Typhoid toxin hijacks Wnt5a to establish host senescence and Salmonella infection

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113181-113181, Article 113181
• Main Authors: ElGhazaly, Mohamed, Collins, Mark O., Ibler, Angela E.M., Humphreys, Daniel
• Format: Article
• Language: English
• Subjects: DNA damage response; host-pathogen interactions; infection; innate immunity; senescence; toxin; virulence factor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113181

Damage to our genome causes acute senescence in mammalian cells, which undergo growth arrest and release a senescence-associated secretory phenotype (SASP) that propagates the stress response to bystander cells. Thus, acute senescence is a powerful tumor suppressor. Salmonella enterica hijacks senescence through its typhoid toxin, which usurps unidentified factors in the stress secretome of senescent cells to mediate intracellular infections. Here, transcriptomics of toxin-induced senescent cells (TxSCs) and proteomics of their secretome identify the factors as Wnt5a, INHBA, and GDF15. Wnt5a establishes a positive feedback loop, driving INHBA and GDF15 expression. In fibroblasts, Wnt5a and INHBA mediate autocrine senescence in TxSCs and paracrine senescence in naive cells. Wnt5a synergizes with GDF15 to increase Salmonella invasion. Intestinal TxSCs undergo apoptosis without Wnt5a, which is required for establishing intestinal TxSCs. The study reveals how an innate defense against cancer is co-opted by a bacterial pathogen to cause widespread damage and mediate infections. [Display omitted] •Salmonella co-opts Wnt5a, INHBA, and GDF15 secreted from toxin-induced senescent cells•Wnt5a suppresses apoptosis, establishing senescence in response to typhoid toxin•Wnt5a and INHBA synergize, causing paracrine senescence in bystander cells•Salmonella hijacks secreted factors Wnt5a and GDF15 to enhance host cell invasion ElGhazaly et al. reveal how Salmonella enterica hijacks a tumor-suppressor mechanism. By uncovering the secreted proteome of human cells undergoing acute senescence in response to typhoid toxin of Salmonella, they show that Wnt5a suppresses apoptosis, enabling senescence while synergizing with INHBA and GDF15 to mediate paracrine senescence and infections.