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David Kadosh, Ph.D.
Room 5.023V 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. In order to gain a better understanding of the mechanisms that control the C. albicans morphological transition in response to specific host environmental cues we have taken a genomic approach. Using whole-genome C. albicans DNA microarrays (Figure 2) we have identified a set of 61 genes that are induced during the yeast-to-filament transition in response to serum and body temperature (37°C). We are specifically interested in determining: 1) the mechanisms that specify C. albicans morphology and control induction of the filamentous growth program in response to host inducing signals, 2) the mechanisms by which individual genes in the C. albicans filamentous growth program function to promote the establishment and maintenance of infection in host tissues.
Determination of Candida albicans Morphology and Virulence
We have previously identified and characterized three key transcriptional regulators of the C. albicans yeast-to-filament transition.
Two of these regulators, Rfg1 and Nrg1, function as promoter-specific DNA-binding proteins and are known to direct transcriptional repression by recruitment of the third protein,
Tup1 corepressor, to the promoters of filament- and virulence-specific target genes. Using comparative DNA microarray analysis we have determined that approximately one-half of all genes in the
C. albicans filamentous growth program are under negative control by Rfg1, Nrg1 and/or Tup1 in the yeast form. We (and others) have also shown that the NRG1 transcript is down-regulated in response
to serum and 37°C, suggesting a model whereby induction of filament-specific genes occurs by the relief of transcriptional repression.
More recently, we have identified a novel filament-specific transcriptional regulator and virulence factor, UME6, which plays an important role in promoting C. albicans hyphal filament extension.
UME6 is a component of the C. albicans filamentous growth program and a downstream target of both the Rfg1-Tup1 and Nrg1-Tup1 pathways. UME6 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 3).
We are currently using a variety of genetic, genomic, molecular and biochemical approaches to examine this mechanism in more detail.
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 filamentous growth and virulence. 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 C. albicans 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.
Lab Rooms: 5.022V, 5.023V