NCI Funded Research Portfolio - Z01 SC 009173 Abstract

Z01 SC 009173 (Z01)
Title	Host Colonization and Vascular Dissemination of <I>Candida albicans</I>
Institution	NCI, Bethesda, MD
Principal Investigator	Roberts, David	NCI Program Director	N/A
Cancer Activity	N/A	Division	CCR
Funded Amount	$207,327	Project Dates	10/01/1989 - N/A
Fiscal Year	2007	Project Type	Intramural
Research Topics (SICs) w/ Percent Relevance		Cancer Types (Disease Sites) w/ Percent Relevance
Antimicrobial Resistance (30.0%) Infectious Diseases (100.0%) Molecular Biology (30.0%)		N/A
Common Scientific Outline
Cancer Progression & Metastasis Systemic Therapies - Discovery and Development
Abstract	<P> Hemoglobin is an abundant protein in the host vascular compartment and a source of iron, heme, and amino acids for many pathogens. The human fungal pathogen <I>Candida albicans</I> uses hemoglobin as an iron source as well as a signaling molecule to alter gene expression and induce adhesion to several extracellular matrix proteins. We now report that hemoglobin can promote true hyphal morphogenesis. Hemoglobin added to yeast cells at 37°C rapidly induced expression of the hypha-specific genes HWP1 and ECE1 coincident with the pattern of hyphal development. A synthetic medium buffered with phosphate at pH 7.2 and containing physiological glucose (5 mM) and low ammonium ion (0.1 mM) was optimal for the response to hemoglobin. High glucose (100 mM), high ammonium ion (20 mM), and 0.1 mM glutamine were all inhibitory. Heme, free globin, or immobilized hemoglobin could not replicate the activity of hemoglobin to induce germ tubes or hypha-specific gene expression at 37°C under optimized conditions. This implicates the previously described Hb-signaling receptor in hyphal formation that requires intact Hb αβ dimer aggregation to function. This response was also dependent upon the presence of the morphogenesis regulator Efg1p although the MAP-kinase specific factor Cph1p was not required. These data define a role for the host-factor hemoglobin in Efg1p-dependent hyphal development. </p> <P> Previously, the high affinity fibronectin receptor was only observed when cells were grown in complex medium. We discovered that sub-inhibitory concentrations of caspofungin, a new antifungal in clinical use that inhibits cell wall glucan synthesis, but not the antifungal fluconazole induce the high affinity fibronectin receptor. The high affinity fibronectin receptor was not inducible in a Kre9 mutant strain of C. albicans, which is deficient in β(1,6) glucans. A mutant strain lacking the fibronectin binding protein Als5p showed no defects in induction of high or low affinity fibronectin receptors. Therefore, the two classes of fibronectin receptors that we identified are distinct from those identified by others. Remarkably, our heterozygous HBR1 mutants lacked detectable high affinity fibronectin receptor expression in response to caspofungin, and re-introduction of the gene restored activity. Therefore, sub-inhibitory dosages of caspofungin induce a high affinity fibronectin receptor that is distinct from the known receptor Als5p and is dependent on β(1,6) glucans and HBR1. This discovery will aid in our identification and cloning of the receptor gene and determining its role in pathogenesis. </p>