We are interested in the cell and molecular biology of protozoan parasites. Most of our work is focused on members of the phylum Apicomplexa. Organisms in this group cause a number of important diseases including malaria, severe opportunistic infections associated with AIDS, and fetal and early childhood diseases. We use a broad array of modern genomic, genetic, cell biological and biochemical approaches to understand fundamental parasite biology and use this knowledge to identify and develop targets for intervention. Currently we are focusing on the following specific areas:
The function and cell biology of the parasite chloroplast.
Toxoplasma gondii
Apicomplexan parasites harbor a remnant chloroplast (the apicoplast) that they obtained through secondary endosymbiosis. This organelle is essential for parasite growth and as human cells lack chloroplasts offers a unique opportunity for anti-parasitic drug development. Using Toxoplasma gondii as a robust genetic model we are characterizing the specific metabolic functions of the organelle to pinpoint which pathway(s) would be most suitable as a drug target. The apicoplast also provides a tractable model to study the cell biology of endosymbiosis. What is the cellular machinery that builds, maintains and replicates an organelle that formed through the merger of three previously independent organisms (one prokaryotes and two eukaryotes)? Our current work uses a mix of genomics and genetics to mechanistically dissect apicoplast biogenesis, protein import and division.
Novel targets for the treatment of CryptosporidiosisCryptosporidium is an important human pathogen causing severe disease in AIDS patients and young children. Neither vaccines nor fully effective drugs are available for this disease. We are studying the nucleotide metabolism of Cryptosporidium parvum in an effort to develop effective therapy. We have discovered that the parasite depends entirely on salvage of purines and pyrimidines from its host cell and that several key enzymes were obtained via horizontal gene transfer from a bacterial source. Current work is focused on the further development of lead compounds obtained through a completed high throughput screen in collaboration with the Hedstrom lab at Brandeis. Taking a broader biological perspective we are also interested to learn what the selective advantages might been that have fixed these bacterial genes in the parasite's eukaryotic genome.
Boris StriepenSearch PubMed for striepen, b
Nair, S.C. and Striepen, B. (2011) What do human parasites do with a chloroplast anyway? PLoS Biology 9:e1001137.
Nair, S.C., Brooks, C.F., Goodman, C.D, Sturm, A., McFadden,G.I., Sndriyal, S., Anglin, J.L, Song, Y., Moreno, N.J., and Striepen, B. (2011) Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma. J. Exp. Med. 208: 1547-1559.
Brooks, C.F., Francia, M.E., Gissot, M., Kroken, M.M., Kim, K., and Striepen B. (2011) Toxoplasma gondii sequesters centromeres to a specific nuclear region throughout the cell cycle. Proc. Natl. Acad. Sci. U.S.A. 108: 3767-3772.
Agrawal, S and Striepen, B. (2010) More membranes, more proteins: complex protein import mechanisms into secondary plastids. Protist.161: 672-87
Sharling, L, Liu, X., Gollapalli D.R., Maurya S. K. Hedstrom, L., Striepen, B. (2010) A screening pipeline for antiparasitic agents targeting Cryptosporidium inosine monophosphate dehydrogenase. PLoS Negl. Trop. Dis. 10: e794.
Sun, X., Sharling, L., Mudeppa, D.G., Pankiewicz, K., Rathod, P.K., Mead, J., Striepen, B., and Hedstrom, L. (2010) Prodrug activation by Cryptosporidium Thymidine Kinase. J. Biol. Chem, 285:15916-15922.
Brooks, C.F., Johnsen, H., van Dooren, G.G., Muthalagi, M., Liu, S.S., Bohne, W., Fischer, K., Striepen B. (2010) The Toxoplasma Apicoplast Phosphate Translocator Links Cytosolic and Apicoplast Metabolism and Is Essential for Parasite Survival. Cell Host & Microbe: 7(1):62-73.
Agrawal, S., van Dooren, G.G., Beatty, W.L., Striepen, B. (2009) Genetic evidence that an endosymbiont-derived ERAD system functions in import of apicoplast proteins. J. Biol. Chem. 284:33683-33691.
Chtanova, T., Han, S.J., Schaeffer, M., van Dooren, G.G., Herzmark, P., Striepen, B., and Robey, E.A. (2009) Dynamics of T cell, antigen presenting cell, and pathogen interactions during recall responses in the lymph node. Immunity 31: 342-355.
Reiff, S. and Striepen, B. (2009) The malaria gatekeeper revealed. Nature 459: 918-919.
Schaeffer M, Han SJ, Chtanova T, van Dooren GG, Herzmark P, Chen Y, Roysam B, Striepen B*, Robey EA* (2009) Dynamic imaging of T cell-parasite interactions in the brains of mice chronically infected with Toxoplasma gondii. J Immunol. 182: 6379-6393. (*joint senior authors)
Breinich MS, Ferguson DJ, Foth BJ, van Dooren GG, Lebrun M, Quon DV, Striepen B, Bradley PJ, Frischknecht F, Carruthers VB, Meissner M. (2009) A dynamin is required for the biogenesis of secretory organelles in Toxoplasma gondii. Curr Biol. 19:277-286.
van Dooren, G.G., Reiff, S, Tomova, C., Meissner, M., S., Humbel, B., M., and Striepen, B. (2009) A novel dynamin-related protein has been recruited for apicoplast fission in Toxoplasma gondii. Curr. Biol. 19: 267-276.
van Dooren, G.G., Tomova, C., Agrawal, S., Humbel, B., and Striepen, B. (2008) Toxoplasma gondii Tic20 is essential for apicoplast protein import. Proc. Natl. Acad. Sci. USA 105:13574-13579.