Structural Basis for Binding of Neutralizing Antibodies to
Clostridioides difficile
X-ray crystallography
neutralizing antibodies
pore-forming toxins
Journal
Journal of bacteriology
ISSN: 1098-5530
Titre abrégé: J Bacteriol
Pays: United States
ID NLM: 2985120R
Informations de publication
Date de publication:
25 04 2023
25 04 2023
Historique:
medline:
27
4
2023
pubmed:
24
3
2023
entrez:
23
3
2023
Statut:
ppublish
Résumé
Clostridioides difficile is a Gram-positive opportunistic human pathogen that causes 15,000 deaths annually in the United States, prompting a need for vaccine development. In addition to the important toxins TcdA and TcdB, binary toxin (CDT) plays a significant role in the pathogenesis of certain C. difficile ribotypes by catalyzing the ADP-ribosylation of actin in host cells. However, the mechanisms of CDT neutralization by antibodies have not been studied, limiting our understanding of key epitopes for CDT antigen design. Therefore, we isolated neutralizing monoclonal antibodies against CDT and characterized their mechanisms of neutralization structurally and biochemically. Here, 2.5-Å and 2.6-Å resolution X-ray crystal structures of the antibodies BINTOXB/22 and BINTOXB/9, respectively, in complex with CDTb-the CDT subunit that forms a heptameric pore for the delivery of toxic CDTa enzyme into the host cytosol-showed that both antibodies sterically clash with adjacent protomers in the assembled heptamer. Assessment of trypsin-induced oligomerization of the purified CDTb protoxin
Identifiants
pubmed: 36951574
doi: 10.1128/jb.00456-22
pmc: PMC10127577
doi:
Substances chimiques
Bacterial Toxins
0
Antibodies, Neutralizing
0
ADP Ribose Transferases
EC 2.4.2.-
Antibodies, Bacterial
0
Antibodies, Monoclonal
0
Bacterial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0045622Références
J Biol Chem. 2015 May 29;290(22):14031-44
pubmed: 25882847
Nature. 1997 Feb 27;385(6619):833-8
pubmed: 9039918
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1049-1058
pubmed: 31896582
Front Cell Infect Microbiol. 2011 Dec 01;1:11
pubmed: 22919577
PLoS Pathog. 2009 Oct;5(10):e1000626
pubmed: 19834554
Clin Vaccine Immunol. 2013 Mar;20(3):377-90
pubmed: 23324518
Infect Immun. 2007 Jul;75(7):3414-24
pubmed: 17452469
Hybridoma. 1997 Aug;16(4):381-9
pubmed: 9309429
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
N Engl J Med. 2018 Nov 1;379(18):1732-1744
pubmed: 30380384
Clin Infect Dis. 2012 Aug;55 Suppl 2:S65-70
pubmed: 22752867
Biochem Biophys Res Commun. 2002 Jun 21;294(4):835-42
pubmed: 12061783
Gastroenterology. 1978 Nov;75(5):778-82
pubmed: 700321
Toxins (Basel). 2016 May 03;8(5):
pubmed: 27153087
Hum Antibodies. 2004;13(4):105-10
pubmed: 15671576
Infect Immun. 2001 Apr;69(4):2435-41
pubmed: 11254604
BMC Infect Dis. 2019 Nov 7;19(1):940
pubmed: 31699037
Sci Rep. 2015 Jul 02;5:11776
pubmed: 26134518
J Gastrointest Surg. 2013 Jan;17(1):118-24; discussion p.124-5
pubmed: 23086451
Toxins (Basel). 2011 Nov;3(11):1433-52
pubmed: 22174979
CMAJ. 2004 Jul 6;171(1):51-8
pubmed: 15238498
mBio. 2013 Apr 30;4(3):e00244-13
pubmed: 23631918
Nat Commun. 2022 Oct 17;13(1):6119
pubmed: 36253419
Microbiol Spectr. 2019 May;7(3):
pubmed: 31124432
Microbiology (Reading). 1996 Mar;142 ( Pt 3):707-715
pubmed: 8868446
J Infect Dis. 2012 Sep 1;206(5):706-13
pubmed: 22732923
Gut Microbes. 2014 Jan-Feb;5(1):15-27
pubmed: 24253566
Nature. 2015 May 28;521(7553):545-9
pubmed: 25778700
Int J Mol Sci. 2021 Mar 13;22(6):
pubmed: 33805767
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
N Engl J Med. 2010 Jan 21;362(3):197-205
pubmed: 20089970
Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
pubmed: 12393927
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):271-81
pubmed: 21460445
Nat Microbiol. 2020 Jan;5(1):102-107
pubmed: 31712627
Curr Opin Crit Care. 2007 Aug;13(4):450-5
pubmed: 17599017
PLoS One. 2020 Sep 11;15(9):e0232311
pubmed: 32915778
Acta Crystallogr D Biol Crystallogr. 2013 Jul;69(Pt 7):1204-14
pubmed: 23793146
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):519-530
pubmed: 29872003
Lancet Infect Dis. 2014 Dec;14(12):1208-19
pubmed: 25455988
Infect Immun. 1997 Apr;65(4):1402-7
pubmed: 9119480
Elife. 2013 Sep 10;2:e01456
pubmed: 24040512
Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6139-6144
pubmed: 32123082
N Engl J Med. 2015 Feb 26;372(9):825-34
pubmed: 25714160
Clin Microbiol Rev. 2010 Jul;23(3):529-49
pubmed: 20610822