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David S. Roos, PhD
Merriam Professor of Biology
Director, Genomics Institute
Ellison Foundation Senior Scholar in Global Infectious Diseases

Office Phone: 215-898-2118
Office Fax: 215-898-8780
Email: droos@sas.upenn.edu
Website(s): http://www.bio.upenn.edu/faculty/roos/

Education: PhD 1984, The Rockefeller University

Keywords: Opportunistic pathogens, Host/pathogen interactions, Toxoplasma gondii, Cell & molecular parasitology, Drug development, Molecular evolution, Genome databases & database mining

Research and/or Clinical Interests:
Research exploits molecular genetic, cell biological, biochemical, pharmacological, and genomic approaches to study host-pathogen interactions, protozoan parasites, and eukary­otic evolution.

Summary:
Our primary emphasis focuses on the phylum Apicomplexa, a group of protozoan parasites that replicate within specialized vacuoles inside eukaryotic host cells, and there­fore depend on cell-mediated immunity for effective control. Toxoplasma gondii and Cryptosporidium parvum are prominent opportunistic pathogens associated with AIDS and other immunosuppressive conditions. Other apicomplexan parasites - including Plasmodium sp. (which cause malaria) and Eimeria sp. (which cause coccidiosis in poul­try) - are also of concern as clinical, veterinary and/or biodefense pathogens independent of their relevance to AIDS. Ongoing projects include:

Cell biology and molecular genetics of protozoan parasites: The ability to saturate the T. gondii genome by insertional mutagenesis (and clone the tagged loci), target defined loci for genetic deletion or allelic replacement, and control the expression of recombinant proteins makes powerful genetic approaches feasible. Success­ful expression of fluorescent reporters facilitates the analysis of subcellular architecture, and the pathogenesis of transgenic parasites in living cells and tissues. These tools have been exploited to isolate mutants elucidating the temporal and developmental controls that regulate differentiation through the complex parasite life cycle (most notably the latent 'bradyzoite' tisue cyst form responsible for toxoplasmic encephalitis) and to devise strategies for examining host/parasite interactions and the host immune response.

Mechanisms of drug action and resistance: Genetic studies have identified key proteins involved in nucleoside transport/metabol­ism, and functional expression and structural studies opens the way to mechanism-based drug design. Gene replacement studies at the DHFR-TS locus have defined the molecu­lar basis of resistance to antifolates in malaria, and the fitness costs of drug-resistance mutations in T. gondii. Studies on the surprising efficacy of certain classical prokaryotic inhibitors against apicomplexan parasites led to the discovery of a novel organelle - the apicoplast - a nonphotosynthetic plastid acquired by lateral genetic transfer of an algal chloroplast. Related studies elucidated a remarkable mechanism used to target proteins to this organelle, which has been exploited identify several promising drug targets.

Designing and mining pathogen genome databases: Focusing on the differences between questions researchers want to ask about patho­gens vs. model organisms, we have been active in developing bioinformatics resources, including genome and EST databases for Toxoplasma <http://ToxoDB.org> and Plasmo­dium <http://PlasmoDB.org>. Current interests include developing new algorithms for comparative genomic analysis, and databases enabling the integration and mining of diverse large-scale post-genomics datasets. Coupling computational database mining with laboratory analysis facilitates the identification of targets for drug, vaccine, and diagnostic development, and provides new insights into eukaryotic biology and evolution. We are also actively engaged in bioinformatics training programs around the world.

Representative Publications:
Köhler, S., Delwiche, C.F., Denny, P.W., Tilney, L.G., Webster, P., Wilson , R.J.M., Palmer, J.D., Roos D.S. A plastid of probable green algal origin in apicomplexan para­sites. Science 275:1485-1488, 1997.

Bohne, W., Roos, D.S. Stage-specific expression of a selectable marker in Toxo­plas­ma gondii permits selective inhibition of either tachyzoites or bradyzoites. Molecular and Biochemical Parasitology 88:115-126, 1997.

Fichera , M.E. , Roos, D.S. A plastid organelle as a drug target in apicom­plexan parasites. Nature 389:407-409, 1997.

Reynolds, M.G., Roos, D.S. A biochemical and genetic model for parasite resis­tance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Journal of Biological Chemistry 273:3461-3469, 1998.

