L. David Sibley Professor Phone, office: (314)-362-8873 Phone, lab: (314)-362-8874 FAX: (314)-362-3203 email: sibley@borcim.wustl.edu Lab Web Page 9230 McDonnell Pediatric Research Building Box 8230 Department of Molecular Microbiology Washington University School of Medicine 660 South Euclid Avenue St. Louis, MO 63110-1093.

Research Interests | CV | Publications | Technology for licensing

Research Interests

We are interested in survival adaptations of intracellular parasites that are important pathogens in man. We study Toxoplasma, a protozoan parasite that infects virtually all types of nucleated vertebrate cells and which provides a model for studying host cell invasion. We have recently demonstrated that the parasite actively penetrates its host cell using a novel process that depends on cytoskeletal proteins within the parasite. Within the host cell, the parasite resides within a specially modified vacuole that forms from the plasma membrane during invasion, but remains segregated from other endocytic compartments and fails to undergo normal processing. The parasite containing vacuole is extensively modified by secretion of proteins and lipids from the parasite. We are also exploring the mechanisms of protein secretion, endocytic trafficking, and antigen processing in Toxoplasma-infected cells.

One important aspect of understanding the molecular basis of intracellular parasitism is the development of molecular genetic techniques to complement cellular and biochemical studies. We are involved in the development of genetic tools for Toxoplasma including the construction of a genomic map, development of vectors for DNA transformation and protein expression, and large-scale sequencing of cDNAs for gene discovery. These approaches are being applied to identify the molecular basis of virulence and to examine mutants with altered phenotypes in adhesion, invasion, and intracellular survival.

Selected Publications in Chronological Order:
(a more comprehensive list is also available from PubMed)

 
1.    Nagamune K, and Sibley LD: Comparative genomic and phylogenetic analysis of calcium ATPases and calcium-regulated proteins in the Apicomplexa. Molec. Biol. Evol., 2006, 23, 1613-1627.
   
   
2.    Khan A, Jordon C, Vallochi A, Bellfort Jr R, Silveira C, LD Sibley. Unusual genotypes predominate among Brazilian strains of Toxoplasma gondii causing human ocular toxoplasmosis. Emerg. Infect. Dis. 2006, 12, 942-949.
   
   
3.    Sahoo N, Beatty WL, Heuser JE, Sept D, and LD Sibley. Unusual kinetic properties control rapid assembly and turnover of actin in the parasite Toxoplasma gondii. Mol. Biol. Cell, 2006, 17, 895-906.
   
   
4.    Gordon JL and LD Sibley. A family of actin-like proteins in the Apicomplexa. BMC Genom. 2005, Dec 12;6(1):179
   
   
5.    Robben PM, LaRegina M, Kuziel W.A., and LD Sibley. Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J. Exp. Med. 2005, 201, 1761-1769.
   
   
6.    Chini EN, Nagamune K, Wetzel DM, and LD Sibley. Evidence that the cADPR signaling pathway controls calcium-mediated microneme secretion in Toxoplasma gondii Biochem. J. 2005, 389, 269-277.
   
   
7.    Khan A, Taylor S, Su CL, Mackey AJ, Boyle J, Cole R, Glover D, Tang K, Paulsen IT, Berriman M, Boothoryd JC, Pfefferkorn ER, Dubey JP, Roos DS, Ajioka JW, Wootton JC, and LD Sibley. Composite genome map and recombination parameters derived from three archetypal lineages of Toxoplasma gondii.. Nuc. Acids Res. 2005, 33, 2980-2992.
   
   
8.    Brossier F, Jewett TJ, Sibley LD, and Urban S: A spatially-localized rhomboid protease cleaves cell surface adhesions essential for invasion by Toxoplasma. Proc. Natl. Acad. Sci. (USA), 2005, 102: 4146-4151
   
   
9.    Charron AJ, LD Sibley. Molecular partitioning during host cell penetration by T. gondii. Traffic, 2004, 5, 865-867.
   
   
10.    Wetzel DM, Chen LA, Ruiz FA, Moreno SNJ, LD Sibley. Calcium-mediated protein secretion potentiates motility by Toxoplasma gondii. J. Cell Sci., 2004, 117, 5739-5748.
    
