parasitology, cell biology, microtubules and tubulin function, drug resistance, genetic analysis
Laboratory of Alan Aderem (macrophage phagocytosis) Rockefeller University & the University of Washington
Laboratory of David Sibley (Toxoplasma dinitroaniline resistance) Washington University, St. Louis
The phylum Apicomplexa contains a number of obligate intracellular parasites that are of medical and agricultural importance, including Plasmodium spp. (agent of malaria), Cryptosporidium (an opportunistic pathogen associated with AIDS), Toxoplasma (an opportunistic infection and cause of birth defects and miscarriage), and Theileria, Babesia and Eimeria (parasites of cattle and chickens with a substantial impact on food production). These parasites share a common ancestor and this is reflected in a number of conserved morphological features.
Research in my laboratory explores how microtubules function in the Apicomplexa. The radically different organization, regulation and use of microtubules in the Apicomplexa represent intriguing departures from our understanding of microtubules in model organisms. Moreover, these distinct properties can be exploited to develop novel anti-parasitic therapies. To establish basic principles, we work with Toxoplasma gondii because of its relative ease of manipulation. Ultimately we will extend our analysis to other apicomplexans, particularly Plasmodium spp.
One primary goal of my research is to understand the basis of dinitroaniline resistance in Toxoplasma. Dinitroanilines, which are used as herbicides, disrupt microtubules in plants and in protozoa, including diverse protozoan parasites. However, these compounds are ineffective against vertebrate or fungal microtubules. Since tubulin is a well-established chemotherapeutic target, the specificity of these compounds for protozoan parasites warrants their further investigation as anti-parasitic agents. Remarkably, the dinitroanilines act on alpha-tubulin. This is unique, as all other known compounds that perturb microtubules function bind to beta-tubulin. Low-level dinitroaniline resistance is invariably associated with point mutations to alpha-tubulin and the point mutations cluster into specific regions of the alpha-tubulin structure. In collaboration with David Sept and Arpita Mitra (Washington University Center for Computational Biology) we have used computational techniques to identify a dinitroaniline binding site on alpha-tubulin. This site lies under the N loop and contains residues that are mutated in several resistant lines. We hypothesize that dinitroanilines disrupt microtubules by disrupting protofilament-protofilament interactions in the microtubule lattice. On-going studies are directed towards defining the determinants of dinitroaniline sensitivity in plants and protozoa. Related experiments will employ these results to develop high-through-put screens to identify additional compounds with activity against protozoa but not vertebrates. We are currently using genetic and reverse genetic screens to identify proteins that control microtubule stability in the Apicomplexa. Lastly, other studies will use cell biological techniques to characterize the behavior of microtubules during parasite replication and host cell invasion.
SPM1 Stabilizes Subpellicular Microtubules in Toxoplasma gondii.
Tran JQ, Li C, Chyan A, Chung L, Morrissette NS.
Eukaryot Cell. 2012 Feb;11(2):206-16. Epub 2011 Oct 21.
Sally B. Lyons-Abbott, Dan L. Sackett, Dorota Wloga, Jacek Gaertig, Rachel E. Morgan, Karl A. Werbovetz and Naomi S. Morrissette. (2010) “Alpha-tubulin Mutations Alter Oryzalin Affinity and Microtubule Assembly Properties to Confer Dinitroaniline Resistance,” Eukaryotic Cell, in press.
Josh R. Beck, Imilce A. Rodriguez-Fernandez, Jessica C. de Leon, My-Hang Huynh, Vern B. Carruthers, Naomi S. Morrissette and Peter J. Bradley. (2010) “A Novel Family of Toxoplasma IMC Proteins Displays a Hierarchical Organization and Functions in Coordinating Parasite Division,” PLoS Pathogens 6:1-21.
Jyothi S. Akella, Dorota Wloga, Jihyun Kim, Natalia Starostina, Sally Lyons-Abbott, Naomi S. Morrissette, Scott T. Dougan, Edward T. Kipreos and Jacek Gaertig. (2010) “MEC-17 is an Alpha-tubulin acetyltransferase,” Nature 467:218–222.
Molla M. Endeshaw, Catherine Li, Jessica de Leon, Ni Yao, Kirk Latibeaudiere, Kokku Premalatha, Naomi Morrissette and Karl A. Werbovetz. (2010) “Synthesis and Evaluation of Oryzalin Analogs against Toxoplasma gondii,” Bioorganic and Medicinal Chemistry Letters 20:5179-83.
Johnson Q. Tran, Jessica de Leon, My-Hang Huynh, Wandy Beatty and Naomi S. Morrissette, “RNG1 is a Novel Marker of the Apical Polar Ring in Toxoplasma gondii”, Cytoskeleton 67:586-98.
Kristen R. Sweeney, Naomi S. Morrissette, Stephanie Lachapelle, Ira J. Blader. (2010) Host Cell Invasion by Toxoplasma gondii is Temporally Regulated by the Host Microtubule Cytoskeleton, Eukaryotic Cell, in press.
Christopher Ma, Johnson Tran, Frank Gu, David Sept, Roxanna Ochoa, Catherine Li, Karl Werbovetz and Naomi S. Morrissette. (2010) “Dinitroaniline Activity in Wild-type and Mutant Tubulins of Toxoplasma gondii,” Antimicrobial Agents and Chemotherapy 54(4): 1453–1460.
Dan Sackett, Karl Werbovetz and Naomi Morrissette. (2010) “Isolating tubulin from nonneural sources,” Invited chapter, Microtubules, In Vitro: A Volume of Methods in Cell Biology, John J. Correia and Les Wilson, editors, volume 95, pp. 17-32.
