competition; translational; Pseudomonas; colonization; adaptation; treatment; transplantation; cystic fibrosis; Swiss Transplant Cohort Study; large nested project (STCS)
Losa Davide, Köhler Thilo, Bacchetta Marc, Saab Joanna Bou, Frieden Maud, van Delden Christian, Chanson Marc (2015), Airway Epithelial Cell Integrity Protects from Cytotoxicity of Pseudomonas aeruginosa Quorum-Sensing Signals., in American journal of respiratory cell and molecular biology
, 53(2), 265-75.
Beaume Marie, Köhler Thilo, Fontana Thierry, Tognon Mikael, Renzoni Adriana, vanDelden Christ (2015), Metabolic pathways of Pseudomonas aeruginosa involved in competition with respiratory bacterial pathogens., in Frontiers in Microbiology
, 6(Article 32), 1-12.
Losa Davide, Köhler Thilo, Bellec Jessica, Dudez Tecla, Crespin Sophie, Bacchetta Marc, Boulanger Pierre, Hong Saw See, Morel Sandrine, Nguyen Tuan H, van Delden Christian, Chanson Marc (2014), Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner., in Journal of immunology (Baltimore, Md. : 1950)
, 192(10), 4804-12.
Köhler Thilo, Ouertani-Sakouhi Hajer, CossonPierre, vanDelden Christian (2014), QsrO a novel regulator of Quorum Sensing and Virulence in Pseudomonas aeruginosa, in PLoS ONe
, 9 (2)(e87814), 1-11.
Lung transplantation (LT) is a widely accepted treatment for end-stage pulmonary disease. Unfortunately the early and late outcome after LT is worse than after other transplants with a 5-year survival of 52% (1). These disappointing results are mostly due both to lethal early allograft infections and a high incidence of progressive loss of graft function secondary to chronic rejection also called obliterans bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS). Preventing both infections and OB/BOS are therefore major challenges to increase survival after LT. Pseudomonas aeruginosa is a particularly threatening microorganism in this setting. Indeed P. aeruginosa is not only responsible for post-transplant pneumonia with high mortality, but chronic airway colonization with this pathogen has also been identified as one of the risk factors for the development of BOS. Preventing bacterial colonization of the allograft might therefore have a significant impact on post-LT survival. Before LT, P. aeruginosa chronically infects almost all end-stage cystic fibrosis (CF) patients in a biofilm mode of growth, as well as many patients with other underlying diseases. In these patients P. aeruginosa colonizes the allograft rapidly after LT 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 CF-recipients followed in the University Hospitals of Geneva, Lausanne and Zurich. In the first part of the project (A) we will collect prospectively bronchoalveolar lavages (BAL), tracheal aspirates (TA) and sinus swabs from CF -patients before and after LT. In those patients colonized pre-LT by P. aeruginosa we will determine the genotypes of sequential isolates and analyze the phenotypic adaptation to the novel non-CF-lung environment and to co-colonizing bacterial species in the allograft. In a second part (B) 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 (C), we propose to investigate a DNA region of strain PAO1, involved in the regulation of essential virulence factors (Quorum sensing and type III secretion system), 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. This clinical context of LT 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 LT-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.