The obligate intracellular protozoan Toxoplasma gondii is the most common cause of infectious retinochoroiditis in the world. Ocular toxoplasmosis is an important cause of loss of visual acuity especially in children with congenital infection as well as the elderly and the immunosuppressed. Unfortunately, current treatment options are not ideal since there is no evidence that they improve visual function or prevent relapses of the disease. A better understanding of the mechanisms that promote ocular toxoplasmosis has the potential to lead to new and improved therapeutic approaches against this disease. T. gondii resides within host cells in a parasitophorous vacuole that must not fuse with lysosomes so that the parasite can survive and replicate. Autophagy is a constitutive process of lysosomal degradation. Recent studies identified a new paradigm of pathogen survival whereby T. gondii activates EGFR signaling in host cells and as a result avoids autophagic degradation. This finding is likely relevant to ocular toxoplasmosis because mice deficient in autophagy proteins have enhanced susceptibility to ocular toxoplasmosis. The objectives of this application are to understand how T. gondii activates EGFR signaling in retinal cells and to determine the role of EGFR signaling in the development of ocular toxoplasmosis. The central hypothesis for the proposed research is that T. gondii causes prolonged EGFR signaling by activating a specific host cell protein kinase and inhibition of EGFR signaling enhances protection against ocular toxoplasmosis. This hypothesis will be tested using genetic approaches that block specific signaling pathways, immunochemical studies and transgenic mice. In the first specific aim we will determine if activation of a protein kinase causes prolonge EGFR activation in T. gondii-infected retinal cells. In the second aim, we will determine if cell type-specific blockade of EGFR enhances resistance to ocular toxoplasmosis. In the third aim, we will determine how inhibition of EGFR protects against ocular toxoplasmosis. The proposed work may lead to new strategies to eradicate T. gondii and treat ocular toxoplasmosis based on modulation host cell signaling.

Public Health Relevance

Ocular toxoplasmosis is a relapsing disease and a major cause of visual loss. Current treatment does not affect visual outcome. We plan studies that will identify the role of molecules that promote the development and progression of this disease and may identify novel therapeutic targets against ocular toxoplasmosis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018341-07
Application #
9060327
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2007-07-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Chen, Yu; Sawada, Osamu; Kohno, Hideo et al. (2013) Autophagy protects the retina from light-induced degeneration. J Biol Chem 288:7506-18
Muniz-Feliciano, Luis; Van Grol, Jennifer; Portillo, Jose-Andres C et al. (2013) Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite. PLoS Pathog 9:e1003809
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Van Grol, Jennifer; Subauste, Cecilia; Andrade, Rosa M et al. (2010) HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3. PLoS One 5:e11733

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