Abstract
Among non-tuberculous mycobacteria, Mycobacterium kansasii is one of the most pathogenic, able to cause pulmonary disease indistinguishable from tuberculosis in immunocompetent susceptible adults. The lack of animal models that reproduce human-like lung disease, associated with the necrotic lung pathology, impairs studies of M. kansasii virulence and pathogenicity. In this study, we examined the ability of the C57BL/6 mice, intratracheally infected with highly virulent M. kansasii strains, to produce a chronic infection and necrotic lung pathology. As a first approach, we evaluated ten M. kansasii strains isolated from Brazilian patients with pulmonary disease and the reference strain M. kansasii ATCC 12478 for virulence-associated features in macrophages infected in vitro; five of these strains differing in virulence were selected for in vivo analysis. Highly virulent isolates induced progressive lung disease in mice, forming large encapsulated caseous granulomas in later stages (120–150 days post-infection), while the low-virulent strain was cleared from the lungs by day 40. Two strains demonstrated increased virulence, causing premature death in the infected animals. These data demonstrate that C57BL/6 mice are an excellent candidate to investigate the virulence of M. kansasii isolates. We observed considerable heterogeneity in the virulence profile of these strains, in which the presence of highly virulent strains allowed us to establish a clinically relevant animal model. Comparing public genomic data between Brazilian isolates and isolates from other geographic regions worldwide demonstrated that at least some of the highly pathogenic strains isolated in Brazil display remarkable genomic similarities with the ATCC strain 12478 isolated in the United States 70 years ago (less than 100 SNPs of difference), as well as with some recent European clinical isolates. These data suggest that few pathogenic clones have been widely spread within M. kansasii population around the world.
Highlights
Mycobacterium kansasii is a slow-growing non-tuberculous mycobacterium (NTM) mainly found in aquatic environments that, differing from many other NTM, can cause human infections in both immunocompetent and immunocompromised individuals (Griffith et al, 2007)
Since intracellular growth and macrophage death induction were previously associated with virulence in pathogenic mycobacteria (Lasunskaia et al, 2010; Sohn et al, 2010), we evaluated these features in M. kansasii clinical isolates
We verified the hypothesis that infection of resistant mice with highly virulent M. kansasii isolates from patients with lung disease, instead of the reference M. kansasii strain, using a high dose of bacilli for intratracheal inoculation, may result in more severe lung disease than that usually seen in the murine models of M. kansasii infection
Summary
Mycobacterium kansasii is a slow-growing non-tuberculous mycobacterium (NTM) mainly found in aquatic environments that, differing from many other NTM, can cause human infections in both immunocompetent and immunocompromised individuals (Griffith et al, 2007). The bacterium most frequently causes chronic pulmonary disease indistinguishable from tuberculosis (TB), resulting in the formation of cavities in more than 70% of cases, or, less frequently, in bronchiectasis or nodules; in contrast, in immunocompromised patients, the disseminated disease is most common (Seiscento et al, 2005; Matveychuk et al, 2012; Moon et al, 2015; Bakuła et al, 2018a; Goldenberg et al, 2020). The prevalence of NTM pulmonary infections in humans have raised in recent decades, demonstrating a 2- to 8-fold increase in different geographic regions (Champa et al, 2020). In some geographic regions, such as Central Europe or Rio de Janeiro in Brazil, M. kansasii is the most common NTM isolate in patients with pulmonary disease, raising the questions about specific features of the local strains, population or transmission (de Mello et al, 2013)
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