Candida albicans is a commensal of mucosal surfaces of the body but becomes infectious when the host is compromised. There is considerable data which indicate that the organism is more than just a passive participant in the establishment of disease. Among its virulence attributes, both blastoconidia and hyphal forms possess cell surface mannoproteins which provide an adhesin function. One of these adhesions has properties similar to the beta-2 integrins of mammalian cells. Our laboratory has focused upon a cell surface mannoprotein of hyphae (H60) which recognizes C3 complement ligands such as C3bi and C3d. This protein, because it bind C3bi, likewise, has a beta-2 integrin activity. We have purified this protein and partially completed the isolation and sequencing of the encoding gene. We have established that mutants with reduced adhesion activity are also less virulent. The experiments described in this application are extensions of our initial observations. There are 2 specific aims.
In Specific aim 1, we will complete the sequencing of the H60. Thus far, we have used a human B-cell VR2 gene fragment to clone the Candida H60. Additionally, peptide sequence of the H60 as well as a functionally similar protein from yeast (Y500 are being used to construct oligos to screen Candida libraries. Additional emphasis will be placed upon the isolation of a Candida lectin-like protein (and gene) which has been suggested as an adhesion for epithelial cells. Thus, we will be able to determine if both activities (beta-2 integrin and lectin) are associated with a single gene product.
Specific aim 2 focuses upon our recent observation that c. albicans expresses new proteins only when adhering to human buccal epithelial cells (HBEC). We will identify these proteins, isolate their genes and determine if signal transduction events specific to adherence occur in Candida. The observations from this research should provide new information on some of the molecular and biochemical events that are essential to the establishment of disease by this organism.
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