Clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis have revealed mutation-induced remodelling of the BfmRS two-component system. Thereby, enabling host adaptation and resulting in a chronic infection state.
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a gram-negative opportunistic pathogen. It is frequently associated with life-threatening infections in humans. Most importantly, it is the leading cause of chronic pulmonary infections and high mortality in cystic fibrosis patients. Once the pathogen has established a chronic infection, it is nearly impossible to eradicate using current antibiotic regimens. In order to design better strategies for clinical intervention, it is vital to develop our understanding of the evolution and adaptation of P. aeruginosa during infection.
During chronic infections, P. aeruginosa undergoes several genetic changes. This leads to the development of mutants with altered phenotypes. For example, conversion to the mucoid colony, reduced production of virulence factors, transition to a biofilm-associated lifestyle and enhanced antibiotic resistance. Genome analyses have found recurrent patterns of mutations within isolates from cystic fibrosis patients. In particular, in genes encoding global transcriptional regulators, such as MucA and LasR.
Survival of P. aeruginosa in the airways of cystic fibrosis patients is, in part, dependent on its ability to sense and respond to environmental changes. In P. aeruginosa cystic fibrosis isolates, researchers have commonly found genetic changes in genes encoding proteins of two-component systems (TCSs). These are part of common bacterial mechanisms for sensing and responding to the extracellular environment.
BfmRS two-component system
In a study, published in Science Signalling, researchers examined the spontaneous missense mutations in bfmS on the physiology of P. aeruginosa and the underlying mechanisms. This gene encodes BfmS – a sensor histidine kinase of the BfmRS TCS – a frequent target of adaptive mutations. It negatively controls the activity of its cognate downstream response regulator BfmR. This is a positively autoregulated transcription factor that plays key roles in biofilm maturation, sensing systems and acute infections.
The team found that spontaneous mutations (L181P and E376Q) in bfmS increased the phosphorylation and thus the transcriptional regulatory activity of BfmR. In other words, it induced remodelling of TCSs and allowed P. aeruginosa to integrate information from multiple sources to activate BfmR. This in turn directed this bacterium towards a chronic infection state by reducing virulence and enhancing biofilm formation.
This study demonstrates the plasticity of TCSs mediated by spontaneous mutations. Moreover, it suggests that mutation-induced activation of BfmRS may contribute to host adaptation by P. aeruginosa during chronic infections. Gaining a more in-depth knowledge about the adaptive changes in signalling pathways, will provide insight into the selective forces that are driving pathogen evolution. Subsequently, helping to improve the treatment of infections.
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