Abstract
Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) invitro. 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 invivo, 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.
Highlights
Typhoid toxin (TT) and cytolethal distending toxins (CDTs), produced by several Gram-negative bacteria, belong to a family of bacterial protein effectors that cause DNA damage in eukaryotic cells (Grasso and Frisan, 2015)
Infection with genotoxin-producing bacteria induces senescence in vivo We have previously demonstrated that infection with S
Consistent with these data, histological evaluation performed at 10 days post-infection revealed that mice infected with the MC1 DcdtB strain exhibited increased severity of enteritis and colitis compared to MC1-TT-treated mice, characterized by areas of superficial erosion and elevated neutrophilic infiltration in the lamina propria, along with increased number of Peyer’s patches (PPs) (Figures 1A–1C, S2A, and S2B)
Summary
Typhoid toxin (TT) and cytolethal distending toxins (CDTs), produced by several Gram-negative bacteria, belong to a family of bacterial protein effectors that cause DNA damage in eukaryotic cells (Grasso and Frisan, 2015). Upon delivery into the nucleus of the target cells, the CdtB subunit induces DNA strand breaks, which activate the DNA damage response (DDR), coordinated by the sensor kinase ataxia telangiectasia mutated (ATM) (Grasso and Frisan, 2015). If the extent of the damage is beyond repair, most cell types undergo senescence (Blazkova et al, 2010; Ibler et al, 2019; Secher et al, 2013). Intoxicated cells may survive and overcome the DDR-induced tumorigenic barrier, leading to genomic instability and acquisition of carcinogenic traits (Guidi et al, 2013a; Hanahan and Weinberg, 2011)
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