Investigating The Role Of The Static And Hyperviscous Mucus Defect On The Development Of Bacterial Infection In The Cystic Fibrosis Rat

Authors

• Mikayla Murphree-Terry, University of Alabama at Birmingham

Advisor(s)

Susan Birket

Committee Member(s)

Craig Maynard
Janet Yother
Jessica Scoffield
Merry-Lynn McDonald
William Swords

School

Joint Health Sciences (Interdisciplinary)

Document Type

Dissertation

Department (new version)

Joint Health Sciences

Date of Award

9-9-2024

Abstract

INVESTIGATING THE ROLE OF THE STATIC AND HYPERVISCOUS MUCUS DEFECT ON THE DEVELOPMENT OF BACTERIAL INFECTION IN THE CYSTIC FIBROSIS RAT MIKAYLA MURPHREE-TERRY GRADUATE BIOMEDICAL SCIENCES - MICROBIOLOGY ABSTRACT Cystic fibrosis (CF) is a genetic disease caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional CFTR. In the lungs, CFTR dysfunction results in dehydrated mucus that is adherent to epithelia. In the gut, thick mucus can mix with feces to form an obstruction, known as distal intestinal obstruction syndrome (DIOS). Additionally, CF mucus has a higher percentage of solids. The main solid component of mucus is mucin. In airway mucus, the major gel-forming mucins are MUC5B and MUC5AC, which are hypersecreted in CF, leading to overaccumulation, mucus hyperconcentration, and infection. Chronic infection with Pseudomonas aeruginosa is a significant driver of morbidity and mortality in people with CF (pwCF). Despite advancements in therapeutics, such as the drug ivacaftor, P. aeruginosa persists in this population. Though much has been learned about the role of the mucus environment in the development of bacterial infection in CF, many questions still linger. To address these questions, we utilized the CF rat model. In the first part, we explored the contribution of Muc5b hypersecretion to the development of persistent P. aeruginosa infection in the CF rat. We found that normalization of airway Muc5b accumulation to that of wildtype (WT) rats decreased clinical morbidity, neutrophilic inflammation, and mucus plugging following persistent P. aeruginosa infection. This is significant because mucus is a genotype-agnostic target that can be applicable to pwCF who are not covered by current therapies. In the second part, we investigated the synergy between Muc5b normalization and CFTR restoration toward eradicating persistent P. aeruginosa infection in the CF rat. We found that the combination of these strategies led to worse outcomes, including increased clinical morbidity, mucus plugging, and tissue inflammation. Finally, we characterized the lung microbiome of the CF rat and found an increased relative abundance of traditional CF pathogens as compared to WT rats prior to DIOS. After DIOS, the lung microbiome of the CF rat is predominated by members seen in the feces, indicating a role for the gut-lung axis in these rats and providing a novel avenue for studying the link between pulmonary infection and DIOS.

ProQuest ID

https://proquest.com/docview/3101861056