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Pseudomonas aeruginosa in lung transplant recipients: adaptation and competition in the new host environment

English title Pseudomonas aeruginosa in lung transplant recipients: adaptation and competition in the new host environment
Applicant Van Delden Christian
Number 159523
Funding scheme Project funding (special)
Research institution Service des Maladies Infectieuses Département de Médecine Interne Hôpital Cantonal - HUG
Institution of higher education University of Geneva - GE
Main discipline Medical Microbiology
Start/End 01.06.2015 - 31.05.2018
Approved amount 426'150.00
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Keywords (15)

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

Lay Summary (French)

Lead
Les infections post transplantation pulmonaire, en particulier par Pseudomonas aeruginosa, sont fréquentes et mettent en danger la survie du greffon. Ces bactéries proviennent souvent des sinus du recevoir et sont en compétition dans le greffon avec le microbiome du donneur. Une meilleure compréhension de la compétition entre microorganismes, et de l’adaptation au microenvironnement du greffon, sont nécessaires pour développer de nouvelles stratégies prévenant cette réinfection et améliorer la survie des patients transplanté pulmonaire.
Lay summary

?La transplantation pulmonaire est acceptée comme traitement de dernier recours de l’insuffisance respiratoire terminale. Malheureusement les résultats de survie après transplantation pulmonaire sont moins bons en comparaison avec d’autres organes solides. Ceci est essentiellement dû à des infections du poumon transplanté. Prévenir les infections pulmonaires post-transplantation est par conséquent une priorité. Plus de 90% des patients souffrant de mucoviscidose sont chroniquement infectés par Pseudomonas aeruginosa. Malheureusement cette bactérie réinfecte le poumon transplanté à partir des sinus. Cette réinfection survient malgré une adaptation de longue date des souches de Pseudomonas à un microenvironnement « mucoïde » et une compétition entre ce pathogène et la flore microbienne résidant du poumon du donneur. Une meilleure compréhension des mécanismes expliquant cette réinfection est essentielle pour définir de nouvelles thérapies préventives.Dans un projet de recherche soutenu auparavant par le FNS, nous avons pu collectionner plus de 338 échantillons respiratoires profonds de patients transplantés pulmonaire. Nous avons démontré que la réinfection survient dans les premiers jours post-transplantation. Le projet actuel prévoit de déterminer le rôle de la formation de biofilm et du système de sécrétion de type VI dans la réinfection par Pseudomonas aeruginosa (partie A), d’analyser la fonction de gènes identifiés auparavant et impliqués dans la compétition avec le Staphylococcus aureus et de former un microbiome artificiel pour de nouvelles expériences de compétition in vitro (partie B), de développer un nouveau modèle ex-vivo de co-cultures directement sur des cultures de cellules épithéliales respiratoires en présence d’antibiotiques et de thérapies immunosuppressive (partie C). Les résultats de nos expériences devraient permettre d’identifier de nouvelles stratégies interférant avec la réinfection post-transplantation du greffon, en améliorant ainsi la survie du greffon.

Direct link to Lay Summary Last update: 01.06.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Co-evolution with Staphylococcus aureus leads to lipopolysaccharide alterations in Pseudomonas aeruginosa
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.
Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation.
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.
Microbial Communities of Conducting and Respiratory Zones of Lung-Transplanted Patients.
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.

Collaboration

Group / person Country
Types of collaboration
SIB Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Awards

Title Year
Best Md-PhD thesis of the University of Geneva 2016

Associated projects

Number Title Start Funding scheme
148512 Swiss Transplant Cohort Study 01.02.2014 Cohort Studies Large
140929 Pseudomonas aeruginosa in lung transplant patients: adaptation, bacterial competition and novel therapeutic approaches 01.06.2012 Project funding (special)
179289 Pseudomonas aeruginosa in lung-transplant recipients: exploiting adaptation and microbial interactions to fight bacterial infections 01.06.2018 Project funding (special)
177522 Swiss Transplant Cohort Study 01.02.2018 Cohort Studies Large

Abstract

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% [1]. 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.
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