Haas, Allison L.
(2023)
The Pseudomonas aeruginosa type VI secretion system shapes microbial interactions in the cystic fibrosis respiratory microbiome.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Chronic respiratory infections with Pseudomonas aeruginosa are a significant cause of morbidity and mortality in people with cystic fibrosis. As CF patients age, P. aeruginosa becomes the most prevalent pathogen causing chronic infection and is associated with declining lung function. In the CF respiratory tract, P. aeruginosa encounters many other microorganisms which modulate its virulence and impact patient morbidity. As such, P. aeruginosa employs a number of competitive strategies to limit the growth of other pathogens and favor its own dominance. One important defensive mechanism is the type VI secretion system (T6SS), a needle-like apparatus that functions to directly puncture neighboring cells to deliver toxic effector molecules. Such effectors function to kill competing bacteria and to evade the host immune response. P. aeruginosa possesses a large repertoire of toxic effector molecules which are exported by three unique T6SS apparatus.
Through the studies presented here, we find that P. aeruginosa displays a high degree of specificity in effector secretion, tailoring its effector cargo to environmental conditions. This underscores the importance of the nutritional environment to inter-species interactions. This is particularly true with iron availability, as we see TseT-mediated competition with Gram-negative organisms in high-iron environments, and TseF-mediated competition with Gram-positive organisms in low-iron environments. These findings also highlight the versatility of the P. aeruginosa T6SS repertoire. Namely, its utility in inter-bacterial competition, biofilm formation, and nutrient acquisition, all of which help P. aeruginosa persist in the CF respiratory tract and dominate over other pathogens to cause chronic infections.
An urgent need for novel therapeutics exists to treat chronic P. aeruginosa infection due to its high level of intrinsic and acquired antibiotic resistance. Our findings suggest that therapeutically modulating environmental conditions in the respiratory tract could be an effective alternative, or work in conjunction with antibiotics, to limit P. aeruginosa dominance and preserve microbial diversity in the respiratory tract by preventing T6SS-mediated competition.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
29 September 2023 |
| Date Type: |
Publication |
| Defense Date: |
24 March 2023 |
| Approval Date: |
29 September 2023 |
| Submission Date: |
28 March 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
188 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pseudomonas aeruginosa, type VI secretion, cystic fibrosis, respiratory microbiome, competition, biofilm, iron, pulmonary exacerbation, viral infection, nutritional immunity |
| Date Deposited: |
29 Sep 2023 14:24 |
| Last Modified: |
29 Sep 2023 14:24 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44346 |
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