Bacterial Quorum Sensing Molecule Targets Host Cell Migration Receptor

Scientists have discovered a new role and important target on human host cells for a signaling molecule known for its role in quorum sensing of the pathogenic bacteria Pseudomonas aeruginosa.

P. aeruginosa uses N-acylhomoserine lactones (AHLs) as signaling molecules in quorum sensing, whereby it coordinates expression and production of biofilm and virulence factors. AHLs can diffuse through bacterial and eukaryotic cell membranes. At low concentrations, white blood cells, for example, can become more flexible and effective, but at high concentrations the opposite occurs, which weakens immune defenses and increases likelihood of progressive infections and inflammations.

A research team at Linköping University (Linköping, Sweden) has now identified a signaling role for an AHL also in host cells by examining effects on human intestinal epithelial Caco-2 cells. The quorum sensing AHL molecule N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C(12)-HSL) produced by P. aeruginosa was found to modulate Caco-2 cell migration in a dose- and time-dependent manner. The team then demonstrated for the first time that 3O-C(12)-HSL interacts and co-localizes with the IQ-motif-containing GTPase-activating protein (IQGAP1) in Caco-2 cells. Moreover, 3O-C(12)-HSL induced changes in the phosphorylation status of Rac1 and Cdc42 and in the localization of IQGAP1. The study, published online October 11, 2012 in the journal PLoS Pathogens, suggests that the IQGAP1 is a novel receptor for P. aeruginosa 3O-C(12)-HSL and is likely the integrator of Rac1 and Cdc42- dependent altered cell migration.

Prof. Elena Vikström, medical microbiologist and senior author of the study, describes IQGAP1 as something of a double agent — “The protein can both listen in on the bacteria’s communication and change the functions in its host cells,” said Prof. Vikström. She adds, “We have proof that physical contact between bacteria and epithelial cells is not always required; the influence can happen at a distance.” The team’s discovery can open the door to new strategies for treatment where antibiotics cannot help. One possibility is designing molecules that bind to the receptor and thereby block the signaling path for the bacteria; a strategy that could work with cystic fibrosis, for example, as the disease involves sticky mucus made of bacterial biofilm and large amounts of white blood cells formed in the airways.

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