Scholarlink

<p>Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe <i>Mycobacterium tuberculosis</i> (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<sup>−/−</sup> mice. The TKS strain had an escape mutation rate of less than 10<sup>−10</sup> per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月10日

查看全文
  • 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

摘要

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.