Interkingdom signalling: how Pseudomonas aeruginosa senses and adapts to the host environment.

This project will determine how mammalian peptide signaling molecules shape the behavior and virulence of the major bacterial pathogen Pseudomonas aeruginosa (Pa). The identification of microbial chemical signatures of infection by host pattern recognition receptors and the subsequent onset of immune responses is recognized as a central tenet of immunology. However, interkingdom signaling is not unidirectional and it is increasingly recognized that the capacity to sense and respond to environmental change is central to the ability of pathogens to survive within the hostile host niche.

Pa is the predominant cause of death in people with cystic fibrosis (CF), the most common inherited genetic condition of Caucasians. People with CF, or with other chronic lung conditions such as non-CF bronchiectasis, develop persistent, chronic Pa infections that are highly resistant to antibiotic treatment and are a major cause of morbidity and mortality. Recent work from the laboratories of the Liverpool supervisors has described how host innate immune defence molecules can shape the processes of Pa adaptation and evolution within the respiratory tract, with consequences for the emergence of antibiotic resistance. Findings from the Leeds supervisor's laboratory have highlighted a mechanism by which Pa senses and responds to host signaling molecules, triggering bacterial defence mechanisms. These studies independently identified host cationic peptides as key players in driving bacterial genotypic, transcriptomic and phenotypic changes during infection and highlighted the importance of Pa two-component regulatory systems in directing the bacterial response to the host environment.

This PhD project aims to:
1. Identify which host cationic peptides are recognized by Pa, and by what mechanisms
2. Explore how this recognition leads to phenotypic change in Pa
3. Examine the effects of host peptide recognition on virulence and pathogenesis in disease-relevant animal models
4. Determine the extent to which host cationic peptides drive Pa evolution and the consequences for the emergence of antibiotic resistance, with a view to informing antibiotic treatment strategies and identifying new target pathways.

We will develop novel chemical tools to investigate host cationic peptide recognition in Pa and will utilize unique mouse models of infection and in vivo imaging approaches, to facilitate an exploration of the impact of host signaling molecules on bacterial in-host evolution.

Pa is a versatile bacterial pathogen found in a wide variety of environments. An adaptable and flexible approach to environmental change is key to its success. The behavioural switch triggered by recognition of host cationic peptides is likely a defence mechanism, and emerging evidence demonstrates it has important consequences for evasion of host immunity, attachment to host surfaces, virulence factor production and antibiotic resistance. Understanding the molecular mechanisms involved in this interkingdom signaling may reveal opportunities for therapeutic intervention designed to block bacterial recognition of host signals, thus stalling the bacterial behavioural switch.