Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models
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| Název: | Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models |
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| Autoři: | Xin Wang, Hongwei Su, Joshua B. Wallach, Jeffrey C. Wagner, Benjamin J. Braunecker, Michelle Gardner, Kristine M. Guinn, Nicole C. Howard, Thais Klevorn, Kan Lin, Yue J. Liu, Yao Liu, Douaa Mugahid, Mark Rodgers, Jaimie Sixsmith, Shoko Wakabayashi, Junhao Zhu, Matthew Zimmerman, Véronique Dartois, JoAnne L. Flynn, Philana Ling Lin, Sabine Ehrt, Sarah M. Fortune, Eric J. Rubin, Dirk Schnappinger |
| Zdroj: | Nat Microbiol |
| Informace o vydavateli: | Springer Science and Business Media LLC, 2025. |
| Rok vydání: | 2025 |
| Témata: | Trimethoprim/pharmacology, Animal, Mycobacteriophages/genetics/physiology, Bacterial Proteins/genetics/metabolismAntitubercular Agents/pharmacology, Antitubercular Agents, Mycobacterium tuberculosis, Mice, SCID, Mycobacteriophages, SCID, Article, Mice, Disease Models, Animal, Bacterial Proteins, Disease Models, Operon, Animals, Tuberculosis, Humans, Tuberculosis/microbiology, Female, Genetic Engineering, WCM Library Coordinated Deposit |
| Popis: | Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain–NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag−/− mice. The TKS strain had an escape mutation rate of less than 10−10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 2058-5276 |
| DOI: | 10.1038/s41564-024-01913-5 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/39794471 |
| Rights: | CC BY CC BY NC ND |
| Přístupové číslo: | edsair.doi.dedup.....f880d58b6a31e7eef5b81e65c723a7f9 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain–NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag−/− mice. The TKS strain had an escape mutation rate of less than 10−10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model. |
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| ISSN: | 20585276 |
| DOI: | 10.1038/s41564-024-01913-5 |