The Pseudomonas aeruginosa Pangenome

P. aeruginosa has become the worldwide most common gram-negative pathogen for community-acquired pneumonia and nosocomial pneumonia including ventilator-associated pneumonia (VAP) in intensive care units. Infections of the respiratory tract with P. aeruginosa moreover contribute substantially to morbidity and mortality in individuals with chronic obstructive pulmonary disease (COPD). The prevalence of chronic airway infections with P. aeruginosa in COPD is about 600,000 cases in Germany thus making it to one of the most frequent severe infections in this country.

This research project has the aim of resolving the pangenome, transcriptome, proteome and lipidome of P. aeruginosa and identifying the genomic differences between strains with high, low or even negligible pathogenic potential for mammals. Sequence and expression analysis will be performed on VAP or COPD isolates of the most common clones in the P. aeruginosa population and environmental isolates belonging to the currently most frequent clones which lack isolates from the clinic. Pathogenicity of the completely sequenced strains will be compared in standardized in vitro and in vivo airway infection models.

Integrity and clearance capacity of the first line of host defense are decisive of whether or not P. aeruginosa will successfully colonize, adapt and persist in the patient's lungs. The project will assess the impact of bacterial genomic diversity on the course of airway infections in an acute murine airway infection model. Completely sequenced P. aeruginosa isolates of the most common cytopathic and cytotoxic clones and the most and least virulent strains of the pathogenicity screen will be inoculated in the airways of immunocompetent mice and congenic knock-out lines that are compromised in distinct steps of the initial host defense. The infectious process will be assessed by lung histopathology, cytokine and immune effector cell profiling in blood and bronchoalveolar lavage fluid and by the quantitative RNA-seq and protein profiling of bacteria and murine lungs. The host-pathogen transcriptome, lipidome and proteome will provide insight into the adaptation of P. aeruginosa of diverse pathogenic potential to the niche of the mammalian lung and the responses evoked in the proficient and compromised host. The generated quantitative datasets will be suitable for a subsequent Systems Biology analysis of airway infections withP. aeruginosa.

The project is funded by the German Federal Ministry of Education and Research (BMBF) under grant number 0315827C. This project is funded within the "Medizinische Infektionsgenomik (Medical Infection Genomics) - Genome research on pathogenic microorganisms" program that aims to unravel the complex interactions between bacterial pathogens and the human host thereby providing the basis for the improvement of prevention, diagnosis and therapy of infectious diseases. Further information can be found on the official project web site.