Abstract
Clostridioides (formerly Clostridium) difficile is a Gram-positive, spore-forming anaerobe and a leading cause of hospital-acquired infection and gastroenteritis-associated death in US hospitals1. The disease state is usually preceded by disruption of the host microbiome in response to antibiotic treatment and is characterized by mild to severe diarrhoea. C. difficile infection is dependent on the secretion of one or more AB-type toxins: toxin A (TcdA), toxin B (TcdB) and the C. difficile transferase toxin (CDT)2. Whereas TcdA and TcdB are considered the primary virulence factors, recent studies suggest that CDT increases the severity of C. difficile infection in some of the most problematic clinical strains3. To better understand how CDT functions, we used cryo-electron microscopy to define the structure of CDTb, the cell-binding component of CDT. We obtained structures of several oligomeric forms that highlight the conformational changes that enable conversion from a prepore to a β-barrel pore. The structural analysis also reveals a glycan-binding domain and residues involved in binding the host-cell receptor, lipolysis-stimulated lipoprotein receptor. Together, these results provide a framework to understand how CDT functions at the host cell interface.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 102-107 |
| Number of pages | 6 |
| Journal | Nature Microbiology |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:The authors thank J. Fitzpatrick and M. Rau (both Washington University), and S. Collier and E. Binshtein (both Vanderbilt University) for their assistance with cryo-EM data collection, and B. Spiller and members of the Lacy laboratory for critical feedback. Flow Cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource, which is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). This work was supported by United States Department of Veterans Affairs Award BX002943, Public Health Service grant AI095755 from the National Institutes of Health, and Vanderbilt University. M.J.S. and J.L.J. are supported by the Training Grant in Gastroenterology (DK007673). A portion of the molecular graphics and analyses was performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at University of California, San Francisco, with support from NIH P41-GM103311.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.