Abstract
Bacterial genotoxins (BTGX) induce DNA damage, which results in senescence or apoptosis of the target cells if not properly repaired. Three BTGXs have been identified: the cytolethal distending toxin (CDT) family produced by several Gram-negative bacteria, the typhoid toxin produced by several Salmonella enterica serovars, and colibactin, a peptide-polyketide, produced mainly by the phylogenetic group B2 Escherichia coli. The cellular responses induced by BTGXs resemble those of well-characterized carcinogenic agents, and several lines of evidence indicate that bacteria carrying genotoxin genes can contribute to tumor development under specific circumstances. Given their unusual mode of action, it is still enigmatic why these effectors have been acquired by microbes and what is their role in the context of the biology of the producing bacterium, since it is unlikely that their primary purpose is to induce/promote cancer in the mammalian host. In this review, we will discuss the possibility that the DNA damage induced by BTGX modulates the host immune response, acting as immunomodulator, leading to the establishment of a suitable niche for the producing bacterium. We will further highlight open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.
Highlights
We propose that some bacteria produce DNA damaging toxins, i.e. Bacterial genotoxins (BTGX), to modulate the host immune response with the final goal to establish a suitable niche for their replication and spread
The interplay between the DNA damage response (DDR) and the immune response (IR) may explain the puzzle regarding BTGXs, a family of effectors that cause DNA damage and senescence in most cell types in vitro and in vivo: a response that has a strong impact in the surrounding tissue microenvironment
These toxins have been shown to possess carcinogenic properties, it is unlikely that bacteria have acquired these effectors to induce/promote cancer in the mammalian host
Summary
Bacteria have acquired a broad array of toxins, which are key virulence factors to ensure host colonization, invasion, and escape from the immune response, allowing replication and spread to a new host or the surrounding environment. Toxins target all the key compartments of the host eukaryotic cells: plasma membrane, cytoskeleton, protein synthesis, intracellular signaling, and even DNA [1] The latter activity is mediated by a family of toxins that are functional homologous to mammalian DNAse I: the cytolethal distending toxin (CDT) and the typhoid toxin, which promote DNA single (SSB) and double strand break (DSB) in the target cells [2]. An additional effector that causes DNA damage, by inducing DNA interstrand cross-links is colibactin, the product of the psk island, present in group B2 E. coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Citrobacter koseri [5] These toxins will be defined in this review as bacterial genotoxins (BTGX). An answer that may be extended to other bacteria that induce DNA damage: (i) directly via activation of host endonucleases XPF and XPG (Helicobacter pylori); (ii) indirectly by downregulation of components of pathways that repair oxidative stress-induced damage or nucleotide mismatch (e.g., H. pylori), or inhibition of effectors of the DNA damage response (DDR) (e.g., Chlamydia trachomatis, Listeria monocytogenes) [6]
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