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Characterizing the immunogenic properties of bacterial extracellular vesicles (EVs) of the Cystic Fibrosis airway


RCSI StAR International PhD Programme Research Projects

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Dr J Coppinger Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

About the Project

Recurrent Pseudomonas (P) aeruginosa infection is common in chronic pulmonary diseases including cystic fibrosis (CF), chronic obstructive lung disease (COPD) and a leading cause of hospital acquired pneumonia. Due to the emergence of multiple-drug resistant isolates, it is become increasingly difficult to cure P. aeruginosa related lung infections. In individuals with CF, lung disease is characterized by persistent P. aeruginosa bacterial infection and neutrophil dominated inflammation that leads to progressive airway destruction and respiratory failure. In addition to established mechanisms of bacterial induced inflammatory cell activation via pattern recognition receptors we hypothesize that bacteria colonizing CF airways may shed EVs composed of immune stimulatory components that could play a role in CF pathogenesis. Outer membrane vesicles isolated from P. aeruginosa have been shown to elicit a chemokine response (IL-8) from CF lung cells. Active immunization with bacterial outer membrane vesicles have been shown to stimulate protective immunity against infections in murine models. We propose to characterize bacterial extracellular vesicle (EVs) from the airways of persons with CF and examine if P.aeruginosa EVs modulate innate and adaptive immune responses in vitro and can protect mice against pseudomonas lung infection. EVs may have the potential to protect the immunized host against subsequent infection.

This PhD project proposes valuable research on EVs from P. aeruginosa from CF airways and investigating novel vaccination strategies to diminish pseudomonas infection in individuals with CF. The project objectives include; (1) Characterising P. aeruginosa EVs isolated from the sputum of individuals with CF at different stages of disease progression (2) Determine if P. aeruginosa EVs cultured from sputum modulate innate and adaptive immune responses in vitro and (3) Examine if mice injected with P. aeruginosa EVs can confer protection against infection in murine models. This project builds on research we currently perform at the National Children’s Research Centre on extracellular vesicles as mediators of inflammatory signalling in children with CF. The project will be performed at the National Children’s Research Centre (adjacent to CHI-Crumlin Children’s Hospital) with sections of the project including mouse work to take place at the RCSI and University College Dublin.

References

1. Innate immunity in cystic fibrosis lung disease. Hartl D, Gaggar A, Bruscia E, Hector A, Marcos V, Jung A, Greene C, McElvaney
G, Mall M, Döring G. J Cyst Fibros. 2012: 11(5):363-82. Review
2. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. Greene CM, Carroll TP, Smith SG,
Taggart CC, Devaney J, Griffin S, O'Neill SJ, McElvaney NG. Journal of Immunol. 2005:174(3):1638–1646.
3. Immune modulation by bacterial outer membrane vesicles. Kaparakis-Liaskos M, Ferrero RL. Nat Rev Immunol. 2015: (6):375-
87. Review.
4. Immunization with Pseudomonas aeruginosa outer membrane vesicles stimulates protective immunity in mice. Zhang X, Yang
F, Zou J, Wu W, Jing H, Gou Q, Li H, Gu J, Zou Q, Zhang. J. Vaccine. 2018:14;36(8):1047-1054.


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