Lectin activity of the TcdA and TcdB toxins of Clostridium difficile

Lauren E. Hartley-Tassell, Milena M. Awad, Kate L. Seib, Maria Scarselli, Silvana Savino, Joe Tiralongo, Dena Lyras, Christopher J. Day, Michael P. Jennings

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 - and -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 - and -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.

Original languageEnglish
Article numbere00676-18
Number of pages9
JournalInfection and Immunity
Volume87
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Clostridium difficile
  • Host cell interactions
  • Pathogenesis
  • Toxin-receptor interaction

Cite this

Hartley-Tassell, L. E., Awad, M. M., Seib, K. L., Scarselli, M., Savino, S., Tiralongo, J., ... Jennings, M. P. (2019). Lectin activity of the TcdA and TcdB toxins of Clostridium difficile. Infection and Immunity, 87(3), [e00676-18]. https://doi.org/10.1128/IAI.00676-18
Hartley-Tassell, Lauren E. ; Awad, Milena M. ; Seib, Kate L. ; Scarselli, Maria ; Savino, Silvana ; Tiralongo, Joe ; Lyras, Dena ; Day, Christopher J. ; Jennings, Michael P. / Lectin activity of the TcdA and TcdB toxins of Clostridium difficile. In: Infection and Immunity. 2019 ; Vol. 87, No. 3.
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Hartley-Tassell, LE, Awad, MM, Seib, KL, Scarselli, M, Savino, S, Tiralongo, J, Lyras, D, Day, CJ & Jennings, MP 2019, 'Lectin activity of the TcdA and TcdB toxins of Clostridium difficile' Infection and Immunity, vol. 87, no. 3, e00676-18. https://doi.org/10.1128/IAI.00676-18

Lectin activity of the TcdA and TcdB toxins of Clostridium difficile. / Hartley-Tassell, Lauren E.; Awad, Milena M.; Seib, Kate L.; Scarselli, Maria; Savino, Silvana; Tiralongo, Joe; Lyras, Dena; Day, Christopher J.; Jennings, Michael P.

In: Infection and Immunity, Vol. 87, No. 3, e00676-18, 01.03.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hartley-Tassell, Lauren E.

AU - Awad, Milena M.

AU - Seib, Kate L.

AU - Scarselli, Maria

AU - Savino, Silvana

AU - Tiralongo, Joe

AU - Lyras, Dena

AU - Day, Christopher J.

AU - Jennings, Michael P.

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N2 - 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 - and -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 - and -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.

AB - 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 - and -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 - and -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.

KW - Clostridium difficile

KW - Host cell interactions

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KW - Toxin-receptor interaction

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Hartley-Tassell LE, Awad MM, Seib KL, Scarselli M, Savino S, Tiralongo J et al. Lectin activity of the TcdA and TcdB toxins of Clostridium difficile. Infection and Immunity. 2019 Mar 1;87(3). e00676-18. https://doi.org/10.1128/IAI.00676-18