Inflammasome signaling during infections results in cell death and processing and secretion of cytokines from the IL-1 family, which facilitates control over an infection. Pseudomonas aeruginosa and Salmonella Typhimurium are opportunistic bacterial pathogens which may induce acute infections and activate various innate immune signaling pathways, including inflammasomes. However, under favourable conditions these pathogens may evade immune clearance resulting in the establishment of a chronic infection. In this study, I evaluated the modulation of host inflammasome signaling induced by P. aeruginosa and S. Typhimurium during chronic infections. I used a collection of P. aeruginosa clinical isolates obtained from the sputum of cystic fibrosis patients collected during stable and exacerbation periods of disease. I demonstrated that the majority of isolates displayed poor inflammasome signaling and only a small proportion of isolates retained their ability to induce inflammasome activation, which may be associated with pulmonary exacerbations in cystic fibrosis. Sequencing and bioinformatics revealed genetic variations within the type III and type VI secretion systems of P. aeruginosa. While an inactivation of the type III secretion system is expected to impair inflammasome signaling, my results indicate that the type VI secretion system inhibits inflammasome signaling in eukaryotic cells. Due to the lack of chronic animal models for P. aeruginosa, I utilized a murine model of chronic S. Typhimurium infection to assess the modulation of inflammasome signaling throughout the course of a chronic infection. I observed that S. Typhimurium isolated during the acute phase of infection displayed an increased potential to activate inflammasome signaling and this ability progressively declined during the chronic phase of infection. This reduction in inflammasome activation was associated with reduced expression of bacterial virulence factors, such as flagella and the type III secretion system, and was dependent on the NLRP3 inflammasome. Overall, these results reveal that the expression of virulence factors is modulated during chronic bacterial infections, which results in a reduction of inflammasome activation leading to co-survival of the pathogen and host.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/43912 |
| Date | 15 August 2022 |
| Creators | Cai, David |
| Contributors | Sad, Subash |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Attribution-NonCommercial-ShareAlike 4.0 International, http://creativecommons.org/licenses/by-nc-sa/4.0/ |
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