Ribosome assembly is an evolutionarily conserved process that begins with the conversion of a polycistronic rRNA precursor into discrete 18S, 5.8S, and 25S RNAs. In the ascomycete fungus C. albicans , we discovered that this conversion differs from that defined in the model organism Saccharomyces cerevisiae . Processing in C. albicans begins with cleavage in internal transcribed spacer-1 at or near the snoU3-independent site A3 rather than in the 5' external transcribed spacer. The result is a 2.6 kb 18S rRNA intermediate with an intact 5-terminus. Subsequent processing in the 5-end at the snoU3-dependent sites, and at the 3-end at site D, yields the mature 18S rRNA. During the diauxic shift, cleavage at these latter sites decreases, and the incompletely-processed 2.6 kb RNA accumulates. In S. cerevisiae , site D cleavage requires the putative NTPase Fap7. In contrast, mutation of the P-loop motif in the C. albicans ortholog Hbr1 abrogated processing at the snoU3-dependent sites. This implicates Hbr1 in snoU3-dependent rRNA processing and may account for the essential nature of this gene. Mammalian inducible heme oxygenase-1 ( HO-1 ) regulates immune response in higher animals during microbial infections. C. albicans ortholog HMX1 has 25% identity to human HO-1 22% identity with Hmx1 in the non pathogenic yeast S. cerevisiae . To determine whether HMX1 in C. albicans is involved in pathogenesis of disseminated candidiasis, we examined the effect of gene deletion on virulence and inflammatory responses in a mouse model of candidemia. We created a homozygous HMX1 null mutant and partially and fully reconstituted strains in C. albicans SC5314 background. Pathogenicity and inflammatory responses were assessed in terms of cytokine expression and histopathology. We found that an HMX1 null mutant (DRL2) is significantly less virulent than the wild-type strain SC5314. DRL2 elicited weaker inflammatory reactions and less organ colonization than the wild-type strain. A comparison of cytokine expression patterns demonstrated that HMX1 expression results in immune dysregulation during disseminated candidiasis that enables C. albicans better invade and colonize certain target organs in the host. These findings suggest that HMX1 is a significant virulence determinant of C. albicans and, therefore, could be an effective drug target.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Clinical Sciences
United States
Zip Code
Navarathna, Dhammika H; Roberts, David D; Munasinghe, Jeeva et al. (2016) Imaging Candida Infections in the Host. Methods Mol Biol 1356:69-78
Navarathna, Dhammika H M L P; Munasinghe, Jeeva; Lizak, Martin J et al. (2013) MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis. NMR Biomed 26:1125-34
Pendrak, Michael L; Roberts, David D (2007) Hemoglobin is an effective inducer of hyphal differentiation in Candida albicans. Med Mycol 45:61-71
Pendrak, Michael L; Rodrigues, Rui G; Roberts, David D (2007) Induction of a high affinity fibronectin receptor in Candida albicans by caspofungin: requirements for beta (1,6) glucans and the developmental regulator Hbr1p. Med Mycol 45:157-68
Pendrak, Michael L; Yan, S Steve; Roberts, David D (2004) Sensing the host environment: recognition of hemoglobin by the pathogenic yeast Candida albicans. Arch Biochem Biophys 426:148-56
Pendrak, Michael L; Yan, S Steve; Roberts, David D (2004) Hemoglobin regulates expression of an activator of mating-type locus alpha genes in Candida albicans. Eukaryot Cell 3:764-75
Pendrak, Michael L; Chao, Mark P; Yan, S Steve et al. (2004) Heme oxygenase in Candida albicans is regulated by hemoglobin and is necessary for metabolism of exogenous heme and hemoglobin to alpha-biliverdin. J Biol Chem 279:3426-33
Pendrak, M L; Krutzsch, H C; Roberts, D D (2000) Structural requirements for hemoglobin to induce fibronectin receptor expression in Candida albicans. Biochemistry 39:16110-8
Lyman, C A; Navarro, E; Garrett, K F et al. (1999) Adherence of Candida albicans to bladder mucosa: development and application of a tissue explant assay. Mycoses 42:255-9