Program Results

Introduction to the event

This study uncovers a previously unrecognized pathogenic mechanism of Salmonella enterica through the action of its genotoxin, typhoid toxin. While typhoid toxin has been primarily studied for its ability to damage host chromosomal DNA, this work demonstrates that the toxin also targets mitochondrial DNA (mtDNA), leading to mitochondrial dysfunction and increased oxidative stress. Damaged mtDNA is released into the cytoplasm, where it serves as a danger-associated molecular pattern that activates the cGAS-STING pathway, a central innate immune signaling cascade. This activation induces the production of type I interferons, a hallmark of antiviral and inflammatory responses. In parallel, the toxin-induced stress triggers the GCN2-dependent integrated stress response (ISR), which synergizes with cGAS-STING signaling to amplify proinflammatory gene expression. Together, these events drive host cells into a state of cellular senescence, characterized by the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). The SASP involves the secretion of a broad array of cytokines, chemokines, and growth factors that perpetuate inflammation. Importantly, this study shows that the SASP induced by typhoid toxin is not confined to the toxin-damaged cells themselves. Through paracrine effects, SASP factors act on neighboring T cells, pushing them into senescence. As a consequence, immune cell function is compromised, which may contribute to impaired tissue repair, defective wound healing, and the development of chronic inflammatory states. The findings also have broader implications beyond typhoidal Salmonella. The authors demonstrate that other non-typhoidal serovars, such as S. Javiana, can also produce typhoid toxin, highlighting the widespread relevance of this virulence mechanism in the genus.

Overall, this work reveals a novel pathogenic axis by which typhoid toxin damages mitochondrial DNA and harnesses innate immune and stress pathways to induce cellular and immune senescence. By linking bacterial infection to host mitochondrial damage, chronic inflammation, and immune aging, the study provides new insights into how bacterial toxins contribute to disease progression. These discoveries open potential avenues for therapeutic intervention, including strategies to neutralize typhoid toxin activity, protect mitochondrial integrity, or modulate SASP responses to mitigate the long-term consequences of infection.