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 blastospores (single round cells) to filaments (elongated cells attached end-to-end, see Figure 1). Previous studies have shown that this morphological 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 blastospore to filament transition in response to serum and body temperature (37°C). We are specifically interested in determining: 1) the transcriptional mechanisms that control induction of the C. albicans filamentous growth program in response to specific host inducing signals, 2) the mechanisms by which individual genes in the C. albicans filamentous growth program function to establish and maintain infection in host tissues:

Transcriptional Regulators of C. albicans Filamentous Growth and Virulence
     We have previously identified and characterized three key transcriptional repressors of the C. albicans blastospore to filament transition. Two of these regulators, Rfg1 and Nrg1, function as promoter-specific DNA-binding proteins and are known to direct 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. 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 the C. albicans filamentous growth program occurs by the relief of transcriptional repression (Figure 3).

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.