The phylum Apicomplexa contains a large group of protozoan parasites responsible for numerous important human and livestock diseases. Several of these organisms (Toxoplasma, Cryptosporidium & Cyclospora) are also listed as type B pathogens of potential biodefense concern. Significant challenges remain in the antimicrobial drug treatment for these diseases. The discovery of a remnant chloroplast, the apicoplast, now presents several parasite specific pathways that can be exploited as specific drug targets to help overcome some of these challenges. Genomie, genetic and pharmacological data show that the apicoplast is essential for development and pathogenesis for Plasmodium and Toxoplasma validating it as a target and demonstrating the importance of the organelle for the biology of the organism. This proposal is focused on unraveling the mechanisms used by the parasite to faithfully replicate and segregate this important organelle and its genome. ? ? The chloroplast division machinery in plants and algae depends overwhelmingly on genes of cyanobacterial origin, with the bacterial tubulin homolog ftsZ being the most prominent. Our genomic analysis has not identified any clear homologs of these genes in Apicomplexa. How is the apicoplast divided in the absence of the conserved machinery? Based on our cell biological studies we hypothesize that in sharp contrast to plants the plastid in Apicomplexa is segregated using a genuinely eukaryotic mechanism - association with the centrosomes of the mitotic spindle. This proposal develops a number of mechanistic models to explain how the plastid is faithfully segregated into daughter cells, how fission occurs and is timed within the parasite cell cycle, and how the replication and maintenance of the organellar genome is tied into this process. To test these hypotheses we have assembled a set of highly compatible cell biological, comparative genomic and genetic experiments. Genomic and genetic screens will permit us to further refine our hypotheses, and will help us to populate them with additional molecular players beyond the genes and proteins already in hand. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064671-02
Application #
7149197
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2005-12-01
Project End
2010-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
2
Fiscal Year
2007
Total Cost
$285,862
Indirect Cost
Name
University of Georgia
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Fellows, Justin D; Cipriano, Michael J; Agrawal, Swati et al. (2017) A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in Toxoplasma gondii. MBio 8:
van Dooren, Giel G; Yeoh, Lee M; Striepen, Boris et al. (2016) The Import of Proteins into the Mitochondrion of Toxoplasma gondii. J Biol Chem 291:19335-50
Lévêque, Maude F; Berry, Laurence; Cipriano, Michael J et al. (2015) Autophagy-Related Protein ATG8 Has a Noncanonical Function for Apicoplast Inheritance in Toxoplasma gondii. MBio 6:e01446-15
Williams, Melanie J; Alonso, Hernan; Enciso, Marta et al. (2015) Two Essential Light Chains Regulate the MyoA Lever Arm To Promote Toxoplasma Gliding Motility. MBio 6:e00845-15
Beckmann, Elena A; Köhler, Anna M; Meister, Cindy et al. (2015) Integration of the catalytic subunit activates deneddylase activity in vivo as final step in fungal COP9 signalosome assembly. Mol Microbiol 97:110-24
Ramakrishnan, Srinivasan; Docampo, Melissa D; MacRae, James I et al. (2015) The intracellular parasite Toxoplasma gondii depends on the synthesis of long-chain and very long-chain unsaturated fatty acids not supplied by the host cell. Mol Microbiol 97:64-76
Suvorova, Elena S; Francia, Maria; Striepen, Boris et al. (2015) A novel bipartite centrosome coordinates the apicomplexan cell cycle. PLoS Biol 13:e1002093
Sheiner, Lilach; Fellows, Justin D; Ovciarikova, Jana et al. (2015) Toxoplasma gondii Toc75 Functions in Import of Stromal but not Peripheral Apicoplast Proteins. Traffic 16:1254-69
Daher, Wassim; Morlon-Guyot, Juliette; Sheiner, Lilach et al. (2015) Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii. Cell Microbiol 17:559-78
Lentini, Gaelle; Kong-Hap, Marie; El Hajj, Hiba et al. (2015) Identification and characterization of Toxoplasma?SIP, a conserved apicomplexan cytoskeleton protein involved in maintaining the shape, motility and virulence of the parasite. Cell Microbiol 17:62-78

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