Clinical Mycology Laboratory
Peter R. Williamson, MD/PhD

Principal Investigator
Associate Professor of Medicine

Infectious Diseases, Dept. of Medicine, MC 735
887 CME
phone: 312-996-6070
fax: (312) 413-1657
prw@uic.edu

Group Members: Shirong Zhang, PhD, Xudong Zhu, PhD, Xiaoguang Liu, PhD, John Panepinto, PhD, Guowu Hu, PhD, Jeanie Ramos, Scott VonBank.

Description of Research Program: The clinical 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. Our laboratory has studied the gene responsible for the copper-dependent virulence factor laccase, CNLAC1, which protects the fungus from oxidative defenses of the host. Molecular characterization of mutants of this factor have identified several genes important to the biosynthesis and regulation of laccase, including a vesicular ATPase and a vesicular chloride channel, both of which appear to be important to the metaliation of laccase and laccase regulators. Mutation of the vesicular ATPase results in a severe attenuation in virulence that suggest that vesicular pumps may make ideal drug targets. In addition, we are investigating the role of a regulatory cascade that receives input from multiple signal cascades and integrates the signal to regulate the mRNA stability of laccase transcription factors. As an example, we have isolated a member of the RCK/p54 class of DEAD-box proteins that regulates decapping prior to mRNA degradation, resulting in suppression of a laccase transcription factor. This factor has been named, virulence- associated DEAD-box protein, VAD1, because mutation of the gene results in a markedly reduced virulence in mice. Studies are ongoing to characterize such regulatory cascades and identify additional virulence determinants that may be useful for the design of new anti-fungal targets.

Selected Publications:

1. 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

2. Liu, L, Tewari, RP, Williamson, PR. Laccase protects Cryptococcus neoformans from fungistasis by bronchoalveolar macrophages. Infect. Immun. 67:6034-6039 1999

3. Zhu, Xudong, Gibbons, J., Garcia-Rivera, A. Casadevall and Williamson, P.R. (2001) Laccase of Cryptococcusneoformans is a cell wall-associated virulence factor. Infect. Immun. 69:5589-5596.

4. 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.

5. 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.