Selection of nanobodies that block the enzymatic and cytotoxic activities of the binary clostridium difficile toxin CDT

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Unger, Mandy ^a   Eichhoff, Anna Marei ^a   Schumacher, Lucas ^a   Strysio, Moritz ^a   Menzel, Stephan ^a   Schwan, Carsten ^b   Alzogaray, Vanina ^c   Zylberman, Vanesa ^d   Seman, Michel ^e   Brandner, Johanna ^a   Rohde, Holger ^a   Zhu, Kai ^f   Haag, Friedrich ^a   Mittrücker, Hans Willi ^a   Goldbaum, Fernando ^c   Aktories, Klaus ^b   Koch Nolte, Friedrich ^a  

^a UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^b UNIVERSITY OF FREIBURG   (Germany)

^c FUNDACIÓN INSTITUTO LELOIR   (Argentina)

^d Inmunova ^*  (Argentina)

^e UNIVERSITY OF ROUEN   (France)

^f SCHRÖDINGER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIN; ACTIN-SPECIFIC ADP-RIBOSYLTRANSFERASE, CLOSTRIDIUM; BACTERIAL PROTEIN; EPITOPE; NANOBODY; NEUTRALIZING ANTIBODY; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROTEIN SUBUNIT; RECOMBINANT PROTEIN;

AMINO ACID SEQUENCE; ANIMAL; BIOSYNTHESIS; CELL SURVIVAL; DOG; DRUG EFFECTS; EPITOPE MAPPING; GENETICS; HT-29 CELL LINE; HUMAN; IMMUNOLOGY; INTERFERENCE MICROSCOPY; MDCK CELL LINE; METABOLISM; MOLECULAR GENETICS; PATHOGENICITY; PEPTOCLOSTRIDIUM DIFFICILE; PROTEIN SUBUNIT; PROTEIN TERTIARY STRUCTURE;

ACTINS; ADP RIBOSE TRANSFERASES; AMINO ACID SEQUENCE; ANIMALS; ANTIBODIES, NEUTRALIZING; BACTERIAL PROTEINS; CELL SURVIVAL; CLOSTRIDIUM DIFFICILE; DOGS; EPITOPE MAPPING; EPITOPES; HT29 CELLS; HUMANS; MADIN DARBY CANINE KIDNEY CELLS; MICROSCOPY, INTERFERENCE; MOLECULAR SEQUENCE DATA; PROTEIN STRUCTURE, TERTIARY; PROTEIN SUBUNITS; RECOMBINANT PROTEINS; SINGLE-DOMAIN ANTIBODIES;

EID: 84923076304     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep07850     Document Type: Article

References (65)

