Wednesday, April 17, 2024
4/17/2024
DESCRIPTION (provided by applicant): Problem: Systemic candidiasis is a serious infection with high mortality. Death results from circulating fungal cells entering the tissues and causing extensive organ damage. The first step in this process is adhesion to the endothelial lining of blood vessels followed by transmigration across the endothelial barrier into the tissues. However, we know little about the mechanisms involved in either of these steps and there is conflicting evidence about the role played by yeast and hyphal forms of Candida albicans in both the adhesion and transmigration process. Background: To date, most in vitro studies exploring candidal adhesion to endothelium have been performed under static conditions although it is clear that adhesion processes are very different under the conditions of flow that occur in blood vessels in vivo. Studying the importance of morphogenetic change in these processes has been difficult, because most mutant strains of C. albicans used in these studies are locked into one or other morphological form and have reduced virulence, while morphogenetic conversion of wild type C. albicans is unpredictable and difficult to control. In preliminary studies, we have developed an engineered stain of C. albicans, SSY50-B, in which we can regulate morphogenetic conversion from yeast to hyphal form whilst maintaining the organism's virulence. Separately we have developed assays that allow us to study the adhesion of cells, particularly leukocytes and tumor cells, to endothelial surfaces under conditions of flow similar to those in blood vessels and to follow their subsequent trans-endothelial migration. Our objective is to bring these technologies together so that we can investigate many of the unanswered questions about how C. albicans moves from the circulation into the tissues in systemic candidiasis. More specifically our aims are: Specific aim 1: To develop an in vitro model that will allow us to study and compare the adhesion characteristics of yeast and hyphal forms of Candida albicans to vascular endothelium under conditions of flow. Specific aim 2: To develop an in vitro model to study the trans-endothelial cell migration of C. albicans under conditions of flow, in order to investigate the role of yeast forms, hyphal forms and morphogenetic conversion in the transmigration process. Public benefit: Systemic Candidiasis is a serious life threatening condition in which circulating fungal cells adhere to and migrate across the endothelial lining of blood vessels to enter the tissues where they cause extensive organ damage. By understand the mechanisms involved in Candida-endothelial adhesion and transmigration, we may be able to inhibit Candida migration into the tissues, prevent the resulting tissue damage and increase the exposure of circulating organisms to anti-fungal agents and the reticuloendothelial system so that they can be destroyed.
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