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 pathways are rate- limiting for parasite growth. Identification of these host cell processes is important because if we can inhibit them or the parasite processes dependent on them from functioning then we can block parasite growth and disease. Modulation of host cell transcription is a common mechanism to make the host cell?s environment permissive for pathogen growth. Hypoxia Inducible Factor 1 (HIF-1) is one example of a host cell transcription that is activated by Toxoplasma infection and is required for parasite growth. In the previous funding period, we found that HIF-1 is activated by Toxoplasma triggering the nuclear export and subsequent lysosomal degradation of the PHD2 protein, which is the key negative regulator of HIF-1. Decreases in PHD2 protein is achieved by the parasite activating a host cell receptor named Activin Like Kinase 4 (ALK4). Finally, we discovered that HIF-1 promotes Toxoplasma growth by upregulating the host glycolytic hexokinase 2. In this proposal we will establish how Toxoplasma stimulates PHD2 nuclear export and lysosomal degradation, what ligand binds to ALK4, and how hexokinase 2 acts to promote parasite growth. These studies are likely to provide important information regarding the interaction between Toxoplasma and its host cell.

Public Health Relevance

Toxoplasma gondii is an important disease-causing parasite that can only grow when it is inside of a host cell. The long-term goal of this project is to understand what specific factors within the host cell are needed by the parasite. This is important because identifying these factors and the parasite processes dependent on these factors represent novel drug targets that are severely needed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069986-13
Application #
9431096
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2006-04-01
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
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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