A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

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

doi:10.1074/jbc.M117.813428

Title: A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

Journal Article · Mon Nov 27 00:00:00 EST 2017 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M117.813428· OSTI ID:1439617

Kroh, Heather K. ^[1]; Chandrasekaran, Ramyavardhanee ^[1]; Zhang, Zhifen ^[2]; Rosenthal, Kim ^[3]; Woods, Rob ^[3]; Jin, Xiaofang ^[3]; Nyborg, Andrew C. ^[3]; Rainey, G. Jonah ^[3]; Warrener, Paul ^[3]; Melnyk, Roman A. ^[2]; Spiller, Benjamin W. ^[4]; Lacy, D. Borden ^[5]

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)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor Grant

Grant/Contract Number:: S10 RR026915; AC02-06CH11357; 085P1000817

OSTI ID:: 1439617

Journal Information:: Journal of Biological Chemistry, Vol. 293, Issue 3; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 16 works

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Title: A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

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