The risk of oral Candida infection in HIV-positive individuals increases as their CD4 count diminishes. The resulting condition, oral candidiasis, affects approximately 90% of patients with acquired immune deficiency syndrome (AIDS). The mechanism by which Candida species adhere to host tissues, the first step in infection, has not been elucidated. By analogy with eukaryotic cell adhesion, Candida adherence is likely to be a multi- component process that involves several ligand-receptor pairs. Recently, we discovered a novel adhesion mechanism that could be a component of the Candida infection process. We showed that C. tropicalis adheres to lysophospholipids, but not to intact phospholipids. Adherence is accompanied by rapid conversion of the lipid substrate into a number of compounds. Additional experiments showed that several other Candida spp. including C. albicans share this adherence mechanism. Building on the knowledge that lysophospholipids are Candida adhesion receptors, the aims of the proposed experiments are twofold: First, we will isolate Candida's lysophospholipid adhesins and characterize their structures by a combination of biochemical and genetic methods. Experiments in this aim are designed to isolate Candida's lysophospholipid-metabolizing enzymes, which could subserve an adhesin function, as well as to identify novel phospholipid binding proteins. N- terminal and, if necessary, internal peptide sequences of these molecules will be determined. Oligonucleotides synthesized on the basis of derived protein sequence will be used to determine if these molecules are encoded by a single gene or are members of a multigene family. Second, we will use the purified molecules, as well as peptides that correspond to cDNA sequences, to produce antibodies. These reagents will be used to determine whether Candida-lysophospholipid interactions are a component of the mechanism these organisms use to adhere to buccal epithelial cells. We will also determine the effects of these antibodies in culture models that more closely mimic candidal infection of oral mucosa in vivo. It is important to note that we will look beyond the initial adhesive event to determine whether Candida-lysophospholipid interactions also affect differentiation of the adherent organisms. Our eventual goal is to identify molecular components of Candida adherence mechanisms so they can be used as targets in the design of therapeutic agents to treat candidiasis. This is especially important since some Candida strains are becoming resistant to current therapy, such as treatment with azole agents. Prevention of candidiasis in HIV-infected individuals is desirable for several reasons. Oral candidiasis causes discomfort, significantly affecting the quality of life of AIDS patients. In addition, resultant changes in the ability to taste may contribute to weight loss. Finally, understanding mechanisms of Candida adherence within the oral cavity and designing inhibitors of this process is of potential benefit to several other affected populations, including patients with diabetes mellitus and those who wear dentures.
| Hoover, C I; Jantapour, M J; Newport, G et al. (1998) Cloning and regulated expression of the Candida albicans phospholipase B (PLB1) gene. FEMS Microbiol Lett 167:163-9 |
| Prakobphol, A; Leffler, H; Hoover, C I et al. (1997) Palmitoyl carnitine, a lysophospholipase-transacylase inhibitor, prevents Candida adherence in vitro. FEMS Microbiol Lett 151:89-94 |
