Tuberculosis is an infectious disease that still kills 1.5 million people per year worldwide. The causative bacteria probably emerged from an environmental source through adaptations of already existing metabolic pathways. By replicating this evolution in the laboratory, the researchers were able to identify mutations in the bacterial genome that favor persistence in the host lungs. These adaptations allow the bacterium to better resist aggression by the immune response. The revelation of these adaptation pathways opens new avenues of research in the fight against this disease. The results of this study are published on July 23 in the journal Nature Microbiology.
Tuberculosis bacilli have been associated with humans for millennia. They have evolved to acquire a unique ability to resist the host immune response to persist for months and induce tissue damage favoring their transmission by aerosol. Evolutionary models indicate that the TB bacillus emerged from an environmental bacterium and then spread into the human population. What adaptations allowed this ancestral bacterium to colonize humans?
To answer this question, the scientists have tried to mimic this transition in the laboratory. To do so, they used bacterial strains, named Mycobacterium canettii, whose genomic characteristics indicate that they could be similar to the ancestor of Mycobacterium tuberculosis, the species responsible for the majority of tuberculosis cases today. In particular, these strains of M. canettii have a lesser ability than M. tuberculosis to persist in the host. By performing cycles of infection with several strains of M. canettii, the scientists were able to select mutants that have an increased ability to persist in the host, similar to that of M. tuberculosis. The genome of these mutants was analyzed to identify the mutations responsible for this adaptation. The impact of these mutations on the biology of the bacteria was then characterized to understand the mechanisms that led to the increased ability to survive in the host. The results indicate that these adaptations can be rapidly acquired and lead the bacteria not to change the host immune response but rather to better resist the toxic compounds it generates, in particular nitric oxide.
The identification of these adaptation pathways allows a better understanding of the emergence and evolution of a major human pathogen responsible for persistent infection. This work opens new perspectives in the fight against tuberculosis.
Figure: Necrotic pulmonary lesions generated in the mouse model by the tuberculosis bacillus. The sections were stained by the Ziehl-Neelsen method and reveal the bacteria in pink that persist in the necrotic zone of the lesion (in blue). © Samantha Milia, Service d’Histopathologie Expérimentale (CREFRE, INSERM, Toulouse)
Parallel in vivo experimental evolution reveals that increased stress resistance was key for the emergence of persistent tuberculosis bacilli (2021) Aideen C. Allen, Wladimir Malaga, Cyril Gaudin, Arnaud Volle, Flavie Moreau, Ali Hassan, Catherine Astarie-Dequeker, Antonio Peixoto, Rudy Antoine, Alexandre Pawlik, Wafa Frigui, Céline Berrone, Roland Brosch, Philip Supply, and Christophe Guilhot. Nature Microbiology. doi.org/10.1038/s41564-021-00938-4
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