A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells
Abstract
Clostridium difficile infection is the leading cause of hospital-acquired diarrhea and is mediated by the actions of two toxins, TcdA and TcdB. The toxins perturb host cell function through a multistep process of receptor binding, endocytosis, low pH–induced pore formation, and the translocation and delivery of an N-terminal glucosyltransferase domain that inactivates host GTPases. Infection studies with isogenic strains having defined toxin deletions have established TcdB as an important target for therapeutic development. Monoclonal antibodies that neutralize TcdB function have been shown to protect against C. difficile infection in animal models and reduce recurrence in humans. Here, we report the mechanism of TcdB neutralization by PA41, a humanized monoclonal antibody capable of neutralizing TcdB from a diverse array of C. difficile strains. Through a combination of structural, biochemical, and cell functional studies, involving X-ray crystallography and EM, we show that PA41 recognizes a single, highly conserved epitope on the TcdB glucosyltransferase domain and blocks productive translocation and delivery of the enzymatic cargo into the host cell. Furthermore, our study reveals a unique mechanism of C. difficile toxin neutralization by a monoclonal antibody, which involves targeting a process that is conserved across the large clostridial glucosylating toxins. The PA41 antibody describedmore »
- Authors:
-
- Vanderbilt Univ. Medical Center, Nashville, TN (United States)
- Univ. of Toronto, ON (Canada); The Hospital for Sick Children, Toronto, ON (Canada)
- MedImmune LLC, Gaithersburg, MD (United States)
- Vanderbilt Univ. Medical Center, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
- Vanderbilt Univ. Medical Center, Nashville, TN (United States); Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE Office of Science (SC); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor Grant
- OSTI Identifier:
- 1439617
- Grant/Contract Number:
- S10 RR026915; AC02-06CH11357; 085P1000817
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 293; Journal Issue: 3; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; antibody; bacterial pathogenesis; bacterial toxin; electron microscopy (EM); membrane transport; toxin; X-ray crystallography; neutralization
Citation Formats
Kroh, Heather K., Chandrasekaran, Ramyavardhanee, Zhang, Zhifen, Rosenthal, Kim, Woods, Rob, Jin, Xiaofang, Nyborg, Andrew C., Rainey, G. Jonah, Warrener, Paul, Melnyk, Roman A., Spiller, Benjamin W., and Lacy, D. Borden. A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells. United States: N. p., 2017.
Web. doi:10.1074/jbc.M117.813428.
Kroh, Heather K., Chandrasekaran, Ramyavardhanee, Zhang, Zhifen, Rosenthal, Kim, Woods, Rob, Jin, Xiaofang, Nyborg, Andrew C., Rainey, G. Jonah, Warrener, Paul, Melnyk, Roman A., Spiller, Benjamin W., & Lacy, D. Borden. A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells. United States. https://doi.org/10.1074/jbc.M117.813428
Kroh, Heather K., Chandrasekaran, Ramyavardhanee, Zhang, Zhifen, Rosenthal, Kim, Woods, Rob, Jin, Xiaofang, Nyborg, Andrew C., Rainey, G. Jonah, Warrener, Paul, Melnyk, Roman A., Spiller, Benjamin W., and Lacy, D. Borden. Mon .
"A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells". United States. https://doi.org/10.1074/jbc.M117.813428. https://www.osti.gov/servlets/purl/1439617.
@article{osti_1439617,
title = {A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells},
author = {Kroh, Heather K. and Chandrasekaran, Ramyavardhanee and Zhang, Zhifen and Rosenthal, Kim and Woods, Rob and Jin, Xiaofang and Nyborg, Andrew C. and Rainey, G. Jonah and Warrener, Paul and Melnyk, Roman A. and Spiller, Benjamin W. and Lacy, D. Borden},
abstractNote = {Clostridium difficile infection is the leading cause of hospital-acquired diarrhea and is mediated by the actions of two toxins, TcdA and TcdB. The toxins perturb host cell function through a multistep process of receptor binding, endocytosis, low pH–induced pore formation, and the translocation and delivery of an N-terminal glucosyltransferase domain that inactivates host GTPases. Infection studies with isogenic strains having defined toxin deletions have established TcdB as an important target for therapeutic development. Monoclonal antibodies that neutralize TcdB function have been shown to protect against C. difficile infection in animal models and reduce recurrence in humans. Here, we report the mechanism of TcdB neutralization by PA41, a humanized monoclonal antibody capable of neutralizing TcdB from a diverse array of C. difficile strains. Through a combination of structural, biochemical, and cell functional studies, involving X-ray crystallography and EM, we show that PA41 recognizes a single, highly conserved epitope on the TcdB glucosyltransferase domain and blocks productive translocation and delivery of the enzymatic cargo into the host cell. Furthermore, our study reveals a unique mechanism of C. difficile toxin neutralization by a monoclonal antibody, which involves targeting a process that is conserved across the large clostridial glucosylating toxins. The PA41 antibody described here provides a valuable tool for dissecting the mechanism of toxin pore formation and translocation across the endosomal membrane.},
doi = {10.1074/jbc.M117.813428},
journal = {Journal of Biological Chemistry},
number = 3,
volume = 293,
place = {United States},
year = {Mon Nov 27 00:00:00 EST 2017},
month = {Mon Nov 27 00:00:00 EST 2017}
}
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