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. During the previous funding period, we demonstrated that Toxoplasma activates a host cell transcription factor named Hypoxia Inducible Factor 1 (HIF-1) and requires HIF-1 for growth. HIF-1 activation is achieved by the parasite decreasing the abundance of the PHD2 protein, which is the key negative regulator of HIF-1. Decreases in PHD2 protein is achieved by the parasite signaling though the Activin Like Kinase (ALK) receptor family. Significantly, inhibition of ALK signaling severely impairs parasite growth. Together these data indicate that ALK/HIF-1 signaling is a key host cell determinant for Toxoplasma gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche. In this proposal we will establish which ALK receptors function during Toxoplasma infection, how PHD2 protein levels are controlled in parasite- infected cells, and define the parasite processes dependent on host ALK/HIF-1 signaling. These studies are likely to provide important information regarding the interaction between Toxoplasma and its host cell.

Public Health Relevance

It is essential to develop new drugs against Toxoplasma gondii, which is a parasite that causes significant disease in AIDS patients as well as cancer patients and fetuses. Because the parasite can only grow inside of a host cell, we focus on and discover host cell pathways that are essential for Toxoplasma to grow. The goal of this proposal is to understand how and why Toxoplasma regulates one of these host cell pathways, which are both key steps towards developing new drugs to treat patients suffering from Toxoplasma infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069986-09
Application #
8596793
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2006-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$353,496
Indirect Cost
$116,821
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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
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; Coleman, Bradley I; Chen, Chun-Ti et al. (2015) Lytic Cycle of Toxoplasma gondii: 15 Years Later. Annu Rev Microbiol 69:463-85
Blader, Ira J (2015) Editorial overview: host-microbe interactions: parasites. Curr Opin Microbiol 26:89-91
Blader, Ira J; Koshy, Anita A (2014) Toxoplasma gondii development of its replicative niche: in its host cell and beyond. Eukaryot Cell 13:965-76
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
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
Zhao, Xiaoyan; Kumar, Praveen; Shah-Simpson, Sheena et al. (2013) Host microtubule plus-end binding protein CLASP1 influences sequential steps in the Trypanosoma cruzi infection process. Cell Microbiol 15:571-84
Butler, Noah S; Harris, Tajie H; Blader, Ira J (2013) Regulation of immunopathogenesis during Plasmodium and Toxoplasma infections: more parallels than distinctions? Trends Parasitol 29:593-602

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