Adhesion as a Candida albicans virulence factor

Candida albicans is fungal pathogen most commonly isolated in humans. C. albicans is a normal component of the oral cavity, the gastrointestinal tract, and the vaginal environment, but this organism is also an opportunistic pathogen, commonly causing infections such as denture stomatitis, thrush, and urinary tract infections. C. albicans can also cause more serious systemic infections. Often these infections are transmitted in hospitals and are much more common in immunocompromised patients. C. albicans infection rates have increased by over a factor of twenty during the past two decades, in a large part resulting from an increase in immunocompromised persons. Mortality associated with systemic Candida infections is approximately 35-50% and annual treatment costs exceed $10 billion in the U.S.

Approximately one half of hospital-acquired C. albicans infections are associated with biofilms formed on an implanted medical device, such as a central venous catheter, urinary catheter, endotracheal tube, prosthetic heart valve, pacemaker, or joint replacement. These devices provide a route through the body’s barrier defenses and also provide a surface for cell growth and development. Cells in biofilms exhibit different growth characteristics and gene expression patterns than cells grown in suspension. For example, cells in biofilms are much more resistant to antifungal agents.

Cell morphogenesis is an important C. albicans virulence factor. Pathogenic strains have the ability to switch between yeast form and filamentous (hyphal or pseudohyphal states)

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C. albicans cells in the yeast and hyphal morphogenesis states.

This switching is thought to contribute to the ability to grow on surfaces and invade tissues. The signals that promote filamentous growth include pH in the neutral-basic range, elevated temperature, nutrient starvation, and serum components. However, the receptors for these factors are largely unknown.

The ability of C. albicans to recognize and bind to host cells or materials implanted in the body is also required for virulence. C. albicans expresses a variety of known and putative adhesion receptors, although the ligands for each, their affinities for different materials and cells, and their roles in the pathogenesis process remain unclear.

We use genetics and molecular biology approaches coupled with quantitative adhesion assays to (1) attempt to discover new adhesion receptors important in adhesion, biofilm formation, and virulence; (2) identify the ligands for C. albicans adhesins; (3) characterize the nature of adhesin-ligand binding; and (4) determine the role of various adhesins in biofilm formation and virulence.

In recent work, we have discovered a novel fungal adhesion receptor encoded by the gene EAP1 (enhanced adhesion to plastic). EAP1 expression allows Candida albicans cells to bind to a variety of materials and mammalian epithelial cells. We are currently investigating the role of Eap1, and other C. albicans adhesins, in biofilm formation and virulence in vitro and in animal models.

Biofilm formed by wild-type C. albicans cells on a catheter wall. Note the “stringy” matrix surrounding the yeast cells. EAP1 null mutants are unable to form biofilm on this material.