    
11.    Sibley LD. Intracellular Parasite Invasion Strategies. Science, 2004, 304, 248-253.
    
    
12.    Jewett TJ and LD Sibley. The Toxoplasma proteins MIC2 and M2AP form a hexameric complex necessary for intracellular survival. J. Biol. Chem. 2004, 279, 9362-9369.
    
    
13.    Morrissette NS, Das A, Sept D, LD Sibley. Dinitroanilines bind alpha-tubulin to disrupt microtubules. Molec. Biol. Cell, 2004, 15, 1960-1968
    
    
14.    Robben PM, Mordue DG, Truscott SM, Takeda K, Akira S, LD Sibley. Induction of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype. J. Immunol., 2004, 172, 3686-3694.
    
    
15.    Su CL, Evans D, Cole RH, Kissinger JC, Ajioka JW, LD Sibley. Enhanced oral transmission acquired through recent recombination led to widespread expansion of Toxoplasma. Science, 2003, 299: 414-416.
    
    
16.    Li L, Brunck B, Kissinger J, Pape D, Martin J, Wylie T, Dante M, Tang K, Cole R, Fogarty S, Howe D, Liberator P, Diaz C, White M, Jerome ME, Johnson EA, Radke JA, Haywood RE, Chakrabarti D, Waterston R, Clifton S, Roos D, LD Sibley. Comparative gene expression in the Apicomplexa revealed by EST sequence analyses. Genome Res., 2003, 13: 443-454.
    
    
17.    Jewett TJ, and LD Sibley. Aldolase forms a bridge between cell surface adhesins and the actin cytoskeleton in apicomplexan parasites. Molec. Cell, 2003, 11: 885-894.
    
    
18.    Brossier F, Jewett TJ, Lovett JL, and LD Sibley. C-terminal processing of TgMIC2 is essential for invasion of host cell by Toxoplasma gondii. J. Biol. Chem., 2003, 278: 6229-6234..
    
    
19.    Wetzel D, Håkansson S, LD Sibley. Actin filament polymerization regulates gliding motility by apicomplexan parasites. Molec. Biol. Cell. 2003, 14, 396-406.
    
20.    Charron A., LD Sibley. Host cells: mobilizable lipid resources for the intracellular parasite Toxoplasma gondii. J. Cell Sci., 2002, 115: 3049-3059
    
    
21.    Su CL, Howe DK, Dubey JP, Ajioka J, LD Sibley. Acute virulence in Toxoplasma is mediated by several discrete loci common to the type I lineage. Proc. Natl. Acad. Sci. (USA), 2002, 99: 10753-10758
    
    
22.    Barragan A, LD Sibley. Transepithelial migration of Toxoplasma gondii is linked to parasite motility and virulence. J. Exp. Med., 2002, 195: 1625-1633.
    
    
23.    Lovett Jl, Moreno SNJ, LD Sibley. Toxoplasma gondii microneme secretion involves intracellular Ca+2 release from IP3/ryanodine sensitive stores. J. Biol. Chem., 2002, 277: 25870-25876.
    
    
24.    Mercier C, Dubremetz JF, Rauscher B, Lecordier L, LD Sibley, MF Cesbron-Delauw. Biogenesis of a nanotubular network in the Toxoplasma parasitophorous vacuole induced by parasite proteins. Molec. Biol. Cell, 2002, 13: 2397-2409.
    
    
25.    Mordue DM, Monroy F, La Regina M, Dinarello C, LD Sibley. Acute toxoplasmosis leads to lethal over-production of Th1 cytokines. J. Immunol. 2001, 167: 4574-4584.
    
    
26.   Håkansson S, Charron AJ, LD Sibley. Toxoplasma evacuoles: a two step process of secretion and fusion forms the parasitophorous vacuole. EMBO J. 2001, 20: 1-13..
    
    
27.    Carruthers VB, Sherman GD, LD Sibley. The Toxoplasma adhesive protein MIC2 is proteolytically processed at multiple sites by two distinct parasite-derived proteases. J. Biol. Chem. 2000, 275, 14346-14353.
    
    
28.    Mordue D, Desai N, Dustin M, LD Sibley. 1999 Invasion by Toxoplasma gondii establishes a moving junction that selectively excludes host cell plasma membrane proteins on the basis of their membrane anchoring. J. Exp. Med. 190, 1783-1792.
    
