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Pauline Ogolla, Jose-Andres Portillo, Genevieve Okenka, Ganes Sen, Carlos Subauste; The Role of PKR in the Control Of Ocular Toxoplasmosis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2761.
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Toxoplasma gondii is a leading cause of infectious retino-choroiditis worldwide. PKR is a serine/threonine kinase that has been shown to control infection by various viruses. However, it is not known if PKR can control a non-viral pathogen such as T. gondii.
Wild type B6 and PKR-/- mice were infected with T. gondii. Eyes were examined for histopathology and T. gondii DNA levels and mRNA levels of IFN-γ, TNF-α and NOS2 assessed by quantitative PCR. Phenotypic composition of the spleen and T cell responses were assessed by flow cytometry. Anti-microbial activity of macrophages and microglia was assessed by microscopy.
PKR-/- mice had a higher parasite load and worsened histopathology of the eye (retinal inflammation, invasion of the retina by retinal pigmented epithelial cells and destroyed retinal architecture). However, compared to wild type B6, PKR-/- mice exhibited unimpaired expression of IFN-γ, TNF-α and NOS2 in the eyes. Additionally, PKR-/- mice had comparable levels of CD4+ and CD8+ T cells, monocytes, Natural killer cells and B lymphocytes in the spleen and were not defective in T cell cytokine responses. In addition to IFN-γ/TNF-α, the CD40 - autophagy pathway is required for protection against ocular toxoplasmosis. Macrophages and microglia from PKR-/- mice were defective in anti-T. gondii activity in response to CD40 stimulation but not in response to stimulation with IFN-γ/TNF-α. PKR was required for CD40-induced recruitment of the autophagy protein LC3 around the parasitophorous vacuole and fusion with the lysosomes.
These studies indicate that PKR is key for the control of ocular toxoplasmosis. PKR is required for the autophagy pathway-dependent killing of T. gondii.
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