Scholarlink

<p>Lethal toxin (LT), the major virulence factor of <i>Bacillus anthracis</i>, proteolytically inactivates MEKs and disables downstream ERK, p38 and JNK pathway signalling leading to tissue damage and mortality. Therapies for LT-induced damage after host cell internalization of the toxin are lacking. Here we constructed MEK variants in which the LT proteolytic site was modified: MEK2(P10V/A11D), MEK3(I27D) and MEK6(I15D). These variants were resistant to proteolysis by LT. Expression in cells enabled sustained activation of ERK and p38 pathways and promoted cell survival upon LT treatment. Survival of LT- or <i>B. anthracis</i>-challenged MEK variant transgenic mice also increased compared with controls. We found that LT-mediated disruption of both ERK and p38 pathway is essential for anthrax pathogenesis. We show that engagement of upstream receptor tyrosine kinases reactivated the LT-disrupted ERK pathway, as did administering a cocktail of EGF, GM-CSF and FGF2 growth factors, which significantly increased survival of LT- or <i>B. anthracis</i>-challenged mice. These findings offer potential towards developing damage-limiting therapeutic strategies for anthrax.</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

ERK pathway reactivation prevents anthrax toxin lethality in mice

  • 期刊论文

  • 发表日期：

    2025年3月28日

查看全文
  • Jie Liu,
  • Zehua Zuo,
  • Michael Ewing,
  • Qing Cao,
  • Liu Cao,
  • Qi Li,
  • Toren Finkel,
  • Stephen H. Leppla,
  • Shihui Liu

摘要

Lethal toxin (LT), the major virulence factor of Bacillus anthracis, proteolytically inactivates MEKs and disables downstream ERK, p38 and JNK pathway signalling leading to tissue damage and mortality. Therapies for LT-induced damage after host cell internalization of the toxin are lacking. Here we constructed MEK variants in which the LT proteolytic site was modified: MEK2(P10V/A11D), MEK3(I27D) and MEK6(I15D). These variants were resistant to proteolysis by LT. Expression in cells enabled sustained activation of ERK and p38 pathways and promoted cell survival upon LT treatment. Survival of LT- or B. anthracis-challenged MEK variant transgenic mice also increased compared with controls. We found that LT-mediated disruption of both ERK and p38 pathway is essential for anthrax pathogenesis. We show that engagement of upstream receptor tyrosine kinases reactivated the LT-disrupted ERK pathway, as did administering a cocktail of EGF, GM-CSF and FGF2 growth factors, which significantly increased survival of LT- or B. anthracis-challenged mice. These findings offer potential towards developing damage-limiting therapeutic strategies for anthrax.