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<p>Pathogenic bacteria rely on the stringent response to adapt to hostile environments encountered within the host. However, the mechanisms by which host-induced stress activates this response remain poorly understood. Here, we identify iron-sulfur (Fe-S) cluster damage as a conserved trigger of the stringent response in major Gram-negative pathogens, including <i>Salmonella enterica</i>, <i>Enterobacter cloacae</i>, and <i>Klebsiella pneumoniae</i>. We demonstrate that Fe-S cluster disruption—triggered by oxidative stress or metal imbalance—limits intracellular pools of sulfur-containing and branched-chain amino acids, thereby activating the (p)ppGpp synthetase RelA. We further show that during Fe-S cluster stress, (p)ppGpp plays a dual role: enhancing bacterial fitness and promoting virulence by upregulating the <i>Salmonella</i> SPI-2 type III secretion system. These findings reveal a conserved mechanism by which pathogenic bacteria integrate host-associated stresses into an adaptive transcriptional response that promotes fitness and virulence, highlighting Fe-S cluster integrity as a central hub for environmental sensing during infection.</p>

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Stress-induced iron-sulfur cluster damage as a conserved trigger of the bacterial stringent response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Eva Michaud,
  • Lorena Ricci,
  • Claire Lallement,
  • Lars Barquist,
  • Vincent Cattoir,
  • Charlotte Michaux,
  • Régis Hallez,
  • Séverin Ronneau

摘要

Pathogenic bacteria rely on the stringent response to adapt to hostile environments encountered within the host. However, the mechanisms by which host-induced stress activates this response remain poorly understood. Here, we identify iron-sulfur (Fe-S) cluster damage as a conserved trigger of the stringent response in major Gram-negative pathogens, including Salmonella enterica, Enterobacter cloacae, and Klebsiella pneumoniae. We demonstrate that Fe-S cluster disruption—triggered by oxidative stress or metal imbalance—limits intracellular pools of sulfur-containing and branched-chain amino acids, thereby activating the (p)ppGpp synthetase RelA. We further show that during Fe-S cluster stress, (p)ppGpp plays a dual role: enhancing bacterial fitness and promoting virulence by upregulating the Salmonella SPI-2 type III secretion system. These findings reveal a conserved mechanism by which pathogenic bacteria integrate host-associated stresses into an adaptive transcriptional response that promotes fitness and virulence, highlighting Fe-S cluster integrity as a central hub for environmental sensing during infection.