Typhoid toxin hijacks Wnt5a to establish host senescence and Salmonella infection
Typhoid toxin hijacks Wnt5a to establish host senescence and Salmonella infection
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DOI：
10.1016/j.celrep.2023.113181
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发表时间：
2023-10-04
期刊：
影响因子：
8.8
通讯作者：
Humphreys，Daniel
中科院分区：
文献类型：
--
作者：
Elghazaly，Mohamed;Collins，Mark O.;Humphreys，Daniel
对我们基因组的损伤导致哺乳动物细胞的急性衰老，这些细胞经历生长停滞并释放衰老相关分泌表型（SASP），该表型将应激反应传播给旁观者细胞。因此，急性衰老是一个强大的肿瘤抑制因子。沙门氏菌通过其伤寒毒素劫持衰老，伤寒毒素篡夺衰老细胞应激分泌组中的未知因子，介导细胞内感染。在这里，毒素诱导的衰老细胞（TxSC）的转录组学和它们的分泌组的蛋白质组学将因子鉴定为Wnt5a、INHBA和GDF15。Wnt5a建立正反馈环，驱动INHBA和GDF15表达。在成纤维细胞中，Wnt5a和INHBA介导TxSC中的自分泌衰老和幼稚细胞中的旁分泌衰老。Wnt5a与GDF15协同增加沙门氏菌侵袭。肠TxSC在没有Wnt5a的情况下经历凋亡，Wnt5a是建立肠TxSC所必需的。这项研究揭示了一种对癌症的先天防御是如何被细菌病原体所吸收，从而造成广泛的损害并介导感染的。
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 entericahijacks 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 increaseSalmonellainvasion. 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.