Bohne, W., Hunter, C.A. , White, M.W., Ferguson , D.J.P., Gross, U., Roos, D.S. Tar­geted disruption of the bradyzoite-specific gene BAG1 does not prevent tissue cyst forma­tion in Toxoplasma gondii. Molecular and Biochemical Parasitology 92:291-301, 1998.

Schumacher, M.A., Carter, D., Scott, D.M., Roos, D.S., Ullman, B., Brennan, R.G. Cry­stal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic structure of pyrimidine discrimination and prodrug binding. EMBO Journal. 17:3219-3232, 1998.

Waller, R.F., Keeling, P.J., Donald, R.G.K., Striepen, B., Handman, E., Lang-Unnasch, N., Cowman, A.F., Besra, G.S., Roos, D.S., McFadden, G.I. Nuclear-encoded proteins tar­get to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proceedings of the National Academy of Sciences USA 95:12352-12357, 1998.

Roos, D.S., Crawford, M.J., Donald, R.G.K., Kissinger, J.C., Klimczak, L.J., Striepen. B. Origins, targeting, and function of the apicomplexan plastid. Current Opinion in Microbiology 2:426-432, 1999.

Schumacher, M.A., Scott, D.M., Mathews, I.I., Ealick, S.E., Roos, D.S., Ullman, B., Brennan, R.G. Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. Journal of Molecular Biology 298:875-893, 2000.

He, C.Y., Shaw, M.K., Pletcher, C.H., Striepen, B., Tilney, L.G., Roos, D.S. A plastid segregation defect in the protozoan parasite Toxoplasma gondii. EMBO Journal 20:330-339, 2001.

Reynolds, M.G., Oh, J., Roos, D.S. In vitro generation of novel pyrimethamine resistance mutations generated in the Toxoplasma gondii dihydrofolate reductase. Antimicrobial Agents and Chemotherapy 45:1271-1277, 2001.

Hu, K., Mann, T., Striepen, B., Beckers, C.J.M., Roos D.S., Murray, J.M. Daughter cell assembly in the protozoan parasite Toxoplasma gondii. Molecular Biology of the Cell 13:593-606, 2002.

Hu, K., Roos, D.S., Murray , J.M. A novel polymer of tubulin forms the conoid in Toxoplasma gondii. Journal of Cell Biology 156:1039-1050, 2002.

Matrajt, M., Donald, R.G.K., Singh, U., Roos, D.S. Identification and characteriza­tion of differentiation mutants in the protozoan parasite Toxoplasma gondii. Molecular Microbiology 44:735-747, 2002.

Joiner, K.A., Roos, D.S. Secretory traffic in Toxoplasma gondii: Less is more. Journal of Cell Biology 156:1039-1050, 2002.

Pelletier, L., et al. Golgi biogenesis in Toxo­plasma gondii. Nature 418:548-552, 2002.

Kissinger, J.C., et al. The Plasmodium genome database: Designing and mining a eukaryotic genomics resource. Nature 419:490-492, 2002.

Gardner , M.J., et al. The genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498-511, 2002.

Bahl, A., et al. PlasmoDB: The Plasmodium genome resource. Tools for integrating experimental and computational data. Nucleic Acids Research 31:212-215, 2003.

Kissinger, J.C., Gajria, B., Li, L., Paulsen, I.T., Roos, D.S. ToxoDB: Accessing the Toxoplasma gondii genome. Nucleic Acids Research 31:234-236, 2003.

Foth, B.J., Ralph, S.A., Tonkin, C.J., Struck, N., Fraunholz, M.J., Roos, D.S., Cowman, A.F., McFadden, G.I. Dissecting apicoplast targeting in the malaria parasite Plasmodium falcipar­um. Science 299:705-708, 2003.

Li, L., et al. Gene discovery in the Apicomplexa as revealed by EST sequencing and assembly of a comparative gene database. Genome Research 13:443-454, 2003.

Li, L., Stoeckert, C.J., Jr., Roos D.S. OrthoMCL: Identification of ortholog groups for eukaryotic genomes. Genome Research: in press, 2003.

Fohl, L.M., Roos, D.S. Fitness effects of DHFR-TS mutations associated with pyrimethamine-resistance in apicomplexan parasites. Molecular Microbiology: in press, 2003.