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.
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.
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| 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 |
| Van Grol, Jennifer; Muniz-Feliciano, Luis; Portillo, Jose-Andres C et al. (2013) CD40 induces anti-Toxoplasma gondii activity in nonhematopoietic cells dependent on autophagy proteins. Infect Immun 81:2002-11 |
| Portillo, Jose-Andres C; Feliciano, Luis Muniz; Okenka, Genevieve et al. (2012) CD40 and tumour necrosis factor-? co-operate to up-regulate inducuble nitric oxide synthase expression in macrophages. Immunology 135:140-50 |
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| Subauste, Carlos S; Ajzenberg, Daniel; Kijlstra, Aize (2011) Review of the series ""Disease of the year 2011: toxoplasmosis"" pathophysiology of toxoplasmosis. Ocul Immunol Inflamm 19:297-306 |
| Tu, Zhidan; Portillo, Jose-Andres C; Howell, Scott et al. (2011) Photoreceptor cells constitutively express functional TLR4. J Neuroimmunol 230:183-7 |
| 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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