Mycobacterium avium Infection in a C3HeB/FeJ Mouse Model

Abstract

Infections caused by Mycobacterium avium complex (MAC) species are increasing worldwide, resulting in a serious public health problem. Patients with MAC lung disease face an arduous journey of a prolonged multidrug regimen that is often poorly tolerated and associated with relatively poor outcome. Identification of new animal models that demonstrate a similar pulmonary pathology as humans infected with MAC has the potential to significantly advance our understanding of nontuberculosis mycobacteria (NTM) pathogenesis as well as provide a tractable model for screening candidate compounds for therapy. One new mouse model is the C3HeB/FeJ which is similar to MAC patients in that these mice can form foci of necrosis in granulomas. In this study, we evaluated the ability of C3HeB/FeJ mice exposure to an aerosol infection of a rough strain of MAC 2285 to produce a progressive infection resulting in small necrotic foci during granuloma formation. C3HeB/FeJ mice were infected with MAC and demonstrated a progressive lung infection resulting in an increase in bacterial burden peaking around day 40, developed micronecrosis in granulomas and was associated with increased influx of CD4 + Th1, Th17, and Treg lymphocytes into the lungs. However, during chronic infection around day 50, the bacterial burden plateaued and was associated with the reduced influx of CD4 + Th1, Th17 cells, and increased numbers of Treg lymphocytes and necrotic foci during granuloma formation. These results suggest the C3HeB/FeJ MAC infection mouse model will be an important model to evaluate immune pathogenesis and compound efficacy.

Subunit vaccine protects against a clinical isolate of Mycobacterium avium in wild type and immunocompromised mouse models

“…1 a). This sustained infection of clinical MAC isolates is in agreement with published studies 33 , 38 , 39 across several models as well as in our own data, whereby C57BL/6 mice challenged with aerosol MAC 101, MAC 2285 R or MAC 2285 S 38 sustain a persistent infection as measured up to 6 weeks post challenge (Supplemental Figure S1 ). Next, we optimized previous models using a virulent M. avium isolate and empirically developed the low dose aerosol (LDA) infection parameters for M. avium 2-151 smt (Fig.…”

“…These mice were used in repeat vaccination experiments as described below or to evaluate other clinical MAC isolates for bacterial burden over time. Some of these animals were challenged via aerosol with M. avium 101 78 (obtained from ATCC), M. avium 2285 S or M. avium 2285 R 38 (obtained from Dr. Kenneth N. Oliver of the NIH Pulmonary Clinical Medicine Section) using a Glas-Col whole body exposure chamber.…”

Lipids of Clinically Significant Mycobacteria

“…Mycobacterium kansasii and Mycobacterium gastri are opportunists that produce tuberculosis-like human disease (Philley et al 2016;Johnston et al 2017). A very broad taxon, infecting humans and animals, was often referred to as the Mycobacterium avium-Mycobacterium intracellulare-Mycobacterium scrofulaceum (MAIS) complex, but more recently, it has been simply termed the Mycobacterium avium complex (MAC) (Falkinham 2015;Philley et al 2016;Turenne 2019;Verma 2019). Humans and fish can suffer from Mycobacterium marinum infections (Johnson and Stout 2015) and a closely related pathogen, Mycobacterium ulcerans, causes human "buruli ulcers" (Sizaire et al 2006;Chany et al 2013).…”

Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research

“…Additionally, the need for an animal model that demonstrates a similar pulmonary disease as humans infected with MAC incited to exploit the “super-susceptibility to tuberculosis” murine model C3HeB/FeJ. This murine strain developed a progressive infection characterized by small foci of necrosis in the lungs after a lower bacterial inoculum than that typically used [ 187 ].…”