A mouse model of pulmonary Mycobacteroides abscessus infection

Emily C Maggioncalda,Peter Illei,Elizabeth Story-Roller,Julian Mylius,Randall J Basaraba,Gyanu Lamichhane

doi:10.1038/s41598-020-60452-1

Abstract

There is no preclinical mouse model to investigate pulmonary Mycobacteroides abscessus (formerly Mycobacterium abscessus) infection in an immunocompetent mouse strain, especially in the context of antibiotic testing and regimen development. We developed a mouse model of pulmonary M. abscessus infection using the aerosolized route of infection that leads to an increase in bacterial burden post- implantation and develops pathology as a result. In this mouse model, treatment with corticosteroid allows for initial proliferation and sustained M. abscessus pulmonary infection and permits evaluation of efficacies of antibiotics. Administration of corticosteroids that permitted higher levels of bacterial burden in the lungs were more likely to have pathology. Treatment of mice with antibiotics administered intranasally or subcutaneously significantly reduced lung M. abscessus burden. In addition to the reference strain, independent clinical isolates of M. abscessus also readily establish infection and proliferate in the lungs of mice in this model.

Highlights

In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis, and COPD, Mycobacteroides abscessus can cause chronic pulmonary infection[1,2] that is often incurable and associated with rapid lung function decline[3,4,5]
Our aim was to meet the need for an animal model that more closely recapitulated pulmonary M. abscessus disease in humans so that it could be used as a tool to study drug efficacy against M. abscessus
As mouse models have contributed extensively to the study of pulmonary disease by another mycobacterium, M. tuberculosis[15,16,17,37], we again leveraged the mouse to develop a model of pulmonary M. abscessus infection that utilized the aerosol route for infection, led to an increase in lung bacterial burden after implantation, and resulted in the development of relevant pulmonary pathology

Summary

Introduction

In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis, and COPD, Mycobacteroides abscessus (formerly Mycobacterium abscessus) can cause chronic pulmonary infection[1,2] that is often incurable and associated with rapid lung function decline[3,4,5]. While there have been many exciting demonstrations of in vitro potencies of antibiotics against M. abscessus[7,8,9,10,11,12,13], it has been established that potency observed in vitro for M. abscessus often does not translate to an equivalent clinical efficacy in the case of pulmonary infections[3] This highlights the need for a preclinical animal model to evaluate experimental antibiotics. We demonstrated proof-of-concept of the utility of pharmacological immunosuppression of C3HeB/ FeJ mice to evaluate efficacies of subcutaneously delivered dual β-lactam regimens to treat pulmonary M. abscessus infection[28]. In this previous study we did not investigate how pathology develops during steroid treatment and upon steroid treatment release. We demonstrate its utility in evaluating efficacy of antibiotic therapies administered via the intranasal route as well as infection with clinical strains of M. abscessus, both of which have not been previously described with this model

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