Utilising the Underlying Genetic Mechanisms of Survival Exhibited by Pseudomonas aeruginosa during Chronic Lung Infection for Novel Drug Target Discov

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

Pseudomonas aeruginosa is a Gram-negative, opportunistic plant and animal pathogen and one of the leading causes of nosocomial infections. As an opportunistic pathogen, P. aeruginosa mainly causes infections in immuno-compromised individuals and its success as a human pathogen can be attributed to its intrinsic resistance to many antibiotics, its adaptability to changes in its environment and its ability to form biofilms.
Understanding the underlying genetic mechanisms essential for bacterial survival in the host is key to identifying novel therapeutic targets. Transposon mutagenesis has been shown to be a valuable genetic tool for linking phenotype to genotype by creating mutant libraries with mutations in all non-essential genes. These mutant libraries can then be used to screen for genes essential for growth and survival under a variety of conditions.
We aim to construct a transposon mutant library from a chronic infection clinical isolate of Pseudomonas aeruginosa which will subsequently be used to screen for genes essential for survival in the lung during chronic infection. These screens have the potential to identify novel drug targets and/or determine the functions for genes of unknown function.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1644274 Studentship BB/M01116X/1 05/10/2015 30/09/2019 Emma Sheehan
 
Description 1. Generated an essential gene list through construction and sequencing of a Pseudomonas aeruginosa transposon mutant library in a clinical lung isolate obtained from a non-cystic fibrosis bronchiectasis patient.

2. Elucidate the mechanism of serum mediated killing of Pseudomonas aeruginosa in healthy individuals - active complement alone is able to kill some strains of P. aeruginosa, however P. aeruginosa specific antibodies can enhance this killing. Healthy individuals can also produce 'inhibitory antibodies' which block the killing of P. aeruginosa

3. How the removal of inhibitory antibodies from non-CF patients with chronic Pseudomonas in by plasmapheresis impacts the P. aeruginosa population of the lungs. Initial characterisation of strains isolated both prior to and post-treatment indicate that the treatment does not promote strain replacement in patients. Variation between isolates is typical of within host evolution.
Exploitation Route The use of plasmapheresis to treat patients with chronic P. aeruginosa infection has only been used as a last resort rescue therapy and is not available as a standard treatment option so understanding the effect that this treatment has on the P. aeruginosa population in the lung will help to determine the efficacy of the treatment.

Identifying that healthy individuals can produce 'inhibitory antibody' even without an active P. aeruginosa infection provided an insight into how these antibodies may arise. No active infection indicates that environmental exposure to antigens could be enough to induce the production of inhibitory antibodies in some individuals. This should be taken into account during antigen selection for the development of vaccines as these may inadvertently induce the production of inhibitory antibodies.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description ThinkTank Birmingham public engagement activity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Aims:
>Encourage an interest into microbiology research/further education in science subjects in school children by creating a fun and relatable activity involving my research for Birmingham ThinkTank Meet The Expert event
>Raise awareness of antibiotic resistance and the importance of using antibiotics correctly by determining participants current understanding through discussion and providing leaflets with take home messages

>Approximately 70 participants ranging from school children to general public
>Sparked an interest in science for younger school children
>Gained an insight into the general publics current thoughts and opinions about antibiotic resistance and genetic modification through discussions after the activities.
Year(s) Of Engagement Activity 2018