Loyola University Chicago

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Professor Ph.D. 1987, Boston University Physiology and Immunology Phone: 773.508.3631 Fax: 773.508.3646 E-Mail: kwilli4@luc.edu

RESEARCH INTERESTS

Malaria is a critical world health problem resulting in 100-200 million clinical cases a year with 2 million deaths, mainly children. Over the last decade the spread of drug-resistant parasites and insecticide-resistant mosquitoes has made the situation worse and the need for new control measures more urgent. At the same time the disease has intensified, advances in recombinant DNA technology have lead to progress in understanding the molecular genetics of the parasites that cause malaria. My work focuses on the sexual/mosquito stages of the parasite, Plasmodium falciparum, that causes the most virulent form of human malaria. Antibodies directed against proteins on the surface of these parasite stages have been shown to preventing the parasites from infecting/colonizing the mosquito, thus blocking malaria transmission.

Ongoing projects in the lab are directed at determining the role of one of the major sexual-stage specific surface proteins, Pfs230, in sexual stage development and malaria transmission-blocking immunity. Molecular approaches such as transfection and targeted-gene disruption are now feasible in this organism and have been used to generate a series of transformants that express distinct regions of Pfs230. These technical advances provide exciting new tools to characterize sexual stage development on the molecular level. Currently the gene expression patterns and ultrastructure of the Pfs230 transformants are being evaluated, as are their ability to infect mosquitoes and evade the immune system.

Future projects include identifying additional genes involved in the transition to sexual stage development and the continued characterization of the trigger and process of gamete emergence from the red blood cell and subsequent fertilization. The generation of transformants that lack or overexpress the genes identified should lead toward the delineation of pathways required for sexual differentiation and transmission to mosquitoes. In addition to elucidating the fundamental biology of this important pathogen this work could lead to novel approaches to control the pathogenesis and transmission of malaria.

REPRESENTATIVE PUBLICATIONS

Eksi, S., Czesny, B., van Gemert, G-J., Sauerwein, R.W., Eling, W., & Williamson, K.C. (2007) Inhibition of P. falciparum oocyst production by treatment with membrane permeant cysteine protease inhibitor, E64d. Antimicrobial Agents and Chemotherapy 51:1064-1070

Eksi, S., Czesny, B., van Gemert, G-J., Sauerwein, R.W., Eling, W., & Williamson, K.C. (2006) Malaria transmission-blocking antigen, Pfs230, mediates human red blood cell binding to exflagellating male parasites and oocyst production. Mol. Micro 61(4):991-998

Eksi, S., Haile, Y., Furuya, T., Ma, L., Su, X., and Williamson, K.C. (2005) Identification of a subtelomeric gene family expressed during the asexual-sexual stage transition in Plasmodium falciparum. Mol. Biochem. Parasitol. 143:90-99

Le Roch, K.G., Johnson, J.R., Florens, L., Zhou, Y., Santrosyan, A., Grainger, M., Yan, S.F., Williamson, K.C., Holder, A.A., Carucci, D.J., Yates, J.R., III, and Winzeler, E.A. (2004) Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. Genome Res.14: 2308-2318.

Eksi, S, Czesny, B, Greenbaum, D.C., Bogyo, M., and Williamson, K.C. (2004) Targeted disruption of Plasmodium falciparum cysteine protease falcipain 1 reduces oocyst production, not the erythrocytic stages of the parasite lifecycle. Mol. Micro. 53(1):243-250.

Williamson, K.C. (2003) Pfs230: From malaria transmission blocking vaccine candidate toward function. Parasite Immunol. 25(7):351-359

Fanning, S.L., Czesny, B., van Gemert, G-J., Eling, W., Sedegah, M. and Williamson, K.C. (2003) A glycosylphosphatidylinositol anchor signal sequence enhances the immunogenicity of a DNA vaccine encoding Plasmodium falciparum sexual-stage antigen, Pfs230. Vaccine 21:3228-3235.

Eksi, S. and Williamson, K.C. (2002) Male-specific expression of the paralog of malaria transmission-blocking target antigen Pfs230, PfB0400w. Mol. Biochem. Parasitol. 122(2)127-130.

Eksi, S., Stump, A., Fanning, S.L., Shenouda, M.I, Fujioka, H., and Williamson, K.C. (2002) Targeting and sequestration of truncated Pfs230 in an intraerythrocytic compartment during Plasmodium falciparum gametocytogenesis. Mol. Micro. 44(6):1507-1516.

Akompong, T., Eksi, S., Williamson, K., and Haldar, K. (2000) Gametocytocidal activity of riboflavin and its synergistic interactions with standard antimalarial drugs against growth of P. falciparum in vitro. Antimicrobial Agents and Chemotherapy 44(11):3107-3111.

Bustamante, P.J., Woodruff, D.C., Oh. J., Muratova, O., Keister, D.B., and Williamson, K.C. (2000) Differential ability of specific regions of Plasmodium falciparum sexual stage antigen, Pfs230 to induce malaria transmission-blocking immunity. Parasite Immunol. 22:373-380.

Brooks, S.R. and Williamson, K.C. (2000) Proteolysis of Plasmodium falciparum surface antigen, Pfs230, during gametogenesis. Mol. Biochem. Parasitol. 106(1):77-82

Fig. The life cycle of the malaria parasite. When a mosquito takes a bloodmeal, parasites in the form of sporozoites are transmitted to humans. These parasites undergo asexual or sexual differentiation in the host. The mature forms of the parasite can be taken up in a mosquito bloodmeal where they further develop and consequently the cycle of infection perpetuates (Oaks, 1991).

• Watch a movie of male gamete exflagellation. Gamete exflagellation (15 MB mpg)
• Dr. Williamson's Lab Website