1. Rupnik, M., Wilcox, M. H. & Gerding, D. N. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7, 526-536 (2009).
2. Huttunen, R., Vuento, R., Syrjanen, J., Tissari, P. & Aittoniemi, J. Case fatality associated with a hypervirulent strain in patients with culture-positive Clostridium difficile infection: a retrospective population-based study. Int J Infect Dis 16, e532-535 (2012).
3. Kelly, C. P.&LaMont, J. T. Clostridium difficile-more difficult than ever. N Engl J Med 359, 1932-1940 (2008).
4. Perelle, S., Gibert, M., Bourlioux, P., Corthier, G. & Popoff, M. R. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect Immun 65, 1402-1407 (1997).
5. Busch, C. & Aktories, K. Microbial toxins and the glycosylation of rho family GTPases. Curr Opin Struct Biol 10, 528-535 (2000).
6. Viswanathan, V. K., Mallozzi, M. J. & Vedantam, G. Clostridium difficile infection: An overview of the disease and its pathogenesis, epidemiology and interventions. Gut Microbes 1, 234-242 (2010).
7. Kuehne, S. A. et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature 467, 711-713 (2010).
8. Lyras, D. et al. Toxin B is essential for virulence of Clostridium difficile. Nature 458, 1176-1179 (2009).
9. Bakker, D. et al. Relatedness of human and animal Clostridium difficile PCR ribotype 078 isolates determined on the basis of multilocus variable-number tandem-repeat analysis and tetracycline resistance. J Clin Microbiol 48, 3744-3749 (2010).
10. Kyne, L. Clostridium difficile-beyond antibiotics. N Engl J Med 362, 264-265 (2010).
11. McDonald, L. C. et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 353, 2433-2441 (2005).
12. Gerding, D. N., Johnson, S., Rupnik, M.& Aktories, K. Clostridium difficile binary toxin CDT: Mechanism, epidemiology, and potential clinical importance. Gut Microbes 5, 15-27 (2013).
13. Gulke, I. et al. Characterization of the enzymatic component of the ADPribosyltransferase toxin CDTa from Clostridium difficile. Infect Immun 69, 6004-6011 (2001).
14. Schwan, C. et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 5, e1000626 (2009).
15. Schwan, C. et al. Cholesterol- and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase (CDT). J Biol Chem 286, 29356-29365 (2011).
16. Aktories, K. et al. Botulinum C2 toxin ADP-ribosylates actin. Nature 322, 390-392 (1986).
17. Barth, H., Aktories, K., Popoff, M. R. & Stiles, B. G. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol Mol Biol Rev 68, 373-402 (2004).
18. Papatheodorou, P. et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A 108, 16422-16427 (2011).
19. Lowy, I. et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362, 197-205 (2010).
20. Hamers-Casterman, C. et al.Naturally occurring antibodies devoid of light chains. Nature 363, 446-448 (1993).
21. Wesolowski, J. et al. Single domain antibodies: promising experimental and therapeutic tools in infection and immunity. Med Microbiol Immunol 198, 157-174 (2009).
22. Muyldermans, S. Nanobodies: natural single-domain antibodies. Annu Rev Biochem 82, 775-797 (2013).
23. Lauwereys, M. et al. Potent enzyme inhibitors derived from dromedary heavychain antibodies. EMBO J 17, 3512-3520 (1998).
24. De Genst, E. et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc Natl Acad Sci U S A 103, 4586-4591 (2006).
25. Tijink, B. M. et al. Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology. Mol Cancer Ther 7, 2288-2297 (2008).
26. Hussack, G. et al. Neutralization of Clostridium difficile toxin A with singledomain antibodies targeting the cell receptor binding domain. J Biol Chem 286, 8961-8976 (2010).
27. Schirrmann, T. & Büssow, K. Transient Production of scFv-Fc Fusion Proteins in Mammalian Cells. in Antibody Engineering Vol. 2. (eds. R. Kontermann & S. Dübel) 387-398 (Springer-Verlag, Berlin Heidelberg; 2010).
28. Zhang, J., MacKenzie, R. & Durocher, Y. Production of chimeric heavy-chain antibodies. Methods Mol Biol 525, 323-336 (2009).
29. Koch-Nolte, F. et al. Single domain antibodies from llama effectively and specifically block T cell ecto-ADP-ribosyltransferase ART2.2 in vivo. Faseb J 21, 3490-3498 (2007).
30. Desmyter, A. et al. Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme. Nat Struct Biol 3, 803-811 (1996).
31. Sundriyal, A., Roberts, A. K., Shone, C. C. & Acharya, K. R. Structural basis for substrate recognition in the enzymatic component of ADP-ribosyltransferase toxin CDTa from Clostridium difficile. J Biol Chem 284, 28713-28719 (2009).
32. Tsuge, H. et al. Structural basis of actin recognition and arginine ADPribosylation by Clostridium perfringens iota-toxin. Proc Natl Acad Sci U S A 105, 7399-7404 (2008).
33. Davies, A. H., Roberts, A. K., Shone, C. C. & Acharya, K. R. Super toxins from a super bug: structure and function of Clostridium difficile toxins. Biochem J 436, 517-526 (2011).
