GOALS OF THE LABORATORY
The goal of our research is to understand mechanisms of host tissue invasion by the fungal pathogen, Candida albicans. C. albicans has become an important pathogen, particularly in hospitals, because immunocompromised patients such as oncology patients or transplant recipients are at risk for life-threatening disseminated candidiasis. It is believed that the morphological conversion of yeast cells to filamentous forms, i.e. hyphae and pseudohyphae, is important for penetration of host tissue by C. albicans. Therefore, we are studying the regulation of filamentation and have focused on the following questions:

What environmental cues stimulate hyphal development?
What protein factors are involved in the response of cells to cues from the environment?
What contribution do these factors make to virulence?

SUMMARY OF RESEARCH
To study how C. albicans invades host tissue, we have developed a simple model system that can be readily studied in the laboratory. We found that C. albicans cells growing within a matrix, such as agarose, undergo the morphological conversion to elongated, hyphal cells that is normally seen when the organism grows within tissue. (Brown, D.H., Jr., A.D. Giusani, X. Chen and C.A. Kumamoto (1999) Mol. Microbiol. 34, 651-662.) We propose that growth within agarose mimics growth within host tissue. To explain why hyphae are produced in this environment, we proposed that growth within matrix causes mechanical forces to act on the cell and that these forces are perceived by C. albicans cells, leading to production of hyphae.

We have identified a putative DNA binding protein, Czf1p, that promotes the conversion of yeast cells to hyphae during growth within matrix (Brown, D.H., Jr., A.D. Giusani, X. Chen and C.A. Kumamoto (1999) Mol. Microbiol. 34, 651-662.). Czf1p binds to a repressor of filamentous growth and promotes filamentation by relieving repression (Giusani, A.D., M. Vinces and C.A. Kumamoto (2002) Genetics 160, 1749-1753).

To determine whether filamentation in response to agarose embedding is relevant during infection, we analyzed a mutant strain. This strain lacks two putative transcription factors, Efg1p and Cph1p, and is defective in filamentation under many standard laboratory conditions. However, despite this defect, the mutant strain is able to filament when grown within an agar matrix. To study the virulence of this mutant strain, we developed a new animal model for mucosal and systemic candidiasis utilizing the immunosuppressed gnotobiotic infant piglet (Andrutis, K.A., P.J. Riggle, C.A. Kumamoto and S.R. Tzipori (2000) J. Clin. Microbiol. 38, 2317-2323.). We demonstrated that the mutant strain forms filaments when growing within host tissue in this animal model, suggesting that a physical environment similar to agarose embedding may be encountered by C. albicans during infection (Riggle, P.J., K.A. Andrutis, X. Chen, S.R. Tzipori and C.A. Kumamoto (1999) Infect. Immun. 67, 3649-3652).