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Deletion of the Aspergillus fumigatus Gene Encoding the Ras-Related Protein RhbA Reduces Virulence in a Model of Invasive Pulmonary Aspergillosis

Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio

Received 20 November 2002/ Returned for modification 30 December 2002/ Accepted 20 January 2003

Aspergillus fumigatus is the predominant mold pathogen in patients who lack functional innate immunity. The A. fumigatus rhbA gene was first identified as a transcript that was upregulated when the organism was grown in the presence of mammalian cells. To gain insight into the function of rhbA in the growth and pathogenesis of A. fumigatus, we constructed a strain that lacks a functional rhbA gene. The rhbA mutant showed a significant reduction in virulence compared to the virulence of the wild type in a mouse model of invasive aspergillosis. Complementation of the deletion with the wild-type gene restored full virulence. Although the rhbA mutant grew as well as the wild type on solid medium containing the rich nitrogen source ammonium, the growth of the mutant was impaired on medium containing poor nitrogen sources. Like the Saccharomyces cerevisiae rhb1 mutant, the rhbA mutant exhibited increased uptake of arginine. In addition, the rhbA strain underwent asexual development in submerged cultures, even under ammonium-excess conditions. Growth of the mutant with poor nitrogen sources eliminated both the arginine uptake and submerged asexual development phenotypes. The mutant showed enhanced sensitivity to the TOR kinase inhibitor rapamycin. These findings establish the importance of rhbA for A. fumigatus virulence and suggest a role for rhbA in nutrient sensing.

Editor: T. R. Kozel

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