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

Abstract

The idea that bacterial toxins are not only killers but also execute more sophisticated roles during bacteria–host interactions by acting as negotiators has been highlighted in the past decades. Depending on the toxin, its cellular target and mode of action, the final regulatory outcome can be different. In this review, we have focused on two families of bacterial toxins: genotoxins and pore-forming toxins, which have different modes of action but share the ability to modulate the host’s immune responses, independently of their capacity to directly kill immune cells. We have addressed their immuno-suppressive effects with the perspective that these may help bacteria to avoid clearance by the host’s immune response and, concomitantly, limit detrimental immunopathology. These are optimal conditions for the establishment of a persistent infection, eventually promoting asymptomatic carriers. This immunomodulatory effect can be achieved with different strategies such as suppression of pro-inflammatory cytokines, re-polarization of the immune response from a pro-inflammatory to a tolerogenic state, and bacterial fitness modulation to favour tissue colonization while preventing bacteraemia. An imbalance in each of those effects can lead to disease due to either uncontrolled bacterial proliferation/invasion, immunopathology, or both.

DNA Damage and the Gut Microbiome: From Mechanisms to Disease Outcomes

“…TT released from bacteria possess endonuclease activities similar to CDT, which can introduce single-strand breaks. [30,34] DNA 2023, 3…”

“…[ 30,31,36] E. coli: Escherichia coli; B. fragilis: Bacteroides fragilis; C. jejuni: Campylobacter jejuni; H. hepaticus: Helicobacter hepaticus; H. pylori: Helicobacter pylori; S. enterica: Salmonella enterica; S. typhi: Salmonella typhi; 8-oxo-dG: 8-hydroxyguanine; CDT: cytolethal distending toxin; pks: polyketide synthase; RNS: reactive nitrogen species; GF: germ free; SPF: specific pathogen-free; TT: typhoid toxin.…”

“…The canonical nomenclature of CDTs uses the initials of the producing bacterium followed by "CDT" (e.g., E. coli CDT as EcCDT) [43]. CDTs are AB 2 dimers, with one of the subunits (CdtB) possessing DNA-cleaving properties similar to DNase I and the other subunits (CdtA and CdtC) as binding components [30]. With the endonuclease activity similar to DNAse I, CDTs primarily and directly induce SSBs.…”

Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies

“…Fusobacterium nucleatum has also been shown to accelerate DNA methylation in cancer-specific genes in patients with UC and appears to inhibit natural killer cell cytotoxicity via the Fap2 protein [169]. Colibactin-producing Escherichia coli (Pks + ) has been shown to mediate cell damage through DNA alkylation and DNA double-strand breaks, contributing to tumorigenesis [110,170]. Colonic inflammation has been shown to further promote the genotoxic effects of Pks + Escherichia coli [171].…”

Visible Light Control over the Cytolytic Activity of a Toxic Pore-Forming Protein

“…Toxins are poisonous substances produced by living organisms, which are present in all kingdoms of life. − A number of known protein-based toxins belong to the pore-forming toxins (PFTs) family. , PFTs are usually produced as water-soluble monomers, with the ability to bind to target membranes and assemble into an oligomeric pore complex, thereby disrupting or perforating the lipid bilayer. , Typically, organisms employ PFTs to gain entry into host cells to acquire nutrition or use PFTs as a defense mechanism. − Of note, the human immune system involves pore-forming proteins in its defense machinery. , Consequently, PFTs are known to play a crucial role in the virulence mechanism of various pathogens. − …”