Martin Océane C B, Bergonzini Anna, Lopez Chiloeches Maria, Paparouna Eleni, Butter Deborah, Theodorou Sofia D P, Haykal Maria M, Boutet-Robinet Elisa, Tebaldi Toma, Wakeham Andrew, Rhen Mikael, Gorgoulis Vassilis G, Mak Tak, Pateras Ioannis S, Frisan Teresa
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden.
Cell Rep. 2021 Apr 6;35(1):108931. doi: 10.1016/j.celrep.2021.108931.
Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.
细菌基因毒素会导致真核细胞中的DNA损伤，在体外引发DNA损伤反应（DDR）的激活。这些毒素由革兰氏阴性菌产生，在炎症性肠病（IBD）和结直肠癌（CRC）患者的微生物群中含量丰富。然而，它们在感染中的作用仍不清楚。我们研究了伤寒毒素在健康和疾病状态下调节宿主-微生物相互作用中的作用。感染产基因毒素的沙门氏菌可保护小鼠免受肠道炎症。我们发现，活性基因毒素的存在会在体内促进DNA片段化和衰老，这与炎症反应无关，且意外地与抗炎环境的诱导有关。当在患有急性结肠炎的小鼠中发生感染时，抗炎反应会丧失。这些数据凸显了细菌基因毒素诱导的DDR与宿主免疫反应之间复杂的、依赖于背景的相互作用，强调了细菌基因毒素的意外作用。
