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Viral-Bacterial Interactions in Cystic Fibrosis Lung Disease

Hendricks, Matthew (2017) Viral-Bacterial Interactions in Cystic Fibrosis Lung Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that chronically infects approximately 80% of cystic fibrosis (CF) patients by early adulthood, accounting for the majority of morbidity and mortality in these patients. The development of chronic P. aeruginosa infections in the CF lung involves the formation of highly recalcitrant biofilm communities. Clinical observations have noted a correlation between respiratory virus infection and the acquisition of chronic P. aeruginosa infection by CF patients, but the mechanism underlying this interaction in the CF lung is not understood. In this dissertation, we hypothesized that respiratory viral co-infection promotes P. aeruginosa biofilm formation on airway epithelial cells (AECs).
We demonstrate that in the presence of respiratory syncytial virus (RSV) co-infection, P. aeruginosa biofilm growth is significantly increased. We observed that RSV infection increased the release of iron-bound transferrin, suggesting that RSV infection disrupts iron homeostasis in the airway epithelium. Iron is an essential nutrient for P. aeruginosa biofilm growth, and both iron chelation and depletion of transferrin from apical secretions collected from AECs blocked the biofilm stimulatory effect of RSV co-infection. We also demonstrate that RSV infection promotes the apical release of extracellular vesicles (EVs) from AECs, which increases the availability of iron-loaded transferrin in the apical secretions of AECs. Interestingly, purified EVs stimulate P. aeruginosa biofilm growth, suggesting that host-derived EVs interact with a bacterium to promote chronic bacterial infections. Finally, the innate immune response to virus infection, measured by type I and type III (IFN-beta and -lambda, respectively) interferon production, peaks at the same time as virus-induced biofilms growth, and treatment of AECs with either IFN replicates the enhanced biofilm growth observed during virus co-infection. Our data suggest a novel mechanism by which the host response to viral infection contributes to the development of chronic pulmonary P. aeruginosa infection and provide mechanistic insight into our understanding of nutritional immunity in the lung.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hendricks, Matthewmrh91@pitt.edumrh91
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBomberger, Jenniferjbomb@pitt.edu
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.edu
Committee MemberCoyne, Carolyncoynec2@pitt.edu
Committee MemberShanks, Robertshanksrm@upmc.edu
Committee MemberSarkar, Saumendrasaumen@pitt.edu
Date: 14 December 2017
Date Type: Publication
Defense Date: 1 December 2017
Approval Date: 14 December 2017
Submission Date: 13 December 2017
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 225
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Pseudomonas aeruginosa, biofilm, respiratory syncytial virus, transferrin, nutritional immunity, cystic fibrosis
Date Deposited: 14 Dec 2017 17:46
Last Modified: 14 Dec 2017 17:46
URI: http://d-scholarship.pitt.edu/id/eprint/33623

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