The obligate intracellular parasite Toxoplasma gondii is a major opportunistic infection of AIDS patients. Toxoplasma also causes devastating disease to fetuses and other immunocompromised patients. While much work has focused on identifying and characterizing Toxoplasma proteins and pathways important for growth and virulence of this intracellular pathogen, less is known about which host cell processes are rate-limiting for parasite growth. Identification of these host cell processes is important because if we can inhibit them from functioning, then we can block parasite growth and disease. Modulation of host cell transcription is a common mechanism that pathogens use to alter the host cell's environment to become permissive for pathogen growth. Our previous work demonstrated that Toxoplasma rapidly and specifically activated a host cell transcription factor named Hypoxia Inducible Factor 1 (HIF1). HIF1 is heterodimeric transcription factor composed of alpha and beta subunits that regulates transcription by either directly binding DNA or by repressing the activity of a second transcription factor, c-myc. Significantly, we find that HIF1 is necessary for Toxoplasma growth at physiological oxygen levels even though this transcription factor is dispensable for host cell growth and survival. These data indicate that HIF1 regulates the expression of host cell genes that function in pathways necessary for Toxoplasma growth. In addition, they are the first to demonstrate that a host cell transcription factor is required for Toxoplasma to grow within its host cell. The goals of this proposal are to elucidate how Toxoplasma activates HIF1 and to identify the HIF1-regulated pathways necessary for parasite growth. Specifically, Specific Aim 1 will identify the step in the HIF1 activation pathway that is modulated by infection.
Specific Aim 2 will examine whether Toxoplasma requires HIF1 to regulate transcription by directly binding DNA and by repressing c-myc.
In Specific Aim 3, we will identify the HIF1 regulated genes and pathways that are important for Toxoplasma growth. These studies are likely to provide important information regarding the interaction between Toxoplasma and its host cell. In addition, they will provide important information to develop new drugs to treat toxoplasmosis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI069986-03S1
Application #
7642335
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2008-07-15
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$32,768
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Wohlfert, Elizabeth A; Blader, Ira J; Wilson, Emma H (2017) Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle. Trends Parasitol 33:519-531
Saha, Sudeshna; Coleman, Bradley I; Dubey, Rashmi et al. (2017) Two Phosphoglucomutase Paralogs Facilitate Ionophore-Triggered Secretion of the Toxoplasma Micronemes. mSphere 2:
Rahman, Kazi; Zhao, Peng; Mandalasi, Msano et al. (2016) The E3 Ubiquitin Ligase Adaptor Protein Skp1 Is Glycosylated by an Evolutionarily Conserved Pathway That Regulates Protist Growth and Development. J Biol Chem 291:4268-80
Dittmar, Ashley J; Drozda, Allison A; Blader, Ira J (2016) Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth. mSphere 1:
Blader, Ira J; Coleman, Bradley I; Chen, Chun-Ti et al. (2015) Lytic Cycle of Toxoplasma gondii: 15 Years Later. Annu Rev Microbiol 69:463-85
Menendez, Matthew T; Teygong, Crystal; Wade, Kristin et al. (2015) siRNA Screening Identifies the Host Hexokinase 2 (HK2) Gene as an Important Hypoxia-Inducible Transcription Factor 1 (HIF-1) Target Gene in Toxoplasma gondii-Infected Cells. MBio 6:e00462
West, Christopher M; Blader, Ira J (2015) Oxygen sensing by protozoans: how they catch their breath. Curr Opin Microbiol 26:41-7
Blader, Ira J (2015) Editorial overview: host-microbe interactions: parasites. Curr Opin Microbiol 26:89-91
Brown, Kevin M; Suvorova, Elena; Farrell, Andrew et al. (2014) Forward genetic screening identifies a small molecule that blocks Toxoplasma gondii growth by inhibiting both host- and parasite-encoded kinases. PLoS Pathog 10:e1004180
Farrell, Andrew; Coleman, Bradley I; Benenati, Brian et al. (2014) Whole genome profiling of spontaneous and chemically induced mutations in Toxoplasma gondii. BMC Genomics 15:354

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