Bacterial communication

Bacteria are no longer thought of as individual single celled organisms but they can co-ordinate and communicate in a multicellular fashion when it is advantageous for them to do so. The majority of microbes are found thriving in complex polymicrobial biofilm communities. In the natural environment bacteria predominantly live adhered to a surface as part of a biofilm. A biofilm is a multicellular community of cells encased in a self-produced extracellular matrix Life in a biofilm offers advantages to the population, including supply of nutrients and protection from environmental stress.

Bacteria have evolved elaborate means to communicate with each other, both within and between species by releasing a wide range of diffusible signaling compounds into their external environment. Once outside the bacterial cell, these molecules freely diffuse until perceived by potential signal recipients. Bacteria can utilize such systems to monitor their population density (the process of quorum sensing) and/or their confinement in particular environmental niches and to activate specific population-wide alterations in gene expression and bacterial behaviour. Cell–cell signalling allows a colony or group of organisms to behave in a coordinated fashion to regulate processes contributing to virulence, antibiotic production, biofilm formation and other developmental programmes. In some cases, bacteria are capable of responding to signals produced by other species of bacteria, eavesdropping on their competitors, or synchronizing with collaborators.

The autoinducer signal molecules produced by bacteria are structurally diverse. Many Gram-negative bacteria use N-acylhomoserine lactones as signals, although other fatty acid derivatives such as cis-unsaturated fatty acids are also found1.

In order to sense these chemical signals, bacteria often employ two-component signal transduction systems allowing respond and adapt to a wide range of signals and stimuli, including nutrient availability, cellular redox state, changes in osmolarity, quorum signals and antibiotics. The canonical two-component signal transduction systems are composed of two proteins; a sensor histidine kinase which responds to a signal and a cognate response regulator which mediates the response. The perceived signal is directly translated into a change in transcriptional regulation, the decision-making level of a prokaryotic cell at which cell-cell communication is integrated with other sensory inputs.

Microbial infections associated with CF

In a healthy respiratory system the upper respiratory tract is colonized by a wide variety of microorganisms, while the lower respiratory tract is maintained in a sterile state by the various innate defences of the host. Failure of any of these innate defences results in susceptibility to pulmonary infection. CF patients have an abnormal mucous composition in the airways and are particularly vulnerable to microbial infection. Such infections are responsible for the early mortality associated with CF.

Ultimately 80 to 95% of patients with CF succumb to respiratory failure brought on by chronic bacterial infection and associated airway inflammation3. Staphylococcus aureus is a Gram-positive bacterium and it is the most common pathogen that colonizes the CF lung in the first few years of life (Fig 2), however Pseudomonas aeruginosa to be the most important pathogen in progressive, severe CF lung disease4. P. aeruginosa is a Gram-negative opportunistic pathogen, and chronic colonization it occurs in 80% of CF patients by 18 years of age4 (Fig 2). These patients can also be co-infected by other pathogens such as Burkholderia cenocepacia and Stenotrophomonas maltophilia.

One of the most problematic of CF pathogens is B. cenocepacia, which accounts for between 50% and 90% of all Burkholderia cepacia complex (Bcc) infections diagnosed in CF patients5. B. cenocepacia is a Gram-negative opportunistic pathogen which is characterized by low responsiveness to antibiotic therapy and the ability to cause significant reductions in lung function, additionally it includes strains exhibiting a high virulence potential as well as strains with a high patient-to patient transmission5.

Stenotrophomonas maltophilia is a Gram-negative bacterium that occurs ubiquitously with Pseudomonas aeruginosa in the environment and both can co-occur in the CF lung. The treatment of S. maltophilia infections is problematic, as isolates are also resistant to many clinically useful antibiotics6.

Communication in Pseudomonas, Burkholderia and Stenotrophomonas

The signalling network of P. aeruginosa consists of multiple interconnected signalling layers that co-ordinately regulate virulence and persistence. The master virulence signalling systems in P. aeruginosa are the N-acyl homoserine lactone (AHL) responsive systems Las and Rhl, which together control the expression of multiple virulence factors in response to cell density. Another group of signalling molecules related to virulence factor production are the 4-quinolones including Pseudomonas Quinolone Signal 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a quorum-sensing (QS) signal that regulates numerous virulence genes including those involved in iron scavenging7.

In addition to producing AHLs as signals, B. cenocepacia produces a diverse set of 2-alkyl-4(1H)-quinolones (AHQs), including the precursor to PQS, 2-heptyl-4(1H)-quinolone (HHQ), but does not synthesize 2-heptyl-3-hydroxy-4(1H)-quinolone8. B. cenocepacia also produces cis-2- dodecenoic acid, a molecule structurally related to the diffusible signal factor (DSF; 11-methyl-cis-2-dodecenoic acid) found in Xanthomonads5. S. maltophilia also possesses a diffusible signal factor (DSF)-mediated cell–cell signalling system that was first identified in the related plant pathogen Xanthomonas campestris pv. campestris6.

Bacterial chatter matters

There is an increasing appreciation of the polymicrobial nature of many bacterial infections such as those associated with CF and of the potentially important role for interspecies interactions in influencing both bacterial virulence and response to therapy. Patients with CF are often co-infected with P. aeruginosa and other pathogens including B. cenocepacia and S. maltophilia.

P. aeruginosa responds to DSF produced by S. maltophilia and BDSF produced by B. cenocepacia leading to changes in biofilm architecture and increased resistance to cationic antimicrobial peptides9. Such interspecies interactions occur in the CF lung where they may influence the efficacy of antibiotic treatment for chronic P. aeruginosa infections9.