Influence of the microenvironment on the modulation of the host response by the typhoid toxin

Abstract

30Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA 31 damage response (DDR) in vitro. These toxins are produced by Gram negative bacteria, en-32 riched in the microbiota of Inflammatory Bowel Disease (IBD) and colorectal cancer (CRC) 33 patients. However, their role in infection remains poorly characterized. We have addressed the 34 role of the typhoid toxin in the modulation of the host-microbial interaction in health and dis-35 ease. 36Infection with a genotoxigenic Salmonella protected mice from intestinal inflammation. The 37 toxin-induced DNA damage caused senescence in vivo, which was uncoupled from the inflam-38 matory response, and associated with the maintenance of an anti-inflammatory environment. 39This effect was lost when infection occurred in mice suffering from inflammatory conditions 40 that mimic Ulcerative Colitis, a form of IBD. 41These data highlight a complex context-dependent crosstalk between bacterial genotoxins-in-42 duced DDR and the host immune response, underlining an unexpected role for bacterial geno-43 toxins. 44 45 cumulates in the cytoplasm of senescent cells (Evangelou et al., 2017). As shown in Figures 2C 130 and S3A, we detected a significant increase in GL13 epithelial positive cells in the colon and 131 small intestine of mice infected with the MC1 TT and MC71 TT strains compared to the levels 132 detected in mice infected with the control Salmonella, with the most prominent effect observed 133 in the C57BL/6 mouse strain (cp Figure 2C and Figure S3A). In our model, induction of senes-134 cence was uncoupled from the activation of a pro-inflammatory response (Figures 1, 3 and S2). 135 136The typhoid toxin maintains an anti-inflammatory microenvironment 137 Supplementary Information