Three-dimensional culture modelling reveals divergent Mycobacterium tuberculosis virulence and antimicrobial treatment response
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Tuberculosis (TB) remains a persistent epidemic, and the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) presents a global healthcare threat. While some new agents have been successfully introduced, innovative technologies to evaluate emerging anti-TB compounds are required to inform transformative approaches. Mtb is an obligate human pathogen, and consequently utilizing models that are consistent with human disease is likely to be critical. We have developed a human 3-dimensional (3-D) cell culture model that reflects human disease gene expression patterns and causes Mtb to become pyrazinamide sensitive in vitro. Here, we identify key differences in virulence between the standard laboratory strain, Mtb H37Rv, and clinical isolates. We demonstrate that Mtb H37Rv is attenuated in the 3-D system, more susceptible to antibiotics and hyperinflammatory compared to clinical isolates. Prolonged in vitro culture of a clinical strain leads to attenuation. We then characterise antibiotic sensitivity of multi-drug-resistant Mtb within the 3-D model and define relative bactericidal activity. Finally, we demonstrate that verapamil increases efficacy of bedaquiline and delamanid antibiotic therapy. Taken together, our findings suggest that studying virulent clinical strains in an advanced cell culture system is a powerful adjunct to established methodologies to evaluate new interventions for TB.
Date Issued
2024-05-03
Date Acceptance
2024-03-11
Citation
Cellular Microbiology, 2024, 2024
ISSN
1462-5814
Publisher
Wiley
Journal / Book Title
Cellular Microbiology
Volume
2024
Copyright Statement
© 2024 Magdalena K. Bielecka et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.hindawi.com/journals/cmi/2024/6458900/
Publication Status
Published
Article Number
6458900
Date Publish Online
2024-05-03