Description of the research
Pathogenic Clostridium difficile strains produce several known virulence factors of which the most well-known are the toxins TcdA and TcdB, and the binary toxin. Toxin expression is positively regulated by the sigma factor TcdR and negatively by the anti-sigma factor TcdC. We investigate the virulence/pathogenesis of C. difficile by characterizing the biochemical properties of TcdC such as dimerization, membrane association, and binding to TcdR. In addition, we aim to identify novel virulence factors through genomic and proteomic approaches. Using these approaches we are also searching for molecular markers that are representative for hypervirulent types of C. difficile. By investigating the signaling pathways and gene networks that regulate these factors and the effects of these factors on the host environment using genetics, molecular biology, cell biology and biochemistry we aim to identify potential targets for the development of novel antibiotics.
- Study the regulation of toxin expression in C. difficile
- Identify novel virulence factors of C. difficile andmolecular markers for C. difficile hypervirulence
- Determine genome wide binding profiles of transcription factors involved in C. difficile virulence and pathogenesis
- Characterize the DNA replication machinery of C. difficile
- Investigate the effect of extracellular C. difficile factors on the host environment
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- Complete genome sequence of the Clostridium difficile laboratory strain 630Δerm reveals differences from strain 630, including translocation of the mobile element CTn5. van Eijk E, Anvar SY, Browne HP, Leung WY, Frank J, Schmitz AM, Roberts AP, Smits WK. BMC Genomics. 2015 Jan 31;16:31. doi: 10.1186/s12864-015-1252-7.
- The HtrA-like protease CD3284 modulates virulence of Clostridium difficile. Bakker D, Buckley AM, de Jong A, van Winden VJ, Verhoeks JP, Kuipers OP, Douce GR, Kuijper EJ, Smits WK, Corver J. Infect Immun. 2014 Oct;82(10):4222-32 doi: 10.1128/IAI.02336-14.
- C. difficile 630Δerm Spo0A regulates sporulation, but does not contribute to toxin production, by direct high-affinity binding to target DNA. Rosenbusch KE, Bakker D, Kuijper EJ, Smits WK. PLoS One. 2012; 7:e48608 doi: 10.1371/journal.pone.0048608.
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- Ilse Boekhoud, MSc - PhD student
- Jeroen Corver, PhD - PI, Molecular Biologist
- Erika van Eijk, MD - PhD student
- Annemieke Friggen, BSc - Technician
- Ed Kuijper, PhD - Medical Microbiologist
- Ana Paiva, MSc - PhD student
- Wiep Klaas Smits, PhD - Assistant professor, Molecular Biologist
- Paul Hensbergen (LUMC)
- Adam Roberts (Liverpool School of Tropical Medicine)
- Brian Mark (University of Manitoba)
- Oleg Klychnikov (KU Leuven)
- Gillian Douce (Glasgow)
- Robert Fagan (University of Sheffield)