little c-di-GMP, they swim individually and freely in the lung secretion of the patient. If the bacteria produce large amounts of c-di-GMP, the bacteria agglomerate into the resistant biofilms.
"We have investigated just one of several clinical SCV isolates so far and now hope to look at 150 different SCV isolates from lungs with cystic fibrosis to analyse if these isolates turn into the high-biofilm variants of P. aeruginosa by different mechanisms," the biochemist says. "But the effect of fatty acids on the release of c-di-GMP was previously unknown though."
The scientists of the Institute for Molecular Bacteriology are now investigating how they can make use of the knowledge about these small colony variants of P. aeruginosa for new therapeutic approaches to the treatment of chronic lung infections in cystic fibrosis patients.
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Original publication:
A. Blanka, J. Düvel, A. Dötsch, B. Klinkert, W.-R. Abraham, V. Kaever, C. Ritter, F. Narberhaus, S. Häussler, Constitutive Production of c-di-GMP Is Associated with Mutations in a Variant of Pseudomonas aeruginosa with Altered Membrane Composition. Sci. Signal. 8, ra36 (2015). DOI: 10.1126/scisignal.2005943.
