三维培养模型揭示了结核分枝杆菌不同的毒性和抗菌治疗反应

IF 2.6 2区 生物学 Q3 CELL BIOLOGY
Magdalena K. Bielecka, Liku B. Tezera, Elena Konstantinopoulou, Nicola Casali, Orestis L. Katsamenis, Ximena Gonzalo, Francis Drobniewski, Paul T. Elkington
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引用次数: 0

摘要

结核病(TB)仍然是一种持续流行的疾病,耐药结核分枝杆菌(Mtb)的出现对全球医疗保健构成了威胁。虽然一些新制剂已经成功问世,但仍需要创新技术来评估新出现的抗结核化合物,从而为变革性方法提供依据。Mtb是人类必经的病原体,因此利用与人类疾病一致的模型可能至关重要。我们开发了一种人类三维(3-D)细胞培养模型,它能反映人类疾病基因的表达模式,并使 Mtb 在体外对吡嗪酰胺敏感。在这里,我们确定了标准实验室菌株 Mtb H37Rv 与临床分离株在毒力方面的主要差异。我们证明,与临床分离株相比,Mtb H37Rv 在三维系统中毒性减弱,对抗生素更敏感,并具有高炎症性。长期体外培养临床菌株也会导致衰减。然后,我们在三维模型中描述了多重耐药 Mtb 的抗生素敏感性,并确定了相对杀菌活性。最后,我们证明维拉帕米能提高贝达喹啉和地拉那米德抗生素的疗效。总之,我们的研究结果表明,在先进的细胞培养系统中研究毒性临床菌株是评估结核病新干预措施的既有方法的有力补充。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Three-Dimensional Culture Modelling Reveals Divergent Mycobacterium tuberculosis Virulence and Antimicrobial Treatment Response

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.

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来源期刊
Cellular Microbiology
Cellular Microbiology 生物-微生物学
CiteScore
9.70
自引率
0.00%
发文量
26
审稿时长
3 months
期刊介绍: Cellular Microbiology aims to publish outstanding contributions to the understanding of interactions between microbes, prokaryotes and eukaryotes, and their host in the context of pathogenic or mutualistic relationships, including co-infections and microbiota. We welcome studies on single cells, animals and plants, and encourage the use of model hosts and organoid cultures. Submission on cell and molecular biological aspects of microbes, such as their intracellular organization or the establishment and maintenance of their architecture in relation to virulence and pathogenicity are also encouraged. Contributions must provide mechanistic insights supported by quantitative data obtained through imaging, cellular, biochemical, structural or genetic approaches.
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