Understanding Mycobacterium abscessus in cystic fibrosis mice
Date
2019
Authors
Vongtongsalee, Kridakorn, author
Ordway, Diane, advisor
Schenkel, Alan, committee member
Chatterjee, Delphi, committee member
Kirby, Michael, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Cystic fibrosis (CF) is caused by mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which normally encodes an ABC transporter-class ion channel protein that allows chloride and thiocyanate ions transport across epithelial cell membranes. Thus, CFTR plays an important role in airway homeostasis. Mutations of CFTR in patients with CF leads to a defect in transport of chloride and thiocyanate ions by epithelial cells, resulting in a multi-system disorder that affects the respiratory tract, gastrointestinal tract, the endocrine system, among others. The epithelial cell dysfunction in the lungs of CF patients also leads to an impaired pulmonary defense mechanism, resulting in decreased bacterial clearance and chronic inflammation. In CF patients, lung disease due to non-tuberculous mycobacteria (NTM) — an environmental organisms found in soil, water, and biofilms — is one of the most feared complications. Among the NTM, the rapidly-growing Mycobacterium abscessus is particularly notorious given its intrinsic resistance to many antibiotics. The transmission of M. abscessus to humans occurs by wound contamination, airborne transmission, or ingestion. Despite the fact that M. abscessus infection is increasing worldwide, little is known about how M. abscessus causes disease. To improve our understanding of M. abscessus in CF patients, we set out to investigate the progression of M. abscessus infection in a CF mouse model by developing a reinfection mouse model using three different strains of "CF mouse" — Beta-ENaC mice, Cftrtm1UNCTgN(FABPCFTR) mice and CFTRtm1UNC/ CFTRtm1UNC mice — to track the bacterial burden and organ pathology. Our results support the hypothesis that repeated infection with M. abscessus is more likely to result in disease progression and increased pathogenesis of the disease in CF mouse models. The high bacterial burden persisted in the lung after four infections in β-ENaC transgenic mice and CFTRtm1UNC/CFTRtm1UNC mice and maintained in the organs by day 30. Cftrtm1UNCTgN(FABPCFTR) mice tended to show slowly increasing bacterial burden in all organs. In summary, we demonstrate that reinfection of the CF mouse models with M. abscessus is more likely to result in a sustained infection in the lungs associated with increased pulmonary pathology.