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Title: Investigating the host innate immune response mechanisms to Candida albicans
Author: Yadev, Nishant
ISNI:       0000 0004 2743 348X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2011
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Candida albicans is a commensal fungal organism that forms part of the normal human oral microbial flora. Although very few individuals will ever develop infection from C. albicans, it has the potential to cause a range of serious mucocutaneous infections. In healthy individuals, C. albicans is able to colonise mucosal surfaces as a commensal organism. However, in certain susceptible individuals changes occur within the host to enable C. albicans to go from being a commensal to a pathogen. Little is known about the local host innate immune defence mechanisms of the oral mucosa that are important in providing protection and maintenance of a commensal relationship. The majority of in vitro studies to investigate the host - C. albicans interaction have used an oral mucosal model based on the TR146 buccal cancer cell line, which lacks the presence of a fibroblast containing connective tissue. This mucosa model was compared for suitability against two full thickness oral mucosa models based upon primary cells seeded onto a fibroblast containing connective tissue; one generated 'in house' and the other a commercially available model (MatTek). Normal oral mucosa was used as a comparison. Immunohistochemical staining and infection studies showed that the mucosal model based upon the TR146 buccal cancer cell line resembled least the oral mucosa in vivo, whilst both full thickness oral mucosal models were more advanced and more closely resembled the oral mucosa in vivo. Infection of the full thickness oral mucosa models with a mutant strain of C. albicans, in which morphogenic properties could be controlled, was performed. Over 48 hours, hyphal-infected models displayed high levels of C. albicans invasion and showed a time-dependent increase in cell death compared to yeast-infected models. In addition, hyphal-infected models demonstrated a rapid host response by inducing cytokine release and affecting the expression of a large number of genes, as shown by microarray analysis, in particular those involved with a pro-inflammatory response. In comparison yeast-infected models caused a slower cytokine release response and affected the expression of fewer genes. The hyphal-infected tissue also demonstrated a greater host antimicrobial peptide (human l3-defensin) response when compared to yeast-infected tissue. Overall this study showed that the oral mucosa responds differently to yeast and hyphal forms of C. albicans with respect to gene, cytokine and antimicrobial peptide expression. These data suggested that the oral mucosa may have detected yeast and hyphae using different mechanisms that may initiate different intracellular signalling XI
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available