33CS30_148512; Swiss Transplant Cohort Study; large nested project; Swiss Transplant Cohort Study; competition; transplantation; resistance; microbiome; large nested project; pathogenesis; adaptation; flora; Pseudomonas; 33CS30_148512; cystic fibrosis
Tognon Mikael, Köhler Thilo, Gdaniec Bartosz G, Hao Youai, Lam Joseph S, Beaume Marie, Luscher Alexandre, Buckling Angus, van Delden Christian (2017), Co-evolution with Staphylococcus aureus leads to lipopolysaccharide alterations in Pseudomonas aeruginosa, in The ISME Journal
, 11(10), 2233-2243.
Beaume M, Köhler T, Greub G, Manuel O, Aubert J-D, Baerlocher L, Farinelli L, Buckling A, van Delden C, van Delden C (2017), Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation., in Scientific reports
, 7, 40309-40309.
Beaume Marie, Lazarevic Vladimir, Köhler Thilo, Gaïa Nadia, Manuel Oriol, Aubert John-David, Baerlocher Loïc, Farinelli Laurent, Gasche Paola, Schrenzel Jacques, van Delden Christian, van Delden Christian (2016), Microbial Communities of Conducting and Respiratory Zones of Lung-Transplanted Patients., in Frontiers in microbiology
, 7, 1749-1749.
Lung transplantation (LT) is a widely accepted treatment for end-stage pulmonary disease. Unfortunately the outcome after LT is worse than after other transplants with a 5-year survival of 52% . This is mostly due both to allograft infections and a progressive loss of graft function secondary to chronic rejection also called bronchiolitis obliterans syndrome (BOS). Preventing both infections and BOS are therefore major challenges to increase survival after LT. P. aeruginosa is not only responsible for 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, multi-drug resistant P. aeruginosa chronically infects almost all end-stage cystic fibrosis (CF) patients, as well as patients with other underlying diseases. In these patients, P. aeruginosa resident in the sinuses rapidly colonizes the allograft after LT despite antimicrobial therapies. A better understanding of bacterial colonization of the allograft will be essential to design new preventive strategies. This grant proposal builds up on the achievements of our current SNF grant, namely: i) establishment of a collection of 338 respiratory samples (BAL, TA) and P. aeruginosa isolates from 39 LT-recipients, ii) demonstration of rapid colonization of CF-recipients (within 24 hours after LT) by P. aeruginosa, iii) association between presence of P. aeruginosa and a decrease of the microbial richness and diversity, iv) identification of biofilm formation capacity as a potential adaptive phenotype to the allograft, and v) design and validation of an in vitro co-evolution model between P. aeruginosa and S. aureus. We suggest pursuing the analyses of additional airway samples to obtain a significant number of patients, and to include P. aeruginosa isolates collected pre and post-sinus surgery. We will focus on biofilm formation as an adaptive mechanism and on the role of the type VI secretion system during allograft colonization (part A). We will investigate the function of the genes identified in the co-evolution experiment against S. aureus, and perform novel co-evolution experiments with other bacterial species. Based on our in patient microbiome data, we further suggest to design an artificial microbiome to test in vitro the possibility to prevent P. aeruginosa development (part B). Following up on previous collaborations, we plan to set-up an ex-vivo evolution experiment between pre and post-LT isolates of P. aeruginosa on primary human airway epithelial cells. This model should mimic the allograft environment, represented by the non-CF airway epithelial cell model and inform on mechanisms of adaptation to this novel condition. We will further evaluate the impact of antibiotic and immune-suppressive treatments, administered to all LT-patients, on the adaptation of P. aeruginosa in this model system (part C). Our project thus combines three complementary approaches to investigate the adaptation of P. aeruginosa to a novel host environment. The in vitro and ex-vivo evolution experiments should provide mechanistic insights, and the ability to test hypothesis emanating from the in patient adaptation and the microbiome data. Altogether the obtained results should allow us to better anticipate the risk of allograft infection, and identify new strategies to prevent colonization by multi-drug resistant pathogens also applicable to other clinical situations.