Lectin Activity of the TcdA and TcdB Toxins of Clostridium difficile
Lectin Activity of the TcdA and TcdB Toxins of Clostridium difficile
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DOI：
10.1128/iai.00676-18
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发表时间：
2019-03-01
影响因子：
3.1
通讯作者：
Jennings, Michael P.
中科院分区：
文献类型：
--
作者：
Hartley-Tassell, Lauren E.;Awad, Milena M.;Jennings, Michael P.
艰难梭菌是医院获得性抗生素相关性腹泻的主要原因。艰难梭菌产生两种细胞毒素：TcdA和TcdB；这两种毒素都是多结构域蛋白，通过修饰和失活Rho/Rac家族的小gtpase而导致细胞毒性。先前的研究表明，宿主聚糖是TcdA和TcdB的靶标，被认为与α -和β -连接的半乳糖相互作用。在目前的研究中，筛选具有不同TcdA和TcdB结构域的聚糖阵列表明，这两种毒素的结合区域与更广泛的宿主糖缀合物相互作用，而不仅仅是末端α -和β -连接的半乳糖，包括血型、Lewis抗原、n -乙酰氨基葡萄糖、甘露糖和糖胺聚糖。采用表面等离子体共振（SPR）检测TcdA和TcdB与ABO血型和Lewis抗原的相互作用。血型A抗原是这两种毒素的最高亲和力配体。游离聚糖单独或联合使用均不能消除TcdB对Vero细胞的细胞毒性。SPR竞争分析表明，TcdB上存在不止一个聚糖结合位点。宿主糖缀合物是细菌毒素的常见靶标，但这种结合通常是与特定结构或相关结构结合。TcdA和TcdB结合广泛的宿主聚糖，在体内提供广泛的靶细胞和组织。
Clostridium difficile is a major cause of hospital-acquired antibiotic-associated diarrhea. C. difficile produces two cytotoxins, TcdA and TcdB; both toxins are multidomain proteins that lead to cytotoxicity through the modification and inactivation of small GTPases of the Rho/Rac family. Previous studies have indicated that host glycans are targets for TcdA and TcdB, with interactions thought to be with both alpha- and beta-linked galactose. In the current study, screening of glycan arrays with different domains of TcdA and TcdB revealed that the binding regions of both toxins interact with a wider range of host glycoconjugates than just terminal alpha- and beta-linked galactose, including blood groups, Lewis antigens, N-acetylglucosamine, mannose, and glycosaminoglycans. The interactions of TcdA and TcdB with ABO blood group and Lewis antigens were assessed by surface plasmon resonance (SPR). The blood group A antigen was the highest-affinity ligand for both toxins. Free glycans alone or in combination were unable to abolish Vero cell cytotoxicity by TcdB. SPR competition assays indicate that there is more than one glycan binding site on TcdB. Host glycoconjugates are common targets of bacterial toxins, but typically this binding is to a specific structure or related structures. The binding of TcdA and TcdB is to a wide range of host glycans providing a wide range of target cells and tissues in vivo.