James W. Ajioka and Naomi S. Morrissette. (2009) “One-hundred Years of Toxoplasma Research,” International Journal for Parasitology 39:859-860.
Naomi S. Morrissette and James W. Ajioka. (2009) “The Early Years of Toxoplasma Research: What’s Past Is Prologue,” International Journal for Parasitology 39:865-869.
Narae Park, Kinrin Yamanaka, Dat Tran, Pete Chandrangsu, Johnny Akers, Jessica de Leon, Naomi S. Morrissette, Michael Selsted and Ming Tan. (2009) “The cell-penetrating peptide, Pep-1, has activity against intracellular chlamydial growth but not extracellular forms of Chlamydia trachomatis” Journal of Antimicrobial Chemotherapy 63:115-123.
Bryan D. Bell, Sabrina Leverrier, Brian M. Weist, Ryan H. Newton, Adrian F. Arechiga, Keith A. Luhrs, Naomi S. Morrissette and Craig M. Walsh. (2008) “FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells.” PNAS 105:16677-82.
Christopher Ma, Johnson Tran, Lakshmi Ganesan, David Wood, Catherine Li and Naomi S. Morrissette. (2008) “Secondary Mutations Correct Fitness Defects in Toxoplasma gondii with Alpha-tubulin Mutations,” Genetics 180: 845-56.
Naomi S. Morrissette and David Sept. (2008) “Dinitroaniline Interactions with Tubulin: Genetic and Computational Approaches to Define the Mechanisms of Action and Resistance,” in “The Plant Cytoskeleton” Yaroslav Blume, Diego Breviario, Vance Baird, (eds), Springer Publishing, pp. 351-372.
Christopher Ma, Catherine Li, Lakshmi Ganesan, Jean Oak, Susan Tsai and Naomi S. Morrissette. (2007) “Mutations in Alpha-tubulin Confer Dinitroaniline Resistance at a Cost to Microtubule Function,” Molecular Biology of the Cell 12: 4711-20.
Naomi S. Morrissette. (2007) “Tubulin, Microtubules and Microtubule-Associated Structures in Toxoplasma gondii,” in Toxoplasma Molecular and Cellular Biology, James Ajioka and Dominique Soldati, editors, Horizon Press, pp 507-522.
Naomi S. Morrissette, Arpita Mitra, David Sept and L. David Sibley. (2004) “Dinitroanilines Bind Alpha-tubulin and Disrupt Microtubules,” Molecular Biology of the Cell 15:1960-68.
Susan K. Dutcher, Naomi S. Morrissette, Andrea M. Preeble, Craig Rackley and John Stanga, (2002) “Epsilon-tubulin is an Essential Component of the Centriole,” Molecular Biology of the Cell 13:3859-69.
Naomi S. Morrissette and L. David Sibley, (2002) “Disruption of Microtubules Uncouples Budding and Nuclear Division in Toxoplasma gondii,” Journal of Cell Science, 115:1017-25.
Naomi S. Morrissette and L. David Sibley, (2002) “Cytoskeleton of Apicomplexan Parasites,” Microbiology and Molecular Biology Reviews, 66:21-38.
Elizaeth S. Gold, Naomi S. Morrissette, David M. Underhill, Jian Guo, Michael Bassetti and Alan Aderem, (2000) “Amphiphysin II-M, a Novel Amphiphysin Isoform, is Required for Macrophage Phagocytosis,” Immunity 12:285-92.
Elizabeth S. Gold, David Underhill, Naomi S. Morrissette, Jian Guo and Alan Aderem (1999) “Dynamin 2 Is Critical For Macrophage Phagocytosis,” Journal of Experimental Medicine 190:1849-56.
Naomi S. Morrissette, Elizabeth S. Gold, Jian Guo, Jessica A. Hamerman, Adrian Ozinsky, Vahe Bedian and Alan Aderem (1999) “Isolation and Characterization of Monoclonal Antibodies Directed Against Novel Components of Macrophage Phagosomes,” Journal of Cell Science 112:4705-4713.
Naomi Morrissette, Elizabeth Gold and Alan Aderem, (1999) “The Macrophage – A Cell for All Seasons,” Trends in Cell Biology 9: 199-201.
Naomi S. Morrissette and David S. Roos, (1998) “Toxoplasma gondii: A Family of Apical Antigens Associated with the Cytoskeleton,” Experimental Parasitology, 89 296-303.
Naomi S. Morrissette, John M. Murray and David S. Roos (1997) “Subpellicular Microtubules Associate with an Intramembranous Particle Lattice in the Protozoan Parasite Toxoplasma gondii,” Journal of Cell Science 110:35-42.
Thomas J. W. Stokkermans, Joseph D. Schwartzman, Karen Keenan, Naomi S. Morrissette, Lewis G. Tilney and David S. Roos (1996) “Inhibition of Toxoplasma gondii Replication by Dinitroaniline Herbicides.” Experimental Parasitology 84:355-370.
David S. Roos, Robert G. K. Donald, Naomi S. Morrissette and A. Lindsay C. Moulton, (1994) “Molecular Tools for Genetic Dissection of the Protozoan Parasite Toxoplasma gondii,” Methods in Cell Biology 45:27-63.
Naomi S. Morrissette, Vahe Bedian, Paul Webster and David S. Roos, (1994) “Characterization of Extreme Apical Antigens from Toxoplasma gondii,” Experimental Parasitology 79:445-59.
NIH RO1 1R01AI067981 “Mechanisms of Dinitroaniline Action, Selectivity and Resistance”
K22 AI055790 NIH Career Development Award, “Dissection of Dinitroaniline Specificity for Tubulin”
American Society for Cell Biology (ASCB)
American Society for Microbiology (ASM)
Genetics Society of America (GSA)