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.
Highlights
The word toxin according to the definition by Merriam-Webster is “a poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic when introduced into tissues, and typically capable of inducing antibody formation,” which entails the concept of tissue destruction
The repair machinery consists of three main pathways: (i) non-homologous end joining (NHEJ) repair promoted by DNA-PK, which is carried out by ligation of the two broken DNA ends without requiring a repair template; (ii) homologous repair (HR), in which the resynthesis of the damaged region is accomplished using the undamaged sister chromatid as a template [50,51]; and (iii) Fanconi anaemia (FA) pathway to repair DNA inter-strand cross-links
bacterial toxins: (a) genotoxins (BTGXs) and pore-forming toxins (PFTs) have been used as models to highlight that there is a spectrum of outcomes during infections in the host, ranging from killing to a refined hijacking of the tolerance mechanism [16], where the same molecule can act as a natural born killer or a negotiator
Summary
The word toxin according to the definition by Merriam-Webster is “a poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic when introduced into tissues, and typically capable of inducing antibody formation,” which entails the concept of tissue destruction (https: //www.merriam-webster.com/dictionary/toxin#note-1). The pro-inflammatory response mediated by PFTs is linked to their capacity to: (i) induce necrosis or pyroptosis, and the subsequent release of damage-associated molecular pattern (DAMPs) into the extracellular environment [5,10]; (ii) activation of the NLR family pyrin domain-containing 3 (NALP3) inflammasome through diverse mechanisms such as alteration of the ion homeostasis (efflux of potassium K+ and influx of calcium Ca2+), or rupture of the phagosome/lysosome compartments, resulting in release of the proinflammatory cytokines IL1β and IL-18 [11]; (iii) activation of the transcription factor NFκB via induction of Ca2+ oscillation at sublethal doses, leading to transcriptional activation and secretion of a broad panel of pro-inflammatory cytokines, such as IL-6 and IL-8 [12,13] Another interesting aspect of the immunomodulatory effects of PFTs and BTGXs is their anti-inflammatory activity, which goes beyond their capacity to induce cell death in general or in cells of the innate or adaptive immune system [4,14,15]. Three families of genotoxins have been described up to date: the cytolethal distending toxins, the typhoid toxin, and colibactin
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