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.
Highlights
Infections due to nontuberculosis mycobacteria (NTM) are increasing worldwide, resulting in a serious public health problem (Prevots and Marras, 2015)
We evaluated aerosol exposure of a clinical, drug- resistant strain of Mycobacterium avium complex (MAC) 2285 (∼2,000 bacilli per mouse) to determine if there is a progressive infection in the C3HeB/FeJ during the acute and relative chronic phases after infection
C3HeB/FeJ mice showed an increase in bacterial burden 40 days after infection, peaking at ∼5.2 log10 Colony forming units (CFU) in the lungs (Figure 1A), followed by bacilli persisting in the lungs and plateauing at ∼5.1 log10 CFU during the chronic phase of disease
Summary
Infections due to nontuberculosis mycobacteria (NTM) are increasing worldwide, resulting in a serious public health problem (Prevots and Marras, 2015). NTM are mycobacterial species other than Mycobacterium tuberculosis complex and Mycobacterium leprae, that can cause pulmonary and extrapulmonary disease in vulnerable individuals, and are reported throughout the world (Prevots and Marras, 2015; Bryant et al, 2016). The most common NTM causing disease and outbreaks in the United States are species within the MAC—comprised of at least 9 species including M. avium, M. intracellulare, and M. chimaera, followed by Mycobacterium abscessus complex (including M. abscessus sensu stricto, M. massiliense and M. bolletii), Mycobacterium chelonae and Mycobacterium kansasii (De Groote and Huitt, 2006). Other host factors and phenotypes that are associated with NTM lung disease include advanced age, thin body habitus often with thoracic cage abnormalities such as scoliosis and pectus excavatum, gastroesophageal reflux, and use of inhaled corticosteroids and anti-tumor necrosis factor-alpha (anti-TNF-α) therapies (Shang et al, 2011; Bryant et al, 2016; Honda et al, 2018)
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