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Abstract：
AB5-type toxins are a diverse family of protein toxins composed of an enzymatic active (A) subunit and a pentameric delivery (B) subunit. Salmonella enterica serovar Typhi\'s typhoid toxin features two A subunits, CdtB and PltA, in complex with the B subunit PltB. Recently, it was shown that S. Typhi encodes a horizontally acquired B subunit, PltC, that also assembles with PltA/CdtB to produce a second form of typhoid toxin. S. Typhi therefore produces two AB5 toxins with the same A subunits but distinct B subunits, an evolutionary twist that is unique to typhoid toxin. Here, we show that, remarkably, the Salmonella bongori species independently evolved an analogous capacity to produce two typhoid toxins with distinct B subunits. S. bongori\'s alternate B subunit, PltD, is evolutionarily distant from both PltB and PltC and outcompetes PltB to form the predominant toxin. We show that, surprisingly, S. bongori elicits similar levels of CdtB-mediated intoxication as S. Typhi during infection of cultured human epithelial cells. This toxicity is exclusively due to the PltB toxin, and strains lacking pltD produce increased amounts of PltB toxin and exhibit increased toxicity compared to the wild type, suggesting that the acquisition of the PltD subunit potentially made S. bongori less virulent toward humans. Collectively, this study unveils a striking example of convergent evolution that highlights the importance of the poorly understood \"two-toxin\" paradigm for typhoid toxin biology and, more broadly, illustrates how the flexibility of A-B interactions has fueled the evolutionary diversification and expansion of AB5-type toxins.
OBJECTIVE: Typhoid toxin is an important Salmonella Typhi virulence factor and an attractive target for therapeutic interventions to combat typhoid fever. The recent discovery of a second version of this toxin has substantial implications for understanding S. Typhi pathogenesis and combating typhoid fever. In this study, we discover that a remarkably similar two-toxin paradigm evolved independently in Salmonella bongori, which strongly suggests that this is a critical aspect of typhoid toxin biology. We observe significant parallels between how the two toxins assemble and their capacity to intoxicate host cells during infection in S. Typhi and S. bongori, which provides clues to the biological significance of this unusual toxin arrangement. More broadly, AB5 toxins with diverse activities and mechanisms are essential virulence factors for numerous important bacterial pathogens. This study illustrates the capacity for novel A-B interactions to evolve and thus provides insight into how such a diverse arsenal of toxins might have emerged.
OBJECTIVE: Typhoid toxin is an important Salmonella Typhi virulence factor and an attractive target for therapeutic interventions to combat typhoid fever. The recent discovery of a second version of this toxin has substantial implications for understanding S. Typhi pathogenesis and combating typhoid fever. In this study, we discover that a remarkably similar two-toxin paradigm evolved independently in Salmonella bongori, which strongly suggests that this is a critical aspect of typhoid toxin biology. We observe significant parallels between how the two toxins assemble and their capacity to intoxicate host cells during infection in S. Typhi and S. bongori, which provides clues to the biological significance of this unusual toxin arrangement. More broadly, AB5 toxins with diverse activities and mechanisms are essential virulence factors for numerous important bacterial pathogens. This study illustrates the capacity for novel A-B interactions to evolve and thus provides insight into how such a diverse arsenal of toxins might have emerged.
摘要：
AB5型毒素是由酶活性(A)亚基和五聚体递送(B)亚基组成的蛋白质毒素的多样化家族。伤寒沙门氏菌具有两个A亚基，CdtB和PltA,与B亚基PltB复合。最近,研究表明，伤寒沙门氏菌编码一个水平获得的B亚基，PltC,这也与PltA/CdtB组合产生第二种形式的伤寒毒素。因此，伤寒沙门氏菌产生两种具有相同A亚基但不同B亚基的AB5毒素，伤寒毒素特有的进化转折。这里,我们证明，值得注意的是，沙门氏菌bongori物种独立进化出类似的能力，可以产生两种具有不同B亚基的伤寒毒素。S.Bongori的备用B亚基，PltD,在进化上远离PltB和PltC，并超过PltB形成主要毒素。我们证明,令人惊讶的是,在培养的人上皮细胞感染过程中，S.bongori引起的CdtB介导的中毒水平与伤寒沙门氏菌相似。这种毒性完全是由于PltB毒素，和缺乏pltD的菌株产生的pltB毒素的数量增加，并表现出增加的毒性与野生型相比，这表明PltD亚基的获得可能使S.bongori对人类的毒性降低。总的来说，这项研究揭示了趋同进化的一个引人注目的例子，强调了对伤寒毒素生物学知之甚少的“双毒素”范式的重要性，更广泛地说，说明了A-B相互作用的灵活性如何推动了AB5型毒素的进化多样化和扩展。
目的：伤寒毒素是一种重要的伤寒沙门氏菌毒力因子，是防治伤寒的治疗干预措施的一个有吸引力的靶点。该毒素的第二版本的最新发现对于理解伤寒沙门氏菌的发病机理和对抗伤寒具有重要意义。在这项研究中,我们发现在沙门菌中独立进化了一个非常相似的双毒素模式，这强烈表明这是伤寒毒素生物学的一个关键方面。我们观察到两种毒素在伤寒沙门氏菌和S.bongori感染期间如何组装及其使宿主细胞中毒的能力之间的显着相似之处，这为这种不寻常的毒素排列的生物学意义提供了线索。更广泛地说,具有多种活性和机制的AB5毒素是许多重要细菌病原体的必需毒力因子。这项研究说明了新型A-B相互作用进化的能力，从而提供了对这种不同毒素库如何出现的见解。
目的：伤寒毒素是一种重要的伤寒沙门氏菌毒力因子，是防治伤寒的治疗干预措施的一个有吸引力的靶点。该毒素的第二版本的最新发现对于理解伤寒沙门氏菌的发病机理和对抗伤寒具有重要意义。在这项研究中,我们发现在沙门菌中独立进化了一个非常相似的双毒素模式，这强烈表明这是伤寒毒素生物学的一个关键方面。我们观察到两种毒素在伤寒沙门氏菌和S.bongori感染期间如何组装及其使宿主细胞中毒的能力之间的显着相似之处，这为这种不寻常的毒素排列的生物学意义提供了线索。更广泛地说,具有多种活性和机制的AB5毒素是许多重要细菌病原体的必需毒力因子。这项研究说明了新型A-B相互作用进化的能力，从而提供了对这种不同毒素库如何出现的见解。