29.    Håkansson S, Morisaki H, Heuser JE, LD Sibley. Time-lapse video microscopy of gliding motility in Toxoplasma gondii reveals a novel, biphasic mechanism of cell locomotion. Molec. Biol. Cell, 1999, 10: 3539-3547.
    
    
30.    Carruthers VB, and Sibley LD: Mobilization of intracellular calcium stimulates microneme discharge in Toxoplasma gondii. Molec. Microbiol. 1999; 31(2): 421-8.
    
    
31.    Mercier C, Cesbron-Delauw MF, and Sibley LD: The amphipathic alpha helices of the Toxoplasma protein GRA2 mediate post-secretory membrane association. J. Cell Sci. 1998; 111: 2171-2180.
    
    
32.    Dobrowolski JM, Carruthers VB, and Sibley LD: Participation of myosin in gliding motility and host cell invasion by Toxoplasma gondii. Molec. Microbiol. 1997; 26: 163-173.
    
    
33.    Mordue D, and Sibley LD: Intracelluar fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends on the mechanism of entry. J. Immunol. 1997; 159: 4452-4459.
    
    
34.    Carruthers VB, and Sibley LD: Sequential protein secretion from three distinct organelles of Toxoplasma gondii accompaines invasion of human fibroblasts. Eur. J. Cell Biol. 1997; 73: 114-123.
    
    
35.    Dobrowolski J, and Sibley LD: Toxoplasma invasion of mammalian cells is powered by the parasite's actin cytoskeleton. Cell 1996; 84: 933-939.
    
    
36.    Messina M, Niesman IR, Mercier C, and Sibley LD: Stable DNA transformation of Toxoplasma gondii using phleomycin selection. Gene 1995; 165: 213-217.
    
    
37.    Howe DK, and Sibley LD:Toxoplasma gondi comprises three clonal lineages: correlation of parasite genotype with human disease. J. Infect. Dis. 1995; 172: 1561-1566.
    
    
38.    Morisaki HM, Heuser JE, and Sibley LD: Invasion of Toxoplasma gondii occurs by active penetration of the host cell. J. Cell Sci. 1995; 108: 2457-2464.
    
    
39.    Asai T, Miura S, Sibley LD, Okabayashi H, and Takeuchi T: Biochemical and molecular characterization of nucleoside triphosphate hydrolase isozymes from the parasitic protozoan Toxoplasma gondii. J. Biolog. Chem. 1995; 270: 11391-11397.
    
    
40.    Sibley LD, Niesman IR, Parmley SF, and Cesbron-Delauw MF: Regulated secretion of multi-lamellar vesicles leads to formation of a tubulo-vesicular network in host cell vacuoles occupied by Toxoplasma gondii. J. Cell Sci. 1995; 108: 1669-1677.
    
    
41.    Sibley LD, Messina M, and Niesman IR: Stable DNA transformation in the obligate intracellular parasite Toxoplasma gondii by complementation of tryptophan auxotrophy. Proc. Nat. Acad. Sci. (USA) 1994; 91: 5508-5512.
    
    
42.    Sibley LD, Leblanc AJ, Pfefferkorn ER, and Boothroyd JC: Generation of a restriction fragment length polymorphism linkage map for Toxoplasma gondii. Genetics 1992; 132: 1003-1015.
    
    
43.    Sibley LD, and Boothroyd JC: Virulent strains of Toxoplasma gondii comprise a single clonal lineage. Nature (Lond.) 1992; 359: 82-85.
    
    
44.    Sibley LD, Adams LB, Fukatomi Y, and Krahenbuhl JL: Tumor necrosis factor-alpha triggers antitoxoplasmal activity of IFN-gamma primed macrophages. J. Immunol. 1991; 147: 2340-2345.
    
    
45.    Sibley LD, Krahenbuhl JL, Adams GMW, and Weidner E: Toxoplasma modifies macrophage phagosomes by secretion of a vesicular network rich in surface proteins. J. Cell Biol. 1986; 103: 867-874.
    
    
46.    Sibley LD, Weidner E, and Krahenbuhl JL: Phagosome acidification blocked by intracellular Toxoplasma gondii. Nature (Lond.) 1985; 315: 416-419.

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