Parasites of the phylum Apicomplexa rely on actin-based motility for invasion of host cells. Included in this group are the opportunistic pathogens Toxoplasma gondii and Cryptosporidium spp. Infections with these opportunistic pathogens remain important complications of AIDS, especially in populations where effective anti-HIV therapies are not widely available. More effective drugs to combat these opportunistic infections are sorely needed and fundamental studies of parasite biology have the potential to identify new targets. Our preliminary studies have revealed important structural, molecular, and kinetic differences in the parasite cytoskeleton. Gliding motility and cell invasion by these parasites depend on the rapid assembly and turnover of actin filaments. Hence, agents that disrupt the actin cytoskeleton are highly toxic to these parasites. A combination of cell biological, biochemical, genetic, and molecular modeling approaches will be used to explore the cytoskeleton in parasites. Fundamental knowledge from these studies will be used to design and synthesize specific inhibitors of the cytoskeleton in parasites. Inhibitors will be screened in vitro and in vivo for activity against the parasite Toxoplasma. The proposed studies have the potential to provide new anti-parasitic agents for control of toxoplasmosis, cryptosporidiosis, and possibly other opportunistic infections in immunocompromised patients with AIDS. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073155-02
Application #
7475708
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rogers, Martin J
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$350,335
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Skillman, Kristen M; Ma, Christopher I; Fremont, Daved H et al. (2013) The unusual dynamics of parasite actin result from isodesmic polymerization. Nat Commun 4:2285
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Mehta, Simren; Sibley, L David (2011) Actin depolymerizing factor controls actin turnover and gliding motility in Toxoplasma gondii. Mol Biol Cell 22:1290-9
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Sibley, L David (2010) How apicomplexan parasites move in and out of cells. Curr Opin Biotechnol 21:592-8

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