Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype

Bacterial genotoxins can damage host cells by targeting their chromosomal DNA. Salmonella Typhi the causative pathogen of typhoid fever in humans, secretes an essential genotoxin called typhoid toxin, which can induce cellular senescence. Here we show that typhoid toxin triggers the senescence-associated secretory phenotype (SASP) by disrupting mitochondrial function, including a decrease in mitochondrial DNA (mtDNA) content and a disturbance of redox homeostasis within mitochondria. This disruption causes the release of mtDNA into the cytosol, which activates type I interferon via the cGAS-STING pathway. We also demonstrate that the GCN2-mediated integrated stress response modulates the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect to CD4 T cells, potentially leading to senescence in these cells. Our research provides a novel insight into how bacterial genotoxins target mitochondria to induce a proinflammatory SASP, which could be a promising therapeutic target for an anti-toxin intervention. Samples represent THP-1-derived macrophages which were treated with either mock, wild-type(WT) typhoid toxin or the mutant toxin variant (PltBS35A) with triplicate data of each treatments.