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

Abstract

Highlights d Typhoid toxin causes DNA fragmentation in vivo not associated with inflammation d Infection with a genotoxin-producing bacterium induces senescence in vivo d The presence of senescent cells is associated with an antiinflammatory response d The anti-inflammatory effect is lost in mice with acute colitis

Chronic exposure to Cytolethal Distending Toxin (CDT) promotes a cGAS-dependent type I interferon response

“…CDT production during bacterial infection is thought to promote inflammation and persistent colonization, eventually contributing to tumorigenesis [9][10][11]56]. However, the situation is probably more complex, as evidenced with the anti-inflammatory function of the typhoid toxin that is related to CDT by sharing the same catalytic subunit [30]. Our findings identify cGAS as a major player linking CDT genotoxic and immunomodulatory activities.…”

“…First, cGAS surveillance of MN in host cells infected with CDT-producing bacteria could elicit a rigorous immune response as previously described for microbial pathogens as DNA viruses, RNA viruses after reverse transcription, or intracellular bacteria [53]. However, CdtB from typhoid toxin rather promotes an anti-inflammatory environment in infected mice [30], which might be a consequence of proinflammatory response inhibition by type I IFN [32]. On the other hand, many ISGs, and notably those addressed in the present study, belong to the Interferon-Related DNA Damage Resistance Signature (IRDS) group, and their upregulation in cancer cells is associated with resistance to DNA damage, suppression of T cell toxicity and enhanced tumor survival [54].…”

“…However, in a Salmonella enterica infection model of immunocompetent mice, typhoid toxin production promotes an intestinal anti-inflammatory environment despite inducting DNA damage and senescence [30]. Indeed, only active CdtB harboring toxins were able to repress the inflammatory response associated with this serovar [31].…”

Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators

“…Infection studies performed with a TT-expressing S. enterica have shown the suppression of gastroenteritis characterised by a decrease in the recruitment of CD45 + (leukocytes), CD3 + (T lymphocytes), and F4/80 + (macrophages) cells [ 122 , 123 , 124 ]. The presence of a functional TT promoted the induction of a Th2 tissue-protective immune response characterised by the presence of anti-inflammatory CD206 + macrophages and T regulatory lymphocytes, and enhanced expression of mRNA for Th2 cytokines ( Il10 , Il4 , Il13 , Il5 ) [ 124 ]. These anti-inflammatory effects were partially ATM-dependent and occurred in spite of the significant induction of DNA fragmentation in the colon mucosa and the substantial presence of senescent cells, supporting the idea that, under these conditions, DNA damage and senescence are uncoupled from inflammation.…”

“…Interestingly, a functional TT did not prevent inflammation in the liver and spleen [ 122 ], and the anti-inflammatory effects were lost when infection occurred in mice suffering from acute DSS-induced colitis [ 124 ]. Therefore, the described effects of a functional TT were context- (healthy vs. colitis) and tissue- (intestine vs. liver and spleen) dependent.…”