NDLI: Targeting surface-layer proteins with single-domain antibodies: a potential therapeutic approach against Clostridium difficile-associated disease

Content Provider	Springer Nature Link
Author	Kandalaft, Hiba Hussack, Greg Aubry, Annie Faassen, Henk Guan, Yonghong Arbabi Ghahroudi, Mehdi MacKenzie, Roger Logan, Susan M. Tanha, Jamshid
Copyright Year	2015
Abstract	Clostridium difficile is a leading cause of death from gastrointestinal infections in North America. Antibiotic therapy is effective, but the high incidence of relapse and the rise in hypervirulent strains warrant the search for novel treatments. Surface layer proteins (SLPs) cover the entire C. difficile bacterial surface, are composed of high-molecular-weight (HMW) and low-molecular-weight (LMW) subunits, and mediate adherence to host cells. Passive and active immunization against SLPs has enhanced hamster survival, suggesting that antibody-mediated neutralization may be an effective therapeutic strategy. Here, we isolated a panel of SLP-specific single-domain antibodies (VHHs) using an immune llama phage display library and SLPs isolated from C. difficile hypervirulent strain QCD-32g58 (027 ribotype) as a target antigen. Binding studies revealed a number of VHHs that bound QCD-32g58 SLPs with high affinity (K D = 3–6 nM) and targeted epitopes located on the LMW subunit of the SLP. The VHHs demonstrated melting temperatures as high as 75 °C, and a few were resistant to the gastrointestinal protease pepsin at physiologically relevant concentrations. In addition, we demonstrated the binding specificity of the VHHs to the major C. difficile ribotypes by whole cell ELISA, where all VHHs were found to bind 001 and 027 ribotypes, and a subset of antibodies were found to be broadly cross-reactive in binding cells representative of 012, 017, 023, and 078 ribotypes. Finally, we showed that several of the VHHs inhibited C. difficile QCD-32g58 motility in vitro. Targeting SLPs with VHHs may be a viable therapeutic approach against C. difficile-associated disease.
Starting Page	8549
Ending Page	8562
Page Count	14
File Format	PDF
ISSN	01757598
Journal	Applied Microbiology and Biotechnology
Volume Number	99
Issue Number	20
e-ISSN	14320614
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-05-05
Publisher Place	Berlin, Heidelberg
Access Restriction	Subscribed
Subject Keyword	Clostridium difficile Surface layer protein Single-domain antibody VHH Nanobody Microbiology Microbial Genetics and Genomics Biotechnology
Content Type	Text
Resource Type	Article
Subject	Medicine Applied Microbiology and Biotechnology Biotechnology

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