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David Kadosh, Ph.D.
Room 4.022V Tel: (210) 567-3976Fax: (210) 567-6612Email:
Our laboratory studies the major human fungal pathogen Candida albicans. Although present as a commensal in the digestive tract of most healthy people, C. albicans is also capable of causing a wide variety of systemic and mucosal infections. Immunocompromised individuals such as AIDS patients, organ transplant recipients, cancer patients undergoing chemotherapy and recipients of artificial joints and prosthetic devices are particularly susceptible to infection. C. albicans is also a highly evolved fungal pathogen, capable of invading nearly every organ and tissue in the human body; indeed, there are no known reservoirs for C. albicans outside the mammalian host.
How is C. albicans able to function so effectively as a pathogen? This organism possesses a number of properties which contribute to its virulence, including secretion of degradative enzymes and adhesion to host cells. Research in our laboratory focuses on one such virulence property, the ability to undergo a
reversible morphological transition from yeast (single oval cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end, see Figure 1). Previous studies have shown that this transition is required for virulence and can occur in response to a wide variety of host inducing signals. We use a variety of genetic, genomic, biochemical and molecular biology approaches to gain a better understanding of the mechanisms that control the C. albicans morphological transition in response to specific host environmental cues.
Determination of Candida albicans Morphology and Virulence
We have identified a novel filament-specific transcriptional regulator, UME6, which plays an important role in promoting C. albicans hyphal filament extension and virulence. UME6 is a component of the C. albicans filamentous growth program and appears to promote hyphal extension by maintaining the level and duration of expression of filament-specific transcripts in response to host environmental cues. Constitutive high-level expression of UME6 is sufficient to drive complete hyphal formation under non-filament-inducing conditions in vitro and causes a significant increase in hyphal formation, tissue invasion and virulence during infection in vivo. These results provide strong evidence that the C. albicans hyphal morphology plays a specific important role in virulence. Strikingly, we have found that as UME6 levels increase C. albicans shifts morphology from yeast to pseudohyphae to hyphae; there is an accompanying increase in both the number of filament-specific genes expressed as well as their level of induction. These results indicate that UME6 levels alone are sufficient to determine C. albicans morphology and suggest that all three morphologies are controlled by a common transcriptional mechanism in a dosage-dependent manner (Figure 2). A whole-genome DNA microarray analysis using this system suggests that genes associated with pseudohyphal growth represent a subset of those associated with hyphal growth and are generally expressed at lower levels. We have also recently demonstrated that C. albicans UME6 possesses one of the longest 5’ untranslated regions (UTRs) identified in yeast to date. This 5’ UTR functions to inhibit translational efficiency of UME6 and reduces the ability of UME6 expression to drive complete hyphal growth. Interestingly, the level of translational inhibition is modulated by host filament-inducing conditions. We are currently using a variety of approaches to further investigate both transcriptional and post-transcriptional mechanisms important for determination of C. albicans morphology and virulence.
Identification and Characterization of Novel C. albicans Virulence Factors
The C. albicans filamentous growth program is comprised of genes involved in a wide variety of biological processes, several of which had not previously been implicated in virulence; many of these genes are also controlled by key transcriptional regulators such as Ume6. We have identified four gene classes which appear to be significantly over-represented in the filamentous growth program compared to their representation in the genome as a whole: 1) cell wall components, 2) cell division genes, 3) secreted/degradative enzymes, 4) ER to Golgi transport and secretion genes. The filamentous growth program also contains a significant number of genes of unknown function. Several of these genes are unique to C. albicans, suggesting the possibility that they may be important for novel virulence mechanisms. Efforts are currently underway to further characterize these genes and determine the precise roles that they play in allowing C. albicans to establish and maintain infection in host tissues.
Complete List of Publications