Toxoplasma gondii is a common parasitic infection of humans that causes opportunistic disease in immunocompromised patients, including those with AIDS or those undergoing chemotherapy for cancer or organ transplant. The symptoms of infection vary considerably, ranging from subclinical to severe, although the factors that control these disparate outcomes are poorly understood. One component that likely contributes to disease severity is the genetic makeup of the parasite. However, little is known about the specific parasite genes that are responsible for influencing disease severity. Our previous studies have shown that T. gondii has a highly unusual genetic makeup consisting of three clonal lineages that are wide spread in North America and Europe. These three strain types differ substantially in the immune responses they evoke and the severity of infections that they cause. The proposed studies will investigate the molecular basis of acute virulence in Toxoplasma gondii using forward and reverse genetics to identify genes important for pathogenesis. We will explore the role of secretory kinases, recently implicated as major virulence determinants of T. gondii, and characterize their cellular and biochemical mechanisms of action. Additional genetic crosses between different parasite genotypes will be undertaken to map genes that regulate differences in pathogenesis, including genes that control tissue migration, induction of immune responses, and acute virulence. Finally, we will identify genes that contribute to pathogenesis of newly described T. gondii lineages from other geographic regions. Forward and reverse genetic analyses will be used to map genes and determine the molecular basis of virulence in these newly identified parasite lineages. These studies will provide important fundamental knowledge about the identify and mechanisms of action of virulence determinants in T. gondii that contribute to human disease.

Public Health Relevance

Toxoplasma gondii is a widespread parasitic infection that can cause severe disease in immunocompromised patients. Our studies seek to define the factors that contribute to the severity of disease caused by this parasite. By understanding the virulence determinants of the parasite that enable it to cause harm, it may be possible to develop new therapeutic approaches to combat human infection. The findings are highly relevant to the pathology of toxoplasmosis in immunocompromised patient, including individuals with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036629-19
Application #
8307417
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Joy, Deirdre A
Project Start
1994-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
19
Fiscal Year
2012
Total Cost
$411,422
Indirect Cost
$129,823
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Choi, Jayoung; Park, Sunmin; Biering, Scott B et al. (2014) The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40:924-35
Etheridge, Ronald D; Alaganan, Aditi; Tang, Keliang et al. (2014) The Toxoplasma pseudokinase ROP5 forms complexes with ROP18 and ROP17 kinases that synergize to control acute virulence in mice. Cell Host Microbe 15:537-50
Dubey, J P; Van Why, K; Verma, S K et al. (2014) Genotyping Toxoplasma gondii from wildlife in Pennsylvania and identification of natural recombinants virulent to mice. Vet Parasitol 200:74-84
Alaganan, Aditi; Fentress, Sarah J; Tang, Keliang et al. (2014) Toxoplasma GRA7 effector increases turnover of immunity-related GTPases and contributes to acute virulence in the mouse. Proc Natl Acad Sci U S A 111:1126-31
Shen, Bang; Brown, Kevin M; Lee, Tobie D et al. (2014) Efficient gene disruption in diverse strains of Toxoplasma gondii using CRISPR/CAS9. MBio 5:e01114-14
Selleck, Elizabeth M; Fentress, Sarah J; Beatty, Wandy L et al. (2013) Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii. PLoS Pathog 9:e1003320
Fleitz, Antoine; Nieves, Edward; Madrid-Aliste, Carlos et al. (2013) Enhanced detection of multiply phosphorylated peptides and identification of their sites of modification. Anal Chem 85:8566-76
Fentress, Sarah J; Sibley, L David (2011) The secreted kinase ROP18 defends Toxoplasma's border. Bioessays 33:693-700
Behnke, Michael S; Khan, Asis; Wootton, John C et al. (2011) Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases. Proc Natl Acad Sci U S A 108:9631-6
Fentress, Sarah J; Behnke, Michael S; Dunay, Ildiko R et al. (2010) Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell Host Microbe 8:484-95

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