Multi-drug resistant Pseudomonas aeruginosa has become an increasing threat. A threat compounded by the fact that the pipeline of antimicrobial discovery continues to lose effectiveness. It is urgent that we identify new strategies to eliminate this and other multi-drug resistant pathogens. Meanwhile, we know that the resident bacteria of the respiratory tract interact with host cells to eliminate incoming threats. The goal of this project is to understand the interactions at play in the microbiota of the respiratory tract and identify the specific commensal bacteria that inhibit P. aeruginosa in the presence of host cells. Using a nasopharyngeal cell culture screen, we were able to identify several human commensals capable of inhibiting the growth of antibiotic-resistant P. aeruginosa in a host-dependent manner. It was also established that this phenotype can be reproduced in more complex systems, including a murine lung slice model, and that the elimination of the pathogen is dependent on the presence of living bacteria, mediated by a secreted factor. We believe that the presence of these commensals has an immunomodulatory effect on the host. By characterizing the cytokines and chemokines produced by the host cells in response to the presence of these commensals, we have shown that these bacteria modify the immune response of the host to the pathogen. Finally, having failed to develop a mouse model of infection, we have determined that the observed phenotype is not a direct action of the host cells, nor the result of hydrogen peroxide secretion. We have further characterized the bacterial strains using genome assembly. This study has confirmed that commensal bacteria create a unique immune environment that contributes to the clearance of pathogens. Identifying bacteria and bacterial products capable of stimulating host defenses and modulating inflammation could provide a new therapeutic approach to reducing infection susceptibility in high-risk patients. / Thesis / Master of Science (MSc) / Antibiotics have for decades facilitated the cure of infections caused by pathogens of all kinds. Unfortunately, repeated exposure to antibiotics has rendered some pathogens highly resistant to traditional treatment. One notorious multi-drug resistant pathogen is Pseudomonas aeruginosa, now responsible for 10-15% of hospital-acquired respiratory infections. In this project we investigate the potential that lies in using commensal bacteria that exist in the microbiota of our respiratory tract to fight against pathogens that no longer respond to antibiotics. Stringent experiments with various models have revealed bacteria capable of killing Pseudomonas aeruginosa and helped us understand the mechanism of inhibition as well as the interactions of the bacteria with the immune system. Our results show that some bacteria of the microbiota are effective against Pseudomonas aeruginosa and that this line of study holds promise for the development of a new arsenal against a growing number of threatening pathogens.

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Revised; Originally Published 2006 / 2 pp.

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