ABC Transporters and Pathogenicity of Candida albicans. ABC transporters form a superfamily of ubiquitous membrane proteins involved in the energy-dependent translocation of a wide variety of substrates across cellular membranes. Multiple drug resistance and many human hereditary diseases have been related to ABC transporter function, however, the physiological roles of only a few of these transporters have been elucidated. One of the largest subfamilies of ABC proteins is the MRP/CFTR family (subfamily C); homologues of this group of ABC transporters are also found in the opportunistic fungal pathogen Candida albicans. In preliminary studies we have already shown that the MRP-related ABC transporter gene MLT1 of C. albicans is crucial for its invasion of parenchymal organs in a peritonitis model. This study focuses on a detailed characterization of the involvement of MRP-related ABC transporters in fungal cell homeostasis networks during in vitro growth and in vivo interaction with the host in commensalism and opportunistic disease. Since the genome sequence of C. albicans is available, genomic expression profiling using DNA microarrays will be used to infer the functional relationships of MLT1 and two of the most closely-related transporters within the MRP/CFTR subfamily. In vitro expression studies in cell culture models will be extended to experimental infection models using innovative methods like in vivo expression technology (IVET) and real-time PCR. Specific ABC transporter gene inactivation mutants derived from wild-type C. albicans strains will be generated by gene disruption or RNA interference and phenotypically characterized. Furthermore, the functional characterization of these transporters will comprise identification of endogenous and exogenous substrates as well as determination of the subcellular localization. Our findings are likely to contribute to new approaches for treatment of fungal infections with specific compounds inhibiting ABC transporters. Since many human ABC transporters of the MRP/CFTR subfamily are involved in drug resistance or inherited disorders, our findings might help to infer their functional properties from those of their fungal homologues.
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| Kohler, Gerwald A; Brenot, Audrey; Haas-Stapleton, Eric et al. (2006) Phospholipase A2 and phospholipase B activities in fungi. Biochim Biophys Acta 1761:1391-9 |
