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Published on: October 5, 2015
A Murine Model of Mycobacterium kansasii Infection Reproducing Necrotic Lung Pathology Reveals Considerable
Vinicius O Mussi1, Thatiana L B V Simão1, Fabrício M Almeida1
1Laboratory of Biology of Recognition, State University of North Fluminense, Campos, Brazil.
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.
Insights
A mouse model using C57BL/6 mice effectively replicates Mycobacterium kansasii lung disease, aiding virulence studies. Genetic analysis reveals widespread, highly pathogenic M. kansasii clones globally.
Area of Science:
- Microbiology
- Infectious Diseases
- Animal Models
Background:
- Mycobacterium kansasii causes pulmonary disease resembling tuberculosis.
- Lack of suitable animal models hinders understanding of M. kansasii virulence and pathology.
Purpose of the Study:
- To evaluate C57BL/6 mice as a model for M. kansasii lung infection.
- To investigate the virulence and pathogenicity of M. kansasii strains in mice.
Main Methods:
- Intratracheal infection of C57BL/6 mice with M. kansasii strains.
- In vitro virulence assessment in macrophages.
- In vivo analysis of lung pathology and survival.
- Genomic comparison of M. kansasii isolates.
Main Results:
- C57BL/6 mice developed chronic lung disease with necrotic pathology.
- Highly virulent M. kansasii strains caused progressive disease and granuloma formation.
- Two strains induced premature death, while a low-virulent strain was cleared.
- Genomic analysis showed similarities between Brazilian and international M. kansasii isolates.
Conclusions:
- C57BL/6 mice provide a clinically relevant model for M. kansasii virulence studies.
- Significant heterogeneity exists in M. kansasii virulence.
- Highly pathogenic M. kansasii clones appear to be globally distributed.
