A New Model of Chronic Mycobacterium abscessus Lung Infection in Immunocompetent Mice.

Camilla Riva,Paolo Miotto,Marco Rossi,Tamara Canu,Federica Cugnata,Alessandra Bragonzi,Anna Colarieti,Cristina Cigana,Enrico Tortoli,Nicola Ivan Loré,Francesca Sanvito,Daniela Maria Cirillo,Antonio Esposito

doi:10.3390/ijms21186590

Abstract

Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades, affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of MA pulmonary infection. To overcome this challenge, we refined the method of agar beads to establish MA chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after MA infection. In this model, MA was able to establish a persistent lung infection for up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of lymphocytes, aggregates of vacuolated histiocytes and a few neutrophils, mimicking the damage observed in humans. Furthermore, MA lung lesions were successfully monitored for the first time by MRI. The availability of this murine model and the introduction of the successfully longitudinal monitoring of the murine lung lesions with MRI pave the way for further investigations on the impact of MA pathogenesis and the efficacy of novel treatments.

Highlights

Nontuberculous mycobacteria (NTMs) are environmental organisms that are ubiquitous in water and soil
Alternative models based on immunocompromised murine models were developed [11,12,13], which have resulted in slower resolution of Mycobacterium abscessus (MA) lung infection than immunocompetent mice
MA subsp. abscessus embedded in the agar beads was intratracheally inoculated in immunocompetent C57BL/6NCrl mice to generate an effective long-term chronic lung infection

Summary

Introduction

Nontuberculous mycobacteria (NTMs) are environmental organisms that are ubiquitous in water and soil. Alternative models based on immunocompromised murine models were developed (e.g., granulocyte-macrophage colony-stimulating factor GM-CSF -/- mice, gamma interferon knockout GKO mice or severe combined immunodeficiency SCID mice) [11,12,13], which have resulted in slower resolution of MA lung infection than immunocompetent mice. Despite these advancements, the lack of a standardized mouse model of persistent chronic infection in immunocompetent mice that reflects the human MA lung pathology, is the major impediment to studying MA pulmonary infection and treatment strategies [14]. We explored the possibility of longitudinally monitoring the MA lung challenge within the same animal by using the MRItechnique for the first time

Objectives

Methods

Results