Laboratory of Medical Mycology: Moshe Hachem, MD/PhD, Guowu Hu, PhD, John Panepinto, PhD,
Yoon-Dong Park, PhD, Soowan Shin, Scott Waterman, PhD, Shirong Zhang, PhD

Peter R Williamson, MD, PhD
Principal Investigator
Associate Professor of Medicine
University of Illinois at Chicago
Section of Infectious Diseases
808 S. Wood St. Rm 888 MC 735
887 CME
phone: 312-996-6070
fax: (312) 413-1657
prw@uic.edu

Description of Research Program

The medical mycology laboratory has focused on molecular mechanisms of pathogenesis of mycoses, particularly, the AIDS-related pathogen, Cryptococcus neoformans. The incidence of fungal diseases, such as cryptococcosis has risen dramatically since the onset of the HIV-1 epidemic and increased immunosuppression related to chemotherapy. In addition, anti-fungals are often ineffective, or produce toxicity that is poorly tolerated by patients. Recently, the genomic sequences of important strains of C. neoformans have been obtained and are actively being investigated. In the post-genome era, identification and organization of regulatory and biosynthetic networks related to virulence are essential to the understanding of how the pathogen responds to the host environment to effect virulence.

Current Projects Include:

• Investigation of the relationship between stress response and fungal virulence by identification and molecular dissection of regulators of the virulence factor laccase. We are currently characterizing a number of transcriptional activators and factors regulating mRNA stability involved in virulence. Methods include genome-wide insertional mutagenesis, transcriptional assays including reporter assays, electromobility shift assays (EMSA), chromatin immunoprecipitation (ChIP) and co-immunoprecipitation as well as methods of RNA study including RNA stability, decapping and de-adenylation and RNA immuno-precipitation (RIP).
• Analyzing mechanisms involved in cellular trafficking of fungal virulence factors. We are currently studying cellular trafficking mechanisms and the biological significance of fungal surface proteins including laccase, as well as factors involved in the remodeling of capsule and adherence to endothelial cells. Methods include immunolocalization of proteins by deconvolution microscopy and immuno-electron microscopy, co-immunoprecipitation and methods of biochemical cellular localization.
• Immunological characterization of molecularly-characterized mutants defective in virulence. Methods include leukocyte recruitment studies, flow cytometry, antibody analyses, RT-PCR and in-situ analyses.
• Translational studies relating functional genomic analyses to infectious outcomes in patients. Methods include microarray analysis, clinical outcomes analysis.

Selected Publications

• Salas, S., J.E. Bennett, K.J. Kwon Chung, J.R. Perfect and P.R. Williamson. (1996) Effect of the laccase gene, CNLAC1 , on virulence of Cryptococcus neoformans. J. Exp. Med. 184:377-386
• Liu, L, Tewari, RP, Williamson, PR. Laccase protects Cryptococcus neoformans from fungistasis by bronchoalveolar macrophages. Infect. Immun. 67:6034-6039 1999
• Zhu, Xudong, Gibbons, J., Garcia-Rivera, A. Casadevall and Williamson, P.R. (2001) Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor. Infect. Immun. 69:5589-5596.
• Erickson, T., Liu, L., Gueyikian, A., Williamson, P.R. Multiple Virulence Factors of Cryptococcus neoformans are dependent on VPH 1. (2001) Mol. Microbiol 42:1121-1131.
• Zhu, X.. and Williamson, P.R. A CLC-type chloride channel gene is required for laccase activity and virulence in Cryptococcus neoformans. Mol. Microbiol. 50:1271-81.
• Panepinto, J, Liu, L, Ramos, J, Zhu, X, Valyi-Nagy, T, Eksi, S, Fu, J, Jaffe, HA, Wickes, B and Williamson, PR. (2005) The DEAD-box RNA helicase VAD1 regulates multiple virulence-associated genes in Cryptococcus neoformans. J Clin Invest 115:632-641.