34. Stiles, B. G.,Wigelsworth,D. J., Popoff, M. R.&Barth, H. Clostridial binary toxins: iota and C2 family portraits. Front Cell Infect Microbiol 1, 11 (2011).
35. Young, J. A. & Collier, R. J. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 76, 243-265 (2007).
36. Feld, G. K. et al. Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers. Nat Struct Mol Biol 17, 1383-1390 (2010).
37. Tang, J. C. et al. A nanobody-based system using fluorescent proteins as scaffolds for cell-specific gene manipulation. Cell 154, 928-939 (2013).
38. Kirchhofer, A. et al. Modulation of protein properties in living cells using nanobodies. Nat Struct Mol Biol 17, 133-138 (2010).
39. Alzogaray, V. et al. Single-domain llama antibodies as specific intracellular inhibitors of SpvB, the actin ADP-ribosylating toxin of Salmonella typhimurium. Faseb J 25, 526-534 (2011).
40. Klein, F. et al.HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118-122 (2012).
41. Tutykhina, I. L. et al. Passive immunization with a recombinant adenovirus expressing anHA(H5)-specific single-domain antibody protects mice from lethal influenza infection. Antiviral Res 97, 318-328 (2013).
42. Barth, H. & Stiles, B. G. Binary actin-ADP-ribosylating toxins and their use as molecular Trojan horses for drug delivery into eukaryotic cells. Curr Med Chem 15, 459-469 (2008).
43. Theiss, A. L. et al. Nanoparticle-based therapeutic delivery of prohibitin to the colonic epithelial cells ameliorates acute murine colitis. Inflamm Bowel Dis 17, 1163-1176 (2011).
44. Carman, R. J. et al. Clostridium difficile binary toxin (CDT) and diarrhea. Anaerobe 17, 161-165 (2011).
45. Cartman, S. T., Heap, J. T., Kuehne, S. A., Cockayne, A. & Minton, N. P. The emergence of 'hypervirulence' in Clostridium difficile. Int J Med Microbiol 300, 387-395 (2010).
46. Stewart, D. B., Berg, A. & Hegarty, J. Predicting recurrence of C. difficile colitis using bacterial virulence factors: binary toxin is the key. J Gastrointest Surg 17, 118-124 (2013).
47. Marsh, J. W. & Curry, S. R. Therapeutic Approaches for Clostridium difficile Infections. Curr Protoc Microbiol 30, 9A 3 1-9 (2013).
48. Cocanour, C. S. Best strategies in recurrent or persistent Clostridium difficile infection. Surg Infect (Larchmt) 12, 235-239 (2011).
49. Khoruts, A. & Sadowsky, M. J. Therapeutic transplantation of the distal gut microbiota. Mucosal Immunol 4, 4-7 (2011).
50. Brandt, L. J. et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 107, 1079-1087 (2012).
51. Andersen, J. T. & Sandlie, I. The versatile MHC class I-related FcRn protects IgG and albumin from degradation: implications for development of new diagnostics and therapeutics. Drug Metab Pharmacokinet 24, 318-332 (2009).
52. Chen, K. et al. Endocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo. Blood 120, 4421-4431 (2012).
53. Van Bockstaele, F., Holz, J. B. & Revets, H. The development of nanobodies for therapeutic applications. Curr Opin Investig Drugs 10, 1212-1224 (2009).
54. Laroui, H. et al. Drug-loaded nanoparticles targeted to the colon with polysaccharide hydrogel reduce colitis in a mouse model. Gastroenterology 138, 843-853 (2010).
55. Hussack, G., Hirama, T., Ding, W., Mackenzie, R. & Tanha, J. Engineered singledomain antibodies with high protease resistance and thermal stability. PLoS One 6, e28218 (2011).
56. Andersen, K. K., Marcotte, H., Alvarez, B., Boyaka, P. N. & Hammarstrom, L. In situ gastrointestinal protection against anthrax edema toxin by single-chain antibody fragment producing lactobacilli. BMC Biotechnol 11, 126 (2011).
57. Vandenbroucke, K. et al. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol 3, 49-56 (2010).
58. Barth, H. et al. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J Biol Chem 275, 18704-18711 (2000).
59. Boersma, W. J., Bogaerts, W. J., Bianchi, A. T. & Claassen, E. Adjuvant properties of stable water-in-oil emulsions: evaluation of the experience with Specol. Res Immunol 143, 503-512 (1992).
60. Daley, L. P., Gagliardo, L. F., Duffy, M. S., Smith, M. C. & Appleton, J. A. Application of monoclonal antibodies in functional and comparative investigations of heavy-chain immunoglobulins in new world camelids. Clin Diagn Lab Immunol 12, 380-386 (2005).
61. Zarebski, L. M.,Urrutia, M. & Goldbaum, F. A. Llama single domain antibodies as a tool for molecular mimicry. J Mol Biol 349, 814-824 (2005).
62. Gekle, M., Wunsch, S., Oberleithner, H. & Silbernagl, S. Characterization of two MDCK-cell subtypes as amodel system to study principal cell and intercalated cell properties. Pflugers Arch 428, 157-162 (1994).
63. Zhu, K. et al. Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction. Proteins 82, 1646-1655 (2014).
64. Kozakov, D., Brenke, R., Comeau, S. R. & Vajda, S. PIPER: an FFT-based protein docking program with pairwise potentials. Proteins 65, 392-406 (2006).
65. Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27, 221-234 (2013).