Establishing a cystic fibrosis ferret model of chronic Mycobacterium abscessus lung infection

About This Grant

Project summary description Cystic fibrosis (CF) lung disease is characterized by polymicrobial infections. Lung infections caused by non- tuberculous mycobacteria (NTM) including Mycobacteroides abscessus (M. abs.) have increased over the last two decades and represent the third most prevalent group of bacterial pathogens in people with CF (PwCF). M. abs. infection has been associated with accelerated lung function decline in CF and excludes PwCF from being eligible for lung transplantation. M. abs. has high intrinsic resistance to many antibiotics that further increases its clinical relevance. Smooth and rough M. abs. variants (morphotypes) have been distinguished. Transition from the early, smooth to the later rough M. abs. morphotype has been associated with more severe lung infection and worse prognosis in PwCF. While mouse models advanced our understanding of several aspects of CF lung disease, their main disadvantage is their differences in respiratory physiology with humans, and their inability to establish chronic pulmonary infections with M. abs. There is an urgent need to develop physiologically relevant animal models of chronic M. abs. lung infection in CF to study disease pathogenesis and to test new antimicrobial therapies. CF ferrets carrying two copies of the correlate to the human G551D CFTR mutation provide an alternative solution as they produce CF disease traits similar to PwCF, respond well to the CFTR potentiator ivacaftor (VX-770) and represent a useful and controllable experimental model to study different aspects of CF lung disease. Our long-term goal is to develop novel therapeutics to combat M. abs. lung infection in PwCF. As part of this goal, the objective of this work is to establish a novel animal model for M. abs. lung infection in CF ferrets and to demonstrate lung pathology, inflammation and infection profiles similar to M. abs-infected PwCF. Our preliminary data demonstrate that G551D/G551D CFTR CF ferrets infected intratracheally with a single dose of smooth or rough M. abs. variant acquire infection, and M. abs. could be detected in their lungs 12 weeks post- infection. Our central hypotheses are that a mixed infection with smooth and rough M. abs. variants yields more severe clinical outcomes than single morphotype infections, and that restoration of CFTR function by restarting CFTR modulator therapy post-infection leads to diminished bacterial burden in M. abs-infected CF ferrets. This will be tested by determining the clinical outcomes of mixed morphotype infection or restarting the CFTR potentiator therapy after M. abs. airway infection in CF ferrets. Our work is expected to deliver an established and optimized, chronic M. abs. lung infection protocol in CF ferrets that results in the chronic presence of M. abs. in the lung with associated inflammatory changes. This high-risk, high-reward, exploratory proposal represents the essential next step to establish a clinically relevant in vivo animal model for chronic M. abs. lung infection in CF. Such an in vivo model will have a positive impact and will enable long-awaited studies on M. abs. lung disease pathogenesis and therapeutic interventions to target this clinically highly relevant pathogen in CF, and in other conditions.