Area(s) of interest
- Molecular bacteriology
- Clostridium difficile virulence
- Mechanism of action of Clostridium difficile toxins
Department of Medical Microbiology
PI Molecular biology of Clostridium difficile
Clostridium difficile is the main cause of nosocomial diarrhoea. Since the appearance of the hypervirulent ribotype 027, the number of CDI (C. difficile infection) patients has increased dramatically. Not only the number of patients has risen, also the severity of the symptoms and complications of the disease has increased. In recent years, numerous countries have reported outbreaks caused by the 027 ribotype, with a steep increase in the morbidity and the mortality. Recently, another hypervirulent ribotype, 078, has emerged in the Netherlands, the United Kingdom and the United States. This type is typically not acquired in the hospital, but in the community.
Well known virulence factors for C. difficile are the two large clostridial toxins, TcdA and TcdB and the binary toxin.
We study factors that help the bacteria survive in the host. More specifically, we study several proteases that are involved in the stress response in Clostridium difficile and a protease that regulates the amount of surface proteins involved in binding of Clostridium difficile to the host cells.
Jeroen Corver got his Master degree in plant pathology at the Agricultural University in Wageningen. His major was Molecular biology and Physiology aspects of Crop Protection, with an emphasis on molecular virology. Subsequently, he got his PhD at the Medical School of Groningen University. The title of his thesis was “Membrane fusion activity of Semliki Forest virus” and was written under supervision of Dr. Jan Wilschut at the department of Physiological Chemistry. Then, he moved to the United States to work in the lab of Prof. Dr. James Strauss at the California Institute of Technology in Pasadena. His research topic there was structure and molecular biology of flaviviruses. After three years abroad, he returned to the Netherlands to work at the Leiden University Medical Center. At the department of medical microbiology, under supervision of Prof. Dr. Willy Spaan, he worked on the molecular biology of hepatitis C virus entry and the molecular biology and biochemistry of the SARS Coronavirus spike protein. Since 2007, he has switched from virology to bacteriology to work on the virulence of Clostridium difficile in the group of Prof. Dr. Ed Kuijper.
Corver J, Cordó V, van Leeuwen HC, Klychnikov OI, Hensbergen PJ. Covalent attachment and Pro-Pro endopeptidase (PPEP-1)-mediated release of Clostridium difficile cell surface proteins involved in adhesion. Mol Microbiol. 2017 Sep;105(5):663-673.
Dedic E, Alsarraf H, Welner DH, Østergaard O, Klychnikov OI, Hensbergen PJ, Corver J, van Leeuwen HC, Jørgensen R. A Novel Fic (Filamentation Induced by cAMP) Protein from Clostridium difficile Reveals an Inhibitory Motif-independent Adenylylation/AMPylation Mechanism. J Biol Chem. 2016 Jun 17;291(25):13286-300.
Hensbergen PJ, Klychnikov OI, Bakker D, Dragan I, Kelly ML, Minton NP, Corver J, Kuijper EJ, Drijfhout JW, van Leeuwen HC. Clostridium difficile secreted Pro-Pro endopeptidase PPEP-1 (ZMP1/CD2830) modulates adhesion through cleavage of the collagen binding protein CD2831. FEBS Lett. 2015 Dec 21;589(24 Pt B):3952-8.
Bakker D, Buckley AM, de Jong A, van Winden VJ, Verhoeks JP, Kuipers OP, Douce GR, Kuijper EJ, Smits WK, Corver J. The HtrA-like protease CD3284 modulates virulence of Clostridium difficile. Infect Immun. 2014 Oct;82(10):4222-32.
Knetsch CW, Connor TR, Mutreja A, van Dorp SM, Sanders IM, Browne HP, Harris D, Lipman L, Keessen EC, Corver J, Kuijper EJ, Lawley TD. Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill. 2014 Nov 13;19(45):20954.
Hensbergen PJ, Klychnikov OI, Bakker D, van Winden VJ, Ras N, Kemp AC, Cordfunke RA, Dragan I, Deelder AM, Kuijper EJ, Corver J, Drijfhout JW, van Leeuwen HC. A novel secreted metalloprotease (CD2830) from Clostridium difficile cleaves specific proline sequences in LPXTG cell surface proteins. Mol Cell Proteomics. 2014 May;13(5):1231-44.
Knetsch CW, Lawley TD, Hensgens MP, Corver J, Wilcox MW, Kuijper EJ. Current application and future perspectives of molecular typing methods to study Clostridium difficile infections. Euro Surveill. 2013; 18:20381.
van Leeuwen HC, Bakker D, Steindel P, Kuijper EJ, Corver J. Clostridium difficile TcdC protein binds to four-stranded G-quadruplex structures. Nucleic Acids Res. 2013; 41:2382-93.
Bakker D, Smits WK, Kuijper EJ, Corver J. TcdC does not significantly repress toxin expression in Clostridium difficile 630Δerm. PLoS One. 2012; 7:e43247.
Goorhuis A, Bakker D, Corver J, Debast SB, Harmanus C, Notermans DW, Bergwerff AA, Dekker FW, Kuijper EJ. Emergence of Clostridium difficile infection due to a new hypervirulent strain, PCR-ribotype 078. Clin Infect Dis. 2008; 47:1162-70.
Leiden University Medical Center
2333 ZA Leiden
P.O. Box 9600
2300 RC Leiden