Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
mBio. 2024 Apr 10;15(4):e0340323. doi: 10.1128/mbio.03403-23. Epub 2024 Mar 19.
AB-type toxins are a diverse family of protein toxins composed of an enzymatic active (A) subunit and a pentameric delivery (B) subunit. serovar Typhi's typhoid toxin features two A subunits, CdtB and PltA, in complex with the B subunit PltB. Recently, it was shown that . Typhi encodes a horizontally acquired B subunit, PltC, that also assembles with PltA/CdtB to produce a second form of typhoid toxin. . Typhi therefore produces two AB 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 species independently evolved an analogous capacity to produce two typhoid toxins with distinct B subunits. '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, elicits similar levels of CdtB-mediated intoxication as . Typhi during infection of cultured human epithelial cells. This toxicity is exclusively due to the PltB toxin, and strains lacking 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 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 AB-type toxins.
Typhoid toxin is an important 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 . Typhi pathogenesis and combating typhoid fever. In this study, we discover that a remarkably similar two-toxin paradigm evolved independently in , 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 . Typhi and , 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.
AB 型毒素是一组由酶活性 (A) 亚基和五聚体输送 (B) 亚基组成的具有多样性的蛋白毒素。伤寒血清型的伤寒毒素具有两个 A 亚基，CdtB 和 PltA，与 B 亚基 PltB 形成复合物。最近，研究表明，伤寒杆菌编码一种水平获得的 B 亚基 PltC，它也与 PltA/CdtB 组装，产生第二种形式的伤寒毒素。因此，伤寒杆菌产生两种具有相同 A 亚基但不同 B 亚基的 AB 毒素，这种进化上的转变是伤寒毒素所特有的。在这里，我们表明，令人惊讶的是，物种独立进化出了产生两种具有不同 B 亚基的类似伤寒毒素的能力。的替代 B 亚基 PltD 与 PltB 和 PltC 在进化上相距甚远，并且与 PltB 竞争形成主要毒素。我们表明，令人惊讶的是，在感染培养的人上皮细胞时， 会引起类似于伤寒杆菌的 CdtB 介导的中毒。这种毒性完全是由 PltB 毒素引起的，并且缺乏 的菌株会产生更多量的 PltB 毒素，并表现出比野生型更高的毒性，这表明 PltD 亚基的获得可能使 对人类的毒力降低。总的来说，这项研究揭示了一个惊人的趋同进化的例子，强调了对伤寒毒素生物学了解甚少的“双毒素”范例的重要性，更广泛地说明了 A-B 相互作用的灵活性如何推动了 AB 型毒素的进化多样化和扩展。
伤寒毒素是伤寒血清型的重要毒力因子，也是治疗干预伤寒热的有吸引力的靶标。最近发现这种毒素的第二种版本对理解伤寒血清型的发病机制和对抗伤寒热具有重要意义。在这项研究中，我们发现了一个非常相似的双毒素范例在 中独立进化，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组装方式和在感染过程中使宿主细胞中毒的能力方面存在显著相似性，这为了解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，具有不同活性和机制的 AB5 毒素是许多重要细菌病原体的重要毒力因子。这项研究说明了新的 A-B 相互作用的进化能力，从而提供了对这种多样化的毒素武器库如何出现的洞察。
