A less resource-intensive mouse model of M. abscessus lung disease

PROJECT SUMMARY Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium that can cause chronic lung disease that is associated with rapid lung function decline and is often incurable. There are no FDA-approved treatments for this indication. Existing treatments are based on repurposing of antibiotics approved for other diseases. Challenges of the currently recommended standard treatment of M. abscessus lung disease include a) poor efficacy, b) need for treatment durations lasting several months, c) frequent drug toxicities, d) need for parenteral (IV) antibiotics, and e) complicated logistics of long-term outpatient IV antibiotic treatment. The cure rate using current treatment recommendations is estimated at 30-50%. A simple and easy-to-implement animal model of M. abscessus lung disease is vital to translate findings from in vitro studies to develop new therapeutics and understand diseases’ pathological basis. By closely mimicking the interaction between the etiological agent and the host, an animal model is more informative than in vitro systems for assessing the potential utility of experimental treatments to humans. The overall aim of this proposal is to develop a simple and inexpensive yet robust mouse model of chronic M. abscessus lung disease that is easy to implement in diverse laboratory settings. We present a proof-of- concept of a new mouse model of M. abscessus lung disease using the BALB/c mouse that requires only once weekly administration of cyclophosphamide and permits the proliferation of M. abscessus in the lungs. In Specific Aim 1, we propose studies to verify the reproducibility of this model using additional M. abscessus isolates, as only a single M. abscessus isolate was used for the proof-of-concept studies. In Specific Aim 2, we will test if this mouse model can faithfully reproduce the efficacy of standard-of-care drugs used to treat M. abscessus disease. We will develop a validated mouse model of M. abscessus lung disease based on the evidence from these studies. We expect the deliverables of this proposal to fulfill the current need for a simple and inexpensive mouse model of chronic Mab lung disease.