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Pseudomonas aeruginosa in lung transplant patients: adaptation, bacterial competition and novel therapeutic approaches

English title Pseudomonas aeruginosa in lung transplant patients: adaptation, bacterial competition and novel therapeutic approache
Applicant Van Delden Christian
Number 140929
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 01.06.2012 - 31.05.2015
Approved amount 402'000.00
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Keywords (10)

competition; translational; Pseudomonas; colonization; adaptation; treatment; transplantation; cystic fibrosis; Swiss Transplant Cohort Study; large nested project (STCS)

Lay Summary (English)

Lead
Lay summary

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.

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Airway Epithelial Cell Integrity Protects from Cytotoxicity of Pseudomonas aeruginosa Quorum-Sensing Signals.
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.
Metabolic pathways of Pseudomonas aeruginosa involved in competition with respiratory bacterial pathogens.
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.
Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner.
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.
QsrO a novel regulator of Quorum Sensing and Virulence in Pseudomonas aeruginosa
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.

Collaboration

Group / person Country
Types of collaboration
John-David Aubert, Service of Pulmonary Diseases, CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Angus Buckling, University of Exceter, UK Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ECCMID 2015 Talk given at a conference Evolution of the Microbiome and Adaptation of Pseudomonas aeruginosa after Lung-Transplantation in Cystic Fibrosis Patients 24.04.2015 Copenhague, Denmark Köhler Thilo;
Genome 2014 EMBO Conference Talk given at a conference Evolution of the Microbiome and Adaptation of Pseudomonas aeruginosa after Lung-Transplantation in Cystic Fibrosis Patients 26.02.2015 Paris, France Beaume Marie;
9th European CF Young Investigator Meeting Talk given at a conference Evolution of the Microbiome and Adaptation of Pseudomonas aeruginosa after Lung-Transplantation in Cystic Fibrosis Patients 18.02.2015 Paris, France Beaume Marie;
ICAAC 2014 Talk given at a conference Evolution of the Microbiome and Adaptation of Pseudomonas aeruginosa after Lung-Transplantation in Cystic Fibrosis Patients 05.09.2014 Washington, United States of America Van Delden Christian; Köhler Thilo;
Swiss Transplant Cohort Study Retreat 2014 Talk given at a conference Evolution of the microbiome and adaptation of Pseudomonas aeruginosa to the allograft after lung-transplantation in cystic fibrosis patients 22.05.2014 Bern, Switzerland Beaume Marie; Van Delden Christian;
Pseudomonas 2013 Poster Interspecies competition between bacterial respiratory pathogens 07.09.2013 Lausanne, Switzerland Beaume Marie; Van Delden Christian; Köhler Thilo; Tognon Mikael;
Pseudomonas 2013 Talk given at a conference Pseudomonas aeruginosa pneumonia: from pathogenesis to prevention 07.09.2013 Lausanne, Switzerland Köhler Thilo; Tognon Mikael; Van Delden Christian; Beaume Marie;
Pseudomonas 2013 Poster Evolution of the microbiome and adaptation of Pseudomonas aeruginosa to the allograft after lung transplantation in CF-patients 07.09.2013 Lausanne, Switzerland Beaume Marie; Köhler Thilo; Van Delden Christian; Tognon Mikael;


Awards

Title Year
Poster award, Nature Reviews Microbiology prize: M. Beaume, T. Köhler, O. Manuel, J.D. Aubert, P. Gasche, C. van Delden and the Swiss Transplant Cohort Study, Evolution of the microbiome and adaptation of Pseudomonas aeruginosa to the allograft after lung-transplantation in cystic fibrosis patients. EMBO conference Genome 2014. 24-27 June 2014. Paris, France. 2014

Associated projects

Number Title Start Funding scheme
134267 Schweizerische Transplantationskohorte 01.02.2011 Cohort Studies Large
120011 Adaptation and persistence of Pseudomonas aeruginosa during colonization and infection of ventilated patients 01.05.2008 Project funding (Div. I-III)
159523 Pseudomonas aeruginosa in lung transplant recipients: adaptation and competition in the new host environment 01.06.2015 Project funding (special)
148512 Swiss Transplant Cohort Study 01.02.2014 Cohort Studies Large
148512 Swiss Transplant Cohort Study 01.02.2014 Cohort Studies Large

Abstract

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.
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