Background: Non-tuberculous mycobacteria (NTM) consist of over 200 species of environmental mycobacteria found typically in water and soil, some of which instigate serious infections in humans, most notably Mycobacterium abscessus (M. abscessus). Current available treatment regimens are complex, requiring multiple antibiotics often with toxic side effects. Indeed, the optimal drugs, regimen, and duration of therapy are not known for M. absessus infection. This is due to a limited arsenal of effective antibiotics and a lack of knowledge on M. abscessus physiology, especially in the understanding of how these opportunistic pathogens adapt to the host lung environment to establish chronic infection and resist antibiotic treatment. There is therefore an urgent need to understand how NTM pathogens withstand and adapt to the stresses of the host microenvironment in order to uncover novel therapeutic targets and strategies for this often-untreatable disease.
This project aims to gain a better understanding of the effect of the host microenvironment on M. abscessus using human bronchoalveolar lavage fluid samples (BALF) samples, serving as a proxy for the human lung microenvironment. We hypothesize that the human lung environment enhances the ability of M. abscessus to withstand antibiotic stress and survival within airway macrophages (AMs), lung resident phagocytes that are the key intracellular niche for NTM to reside and replicate. The objectives of this project are (1) to determine the effect of human BALF on M. abscessus susceptibility in vitro to antibiotics commonly used in NTM therapy – e.g. amikacin, azithromycin; and (2) to determine the effect human BALF on antibiotic killing of intracellular M. abscessus during AM infection. We expect that exposure to BALF will enhance the ability of M. abscessus with withstand antibiotic treatment and survival within macrophages. This work will further our understanding of this emerging pathogen in the context of human disease.