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Evolution of host adaptation in the Salmonella typhoid toxin

机译：沙门氏菌毒素毒素中宿主适应的演变

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摘要

The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host1-5. Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi6,7, the cause of typhoid fever in humans8-12. Typhoid toxin has a unique A2B5 architecture with two covalently linked enzymatic 'A' subunits, PltA and CdtB, associated with a homopentameric 'B' subunit made up of PltB, which has binding specificity for the N-acetylneuraminic acid (Neu5Ac) sialoglycans6,13 prominently present in humans14. Here, we examine the functional and structural relationship between typhoid toxin and ArtAB, an evolutionary related AB5 toxin encoded by the broad-host Salmonella Typhimurium15. We find that ArtA and ArtB, homologues of PltA and PltB, can form a functional complex with the typhoid toxin CdtB subunit after substitution of a single amino acid in ArtA, while ArtB can form a functional complex with wild-type PltA and CdtB. We also found that, after addition of a single-terminal Cys residue, a CdtB homologue from cytolethal distending toxin can form a functional complex with ArtA and ArtB. In line with the broad host specificity of S. Typhimurium, we found that ArtB binds human glycans, terminated in N-acetylneuraminic acid, as well as glycans terminated in N-glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals14. The atomic structure of ArtB bound to its receptor shows the presence of an additional glycan-binding site, which broadens its binding specificity. Despite equivalent toxicity in vitro, we found that the ArtB/PltA/CdtB chimaeric toxin exhibits reduced lethality in an animal model, indicating that the host specialization of typhoid toxin has optimized its targeting mechanisms to the human host. This is a remarkable example of a toxin evolving to broaden its enzymatic activities and adapt to a specific host.
机译：毒力特征的演变是出苗或重新出现微生物病原体的核心，以及它们适应特定的Host1-5。 Typhoid毒素是人适应的细菌病原体沙门氏菌Typhi6,7的基本毒力因子，在人类8-12中的伤寒原因。 Typhoid毒素具有独特的A2B5架构，其具有两个共价连接的酶促的酶，PLTA和CDTB，与由PLTB组成的同源大众'B'亚基相关，其对N-乙酰甘氨酸（NEU5AC）唾液酸的结合特异性Sialoglycans6,13具有结合特异性在人类14中突出。在这里，我们研究毒黑阴性毒素和ARGAB之间的功能和结构关系，是由广播沙门氏菌的广泛宿主沙门氏菌的进化相关的AB5毒素。我们发现ARTA和ARTB，PLTA和PLTB的同源物，可以在替代ARTA中取代单个氨基酸后的毒素毒素CDTB亚基，而ARTB可以与野生型PLTA和CDTB形成官能复合物。我们还发现，在加入单末端Cys残留物之后，来自细胞素脱光的CDTB同源物可以形成与ARTA和ARTB的官能复合物。符合S. Typhimurium的较大的宿主特异性，我们发现ArtB结合人聚糖，终止于N-乙酰呋喃酸酸，以及终止于N-糖氨酰氨基酸（Neu5GC）的聚糖，其在大多数其他哺乳动物14中表达。与其受体结合的ArtB的原子结构表明存在另外的甘油结合位点，其拓宽其结合特异性。尽管体外等同毒性，但我们发现ArtB / PLTA / CDTB嵌入毒素在动物模型中表现出降低的致死态，表明毒毒素毒素的宿主专业化已经优化了其对人宿主的靶向机制。这是一种显着的毒素演变，以扩大其酶活性并适应特定宿主。

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  • 来源
    《Nature Microbiology》 |2017年第12期|共8页
  • 作者

    Xiang Gao; Lingquan Deng; Gabrielle Stack; Hai Yu; Xi Chen; Yuko Naito-Matsui; Ajit Varki; Jorge E. Galan;

  • 作者单位

    Department of Microbial Pathogenesis Yale University School of Medicine New Haven CT 06536 USA;

    Glycobiology Research and Training Center Departments of Medicine Pathology and Cellular and Molecular Medicine University of California San Diego La Jolla CA 92093 USA;

    Department of Microbial Pathogenesis Yale University School of Medicine New Haven CT 06536 USA;

    Department of Chemistry University of California Davis Davis CA 95616 USA;

    Department of Chemistry University of California Davis Davis CA 95616 USA;

    Glycobiology Research and Training Center Departments of Medicine Pathology and Cellular and Molecular Medicine University of California San Diego La Jolla CA 92093 USA;

    Glycobiology Research and Training Center Departments of Medicine Pathology and Cellular and Molecular Medicine University of California San Diego La Jolla CA 92093 USA;

    Department of Microbial Pathogenesis Yale University School of Medicine New Haven CT 06536 USA;

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  • 正文语种 eng
  • 中图分类 微生物学;
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