Malaria is the most common and deadly parasitic disease in the world. A number of factors have contributed to making malaria as serious a problem now as it was during the first half of the twentieth century. In any given year, there will be 300-500 million cases of malaria and 1-3% of those who contract the disease will not survive. Over 90% of the cases and deaths occur in Africa. As bad as that is, some experts foresee as much as a 20% annual increase in Africa's rate of malaria-related illness and death. Each year the world over, malaria destroys, through premature death and disability, the equivalent of at least 35 million years of healthy, productive human life and to date, there is no effective subunit vaccine for malaria. The incidence of drug-resistant parasite is increasing worldwide. The sequencing of the Plasmodium falciparum (and Plasmodium yoelii), the Anopheles gambiae and the Homo sapiens (and Mus musculus) genomes, the three organisms that comprise the complex life cycle of the malaria parasite, is complete and will aid in the study of the complex interactions responsible for the disease. Our laboratory is undertaking the investigation of two diverse topics, the protein-protein interactions involved in the invasion pathway and the whole genome expression analysis of various stages of the parasite life cycle, to potentially identify new targets for immunologic or chemotherapeutic intervention.
The invasive stages of apicomplexan parasites actively penetrate host cells, an essential ability for maintaining an intracellular lifestyle. What has become clear is that numerous parasite and host cell components participate in the rapid invasion process. The process of parasite invasion also involves a unique actin-myosin based motor that is localized between the plasma membrane and the inner membrane complex, a structure formed by two closely aligned membranes and supported by microtubules. Transmembrane proteins displaying adhesive properties were predicted to link the extracellular substrates with the motor. Studies are underway to analyze the proposed merozoite specific parasite ligand that links the red blood cell being invaded to the parasite actin-myosin motor. Again, using the yeast two-hybrid system and a bioinformatic approach we have identified components that link the actin-myosin motor to the inner membrane complex and may form one of the junctions involved in linking the parasite to the RBC to be invaded. Using structural information of the myosin-myosin light chain complex, we have potentially identified small molecule inhibitors of the invasion process. These studies have further led us to initiate the characterization of a second unique parasite myosin motor and its role in the life cycle of the parasite.
The second major aspect of the work in the laboratory involves the use of long-oligonucleotide gene-specific microarray to examine global patterns of gene expression in various stages of the rodent malaria P. yoelii. We have begun to characterize several potential nucleic acid binding proteins and the effects of over-expression or depletion on the global pattern of gene expression in the parasite.
Elevated levels of the Plasmodium yoelii homologue of macrophage migration inhibitory factor attenuate blood-stage malaria.
Thorat S, Daly TM, Bergman LW and Jr. Burns JM.
Infection and Immunity, 78: 5151-5162, 2010.
Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum
Kortagere S, Welsh WJ, Morrisey JM, Daly T, Ejigiri I, Sinnis P, Vaidya AB and Bergman LW.
Journal of Chemical Information and Modeling, 50: 840-849, 2010.
High mobility group protein HMGB2 is a critical regulator of plasmodium oocyst development.
Gissot M, Ting LM, Daly TM, Bergman LW and Sinnis P.
Journal of Biological Chemistry., 283: 17030-17038, 2008.
Functional characterization of a redundant Plasmodium TRAP family invasin, TRAP-like protein, by aldolase binding and a genetic complementation test.
Heiss K, Nie H, Kumar S, Daly TM, Bergman LW and Matuschewski K.
Eukaryotic Cell, 7: 1062-1070, 2008.
DNA microarrays detect effects of soil contamination on Arabidopsis thaliana gene expression.
Magrini KD, Basu A, Spotila JR, Avery HW, Bergman LW, Hammond R and Anandan S.
Environmental Toxicology & Chemistry., 27: 2476-2487, 2008.
Distinct malaria parasite sporozoites reveal transcriptional changes that cause differential tissue infection competence in the mosquito vector and mammalian host.
Mikolajczak SA, Silva-Rivera H, Peng X, Tarun AS, Camargo N, Jacobs-Lorena V, Daly TM, Bergman LW, de la Vega P, Williams J, Aly AS and Kappe SH.
Molecular and Cellular Biology., 28: 6196-6207, 2008.
A combined transcriptome and proteome survey of malaria parasite liver stages.
Tarun AS, Peng X, Dumpit R. F, Ogata Y, Silva-Rivera H, Camargo N. Daly TM, Bergman LW and Kappe SH.
Proceedings of the National Academy of Sciences of the United States of America. 105: 305-310, 2008.
The closed MTIP-myosin A-tail complex from the malaria parasite invasion machinery.
Bosch J, Turley S, Roach CM, Daly TM, Bergman L. W and WG. J Hol.
Journal of Molecular Biology, 372: 77-88, 2007.
Structure of the MTIP-MyoA complex, a key component of the malaria parasite invasion motor.
Bosch J, Turley S, Daly TM, Bogh SM, Villasmil ML, Zhou N, Morrisey JM, Vaidya AB, Bergman LW and Hol WG J.
Proceedings of the National Academy of Sciences of the United States of America, 103: 4852-4857, 2006.
Alteration in host cell tropism limits the efficacy of immunization with a surface protein of malaria parasites.
Shi Q, Cernetich A, Daly TM, Galvin G, Vaidya AB, Bergman LW and. Burns JM.
Infection & Immunity, 73: 6363-6371, 2005.
A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3.
Li X, Chen H, Oo TH, Daly TM, Bergman LW, Chishti, AH, and Oh SS.
The Journal of Biological Chemistry., 279: 5765-5771, 2004.
MSP-7 family members with similar expression patterns differ in ability to immunize against Plasmodium yoelii malaria.
Mello K, Daly TM, Long CA, Burns JM, and LW Bergman.
Infection and Immunity, 72: 1010-1018, 2004.
Apicomplexan gliding motility and host cell invasion: overhauling the motor model.
Kappe SHI, Buscaglia CA, Bergman LW, Coppens I, and Nussenzweig V.
Trends in Parasitology, 20: 13-16, 2004.
Myosin A tail domain interacting protein (MTIP) localizes to the inner membrane complex of Plasmodium sporozoites.
Bergman LW, Fujioka H, Daly TM, Fox S, Matuschewski K, Nussenzweig V, and Kappe SHI.
Journal of Cell Science, 116: 39-49, 2003.
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