The bacterial ADP-ribosylating exotoxins are produced by bacteria and infect different human body tissues.Herein,we investigated the molecular evolution of AB5-type bacterial toxins expressed by Vibrio cholerae and other bacteria with similar invasion mechanisms to interpret the co-evolutionary history of V.cholerae cholera toxin(CT)and their hosts,aiming to reveal the causes of its transdermal immuno-genicity.We elaborated on the intracellular toxicity mechanisms of CT,including ganglioside receptor-mediated endocytosis and hyperactivation of the cAMP pathway,as well as the behavioral traces of related bacteriophages within the genomes of these bacteria.Models such as the relatively decoupled evolution of A and B subunits of CT and the evolutionary coupling of transdermal and mucosal immunity were summa-rized.Furthermore,we described mechanisms including phage-mediated horizontal gene transfer(exem-plified by Vibrio phage CTXΦ),toxin targeting variation,expansion of molecular recognition domains,and functional adaptive evolution of the toxins.In this research,we employed bioinformatic tools to con-struct phylogenetic trees and analyze genetic variations in the amino acid sequences of toxin A/B subunits and proteins of secretion systems.Tajima's test was utilized to quantify genetic distance,diversity,and neutral selection pressure.Key findings include:(1)a"decoupled evolution"mode for the A and B subunits of CT,with the B subunit under stronger negative selection;(2)horizontal gene transfer media-ted by CTXΦ and other phages drives the cross-species spread of toxin genes;(3)the interaction be-tween the toxin co-regulated pilus(TCP)and the TLR-5(Toll-like receptor 5)promotes the transdermal immunogenicity of the CT B subunit.These findings suggest the role of"toxin-host arm race"co-evolu-tion,and are consistent with the hypothesis of intergenerational transmission of immune memory in CT e-volution,thereby providing theoretical support for further research into the biological mechanisms and co-evolutionary history of AB5-type bacterial toxins.

The bacterial ADP-ribosylating exotoxins are produced by bacteria and infect different human body tissues.Herein,we investigated the molecular evolution of AB5-type bacterial toxins expressed by Vibrio cholerae and other bacteria with similar invasion mechanisms to interpret the co-evolutionary history of V.cholerae cholera toxin(CT)and their hosts,aiming to reveal the causes of its transdermal immuno-genicity.We elaborated on the intracellular toxicity mechanisms of CT,including ganglioside receptor-mediated endocytosis and hyperactivation of the cAMP pathway,as well as the behavioral traces of related bacteriophages within the genomes of these bacteria.Models such as the relatively decoupled evolution of A and B subunits of CT and the evolutionary coupling of transdermal and mucosal immunity were summa-rized.Furthermore,we described mechanisms including phage-mediated horizontal gene transfer(exem-plified by Vibrio phage CTXΦ),toxin targeting variation,expansion of molecular recognition domains,and functional adaptive evolution of the toxins.In this research,we employed bioinformatic tools to con-struct phylogenetic trees and analyze genetic variations in the amino acid sequences of toxin A/B subunits and proteins of secretion systems.Tajima's test was utilized to quantify genetic distance,diversity,and neutral selection pressure.Key findings include:(1)a"decoupled evolution"mode for the A and B subunits of CT,with the B subunit under stronger negative selection;(2)horizontal gene transfer media-ted by CTXΦ and other phages drives the cross-species spread of toxin genes;(3)the interaction be-tween the toxin co-regulated pilus(TCP)and the TLR-5(Toll-like receptor 5)promotes the transdermal immunogenicity of the CT B subunit.These findings suggest the role of"toxin-host arm race"co-evolu-tion,and are consistent with the hypothesis of intergenerational transmission of immune memory in CT e-volution,thereby providing theoretical support for further research into the biological mechanisms and co-evolutionary history of AB5-type bacterial toxins.