About the Project
Clostridium difficile, an anaerobic bacterial pathogen, causes C. difficile infection (CDI), a major healthcare-associated challenge worldwide. It is a leading cause of hospital associated diarrhea with high rates of infection in the elderly. C. difficile has also been isolated from multiple animal hosts and is a common cause of diarrhoea in piglets in several parts of the world. The strains that cause disease in pigs were found identical to human isolates, indicating an animal reservoir of C. difficile. Community-acquired CDI has been on the rise in recent years, and studies have suggested that livestock via the environment and/or food.
Colonisation of the gut by C. difficile is an important part of CDI pathogenesis. However, C. difficile colonisation is modulated by the resident microbiota, which confers colonization resistance against invading pathogens. Usually, C. difficile can establish an infection only when the native microbiota is disrupted upon antibiotic treatment. Hence, in addition to interactions with host factors, C. difficile interactions with the native microbiota are key for a successful infection. Identification of novel bacterial factors that modulate colonisation and understanding their mechanism of action during infection is crucial for the development of efficacious therapeutic or preventive strategies.
We recently identified a novel zinc metalloprotease, Zmp1 (proline-proline endopeptidase PPEP-1). Zmp1 is a zinc-dependent enzyme that specifically cleaves mammalian extracellular matrix proteins such as fibronectin, fibrinogen, as well as C. difficile cell wall-associated proteins (2). Zmp1 is believed to modulate the motility and attachment of bacteria through cleaving surface proteins. The precise biological roles of extracellular metalloproteases during C. difficile gut colonisation and interactions with the gut microbiota are currently unclear.
The goal of this study is to investigate the biological functions of secreted metalloproteases in C. difficile-microbiota interactions and during C.difficile infection. This project will involve basic microbiology, infection biology and and advanced analytical approaches, involving techniques like mixed biofilm and infection assays, confocal microscopy, mass spectrometry and in vitro human gut mimics. Elucidating the biological roles of secreted enzymes in the gut will enhance our understanding of clostridial mechanisms of colonisation.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Immunology & Microbiology
Techniques that will be undertaken during the project:
• Anaerobic bacterial culture
• Mixed biofilm assays
• Widefield and confocal microscopy
• biochemical enzymatic assays
• Liquid chromatography-mass spectrometry analysis and data analysis
• mammalian tissue culture
• in vitro infection/ coculture assays
• human gut model studies
2. 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
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