Aspergillus fumigatus is an opportunistic fringal pathogen that causes invasive pulmonary infections in neutropenic patients. The infections carry high morbidity and mortality, especially when dissemination has occurred. A. fumigatus is able to penetrate blood vessels, and this property of angioinvasion allows the organism entry into the vascular compartment. During this past cycle, we identified a gene (rhbA) in the Ras family of small GTPases that is upregulated in A. fumigatus when it is grown on a monolayer of endothelial cells, as a model of angioinvasion. The gene is in the newly recognized Rheb group of the Ras family. Functions of Rheb proteins are not fully understood in mammalian or lower eukaryotic systems. Mammalian Rheb genes may serve to coordinate Ras and PKA signaling. In yeast, the gene appears to regulate arginine uptake, and in fission yeast, the gene is essential and its loss causes growth arrest in Go. In A. fumigatus, we have found that deletion of the gene results in attenuation of virulence in a mouse model of disseminated infection. We propose the following four specific aims to test our hypothesis that rhbA is a general regulator of transport in A. fumigatus The first aim is to determine what types of transporters may be disregulated in the ArhbA mutant, based on our discovery that the mutant is hypersensitive to the drugs FK506 and rapamycin and to sulfate.
The second aim i s to determine whether rhbA has the same function in A. fumigatus as has been reported for RSG] in S. cerevisiae. We will also test whether rhbA antagonizes the action of dominant active Ras.
The third aim i nvestigates the proteins with which RHBA interacts using the yeast two-hybrid assay.
The fourth aim tests whether the decrement in virulence seen in the deltarhbA mutant is due to lack of regulation of a specific interacting partner or whether it is due to the overall disregulation of transport that is seen in the null mutant. Completion of these aims should significantly clarify the function of rhbA in A. fumigatus.
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