Project

Lung transplantation is a widely accepted treatment for end-stage pulmonary disease. Unfortunately the early and late outcome after lung transplantation is worse than after other organ transplantations with a 5-year survival of 52%. These disappointing results are mostly due to early lung graft infections and a progressive loss of graft function due to chronic rejection, also called bronchiolitis obliterans syndrome (BOS). Preventing both infections and BOS are therefore major challenges to increase survival after lung transplantation. Pseudomonas aeruginosa is a particularly threatening microorganism in this context. Indeed P. aeruginosa is not only responsible for post-transplant pneumonia with high mortality, but chronic airway colonization with this pathogen also favors the development of BOS. Preventing bacterial colonization of the allograft might therefore have a significant impact on the survival of lung transplant patients. P. aeruginosa chronically infects 70-80% of all cystic fibrosis (CF) patients, as well as many patients with other underlying diseases. In these patients P. aeruginosa colonizes the lung graft rapidly after transplantation despite antimicrobial therapies. A better understanding of bacterial colonization of the allograft will be essential to design new preventive strategies.

The project proposes to investigate the dynamics of bacterial colonization of the lung allograft in cystic fibrosis patients followed in the University Hospitals of Geneva, Lausanne and Zurich. The first part of the project will establish a collection of bronchoalveolar lavages, tracheal aspirates and sinus swabs which are routinely collected from these patients before and after lung transplantation. P. aeruginosa strains isolated from these sequential samples will be compared genetically (are isolates identical or different before and after transplantation) and phenotypically (growth, production of virulence factors, biofilm formation, etc). This will show which characteristics of this organism are important for the adaptation to the novel non-CF-lung environment and for development of acute and chronic infections. In a second part we will investigate the molecular mechanisms involved in bacterial interspecies competition with host flora and co-colonizing pathogens like Burkholderia spp, Staphylococcus aureus and Escherichia coli. In a third part, we propose to investigate a DNA region of a P. aeruginosa strain, involved in the regulation of important virulence factors, which could represent a novel target for anti-infective treatments. Furthermore, we will assess in vitro the effect of biofilm disrupting agents in combination with pyocins as specific bactericidal agents against P. aeruginosa.

The clinical context of lung transplantation is a unique opportunity to study an essential event in bacterial pathogenesis, namely the colonization of a novel host environment (the lung of a healthy donor) by an endogenous microbial community (provided by the lung transplant-recipient). This issue is of interest not only to clinicians but also to evolutionary and ecological microbiologists. The information on intra- and interspecies competition mechanisms could be exploited to reduce or prevent colonization by pathogenic species in other clinical and environmental situations. Altogether the obtained results should allow us to better anticipate the risk of re-infection and to take the necessary steps for an optimal follow-up of the lung transplant recipients.