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Initiation of innate immunity to Pse...

Reiniger, Nina.

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Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR./
Author:	Reiniger, Nina.
Description:	111 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0690.
Contained By:	Dissertation Abstracts International67-02B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205945
ISBN:	9780542549489

Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR.
Reiniger, Nina.

Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR. - 111 p.

Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0690.

Thesis (Ph.D.)--Harvard University, 2006.

Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting 1 in 3500 children born in the United States each year. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Chronic lung infection by Pseudomonas aeruginosa causes significant morbidity in cystic fibrosis patients due to failure of innate immune responses to this pathogen. CFTR is a cellular receptor for P. aeruginosa allowing bacterial internalization by respiratory epithelial cells and initiation of the host immune response, promoting bacterial clearance in individuals with wild type CFTR. Understanding the interaction between P. aeruginosa and the wild type (WT) respiratory epithelial cells they infect is critical to our understanding of what constitutes an effective immune response and how it is initiated. In this dissertation, I have studied the cellular consequences of the interaction of P. aeruginosa and respiratory epithelial cells, identifying several important components that work together to successfully resolve P. aeruginosa infection in the lung. I begin by presenting in vivo and in situ evidence that P. aeruginosa is internalized by cells containing WT CFTR by comparing WT and CF mice infected by P. aeruginosa. Subsequently, I used microarray analysis and real time PCR to detect transcriptional changes associated with the innate immune response in isogenic bronchial epithelial cell lines with either WT or mutant CFTR in response to P. aeruginosa infection. Four NF-kappaB regulated genes were identified whose transcription was maximal in the presence of WT CFTR: IL-8, IL-6, CXCL1 and ICAM-1. Protein level measurements confirmed that IL-8, IL-6 and CXCL1 expression is enhanced by WT CFTR. To conclude these studies, I identified IL-1beta and IL-1R as key components regulating NF-kappaB in response to P. aeruginosa infection. In cultured bronchial epithelial cells, we show that IL-1beta release is enhanced in the presence of WT CFTR. Using IL-1R knock out mice we demonstrate that IL-1R is critical to successful clearance of P. aeruginosa from the lung. This dissertation furthers our understanding of the interaction of P. aeruginosa with respiratory epithelial cells, the ensuing immune response and the misregulation of this response in CF.

ISBN: 9780542549489Subjects--Topical Terms:

1017734
Biology, Microbiology.

Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR.
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245 1 0 $a Initiation of innate immunity to Pseudomonas aeruginosa lung infection: Impact of wild type and mutant CFTR.
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500 $a Adviser: Gerald Pier.
502 $a Thesis (Ph.D.)--Harvard University, 2006.
520 $a Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting 1 in 3500 children born in the United States each year. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Chronic lung infection by Pseudomonas aeruginosa causes significant morbidity in cystic fibrosis patients due to failure of innate immune responses to this pathogen. CFTR is a cellular receptor for P. aeruginosa allowing bacterial internalization by respiratory epithelial cells and initiation of the host immune response, promoting bacterial clearance in individuals with wild type CFTR. Understanding the interaction between P. aeruginosa and the wild type (WT) respiratory epithelial cells they infect is critical to our understanding of what constitutes an effective immune response and how it is initiated. In this dissertation, I have studied the cellular consequences of the interaction of P. aeruginosa and respiratory epithelial cells, identifying several important components that work together to successfully resolve P. aeruginosa infection in the lung. I begin by presenting in vivo and in situ evidence that P. aeruginosa is internalized by cells containing WT CFTR by comparing WT and CF mice infected by P. aeruginosa. Subsequently, I used microarray analysis and real time PCR to detect transcriptional changes associated with the innate immune response in isogenic bronchial epithelial cell lines with either WT or mutant CFTR in response to P. aeruginosa infection. Four NF-kappaB regulated genes were identified whose transcription was maximal in the presence of WT CFTR: IL-8, IL-6, CXCL1 and ICAM-1. Protein level measurements confirmed that IL-8, IL-6 and CXCL1 expression is enhanced by WT CFTR. To conclude these studies, I identified IL-1beta and IL-1R as key components regulating NF-kappaB in response to P. aeruginosa infection. In cultured bronchial epithelial cells, we show that IL-1beta release is enhanced in the presence of WT CFTR. Using IL-1R knock out mice we demonstrate that IL-1R is critical to successful clearance of P. aeruginosa from the lung. This dissertation furthers our understanding of the interaction of P. aeruginosa with respiratory epithelial cells, the ensuing immune response and the misregulation of this response in CF.
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