Abstract
When a person becomes infected with Toxoplasma gondii, ocular toxoplasmosis is the most common clinical presentation. The medical literature describes retinitis with surrounding hyperpigmentation secondary to proliferative changes in the retinal pigment epithelium, which is sufficiently characteristic that investigation often is not needed to make the diagnosis. We aimed to establish the frequency of “typical” ocular toxoplasmosis and delineate its molecular basis. Among 263 patients presenting consecutively with ocular toxoplasmosis to Ribeirão Preto General Hospital in Brazil, where T. gondii infection is endemic, 94.2% of 345 eyes had retinal hyperpigmentation. In ARPE-19 and primary human retinal pigment epithelial cell monolayers exposed to minimal numbers of T. gondii tachyzoites, the proliferation marker–KI-67–was increased in uninfected cells, which also were rendered more susceptible to infection. RT-qPCR and ELISA detected increased expression of vascular endothelial growth factor A (VEGF) and insulin-like growth factor (IGF)1, and decreased expression of thrombospondin (TSP)1 by infected cells. Blockade of VEGF and IGF1—or supplementation of TSP1—reversed the proliferation phenotype in uninfected cells. Our findings confirm that hyperpigmentation is a characteristic feature of retinitis in ocular toxoplasmosis, and demonstrate that T. gondii-infected human retinal pigment epithelial cells secrete VEGF and IGF1, and reduce production of TSP1, to promote proliferation of adjacent uninfected cells and create this disease-specific appearance.
Highlights
When a human is infected with the protozoan parasite, Toxoplasma gondii, the most common clinical manifestation is an inflammatory eye condition known as ocular toxoplasmosis [1]
We show that human retinal epithelial cells secrete growth factors in response to infection with T. gondii that promote the proliferation of neighboring uninfected cells, which increases the susceptibility of these cells to infection with the parasite
To address clinical relevance of the changes in vascular endothelial growth factor A (VEGF), insulin-like growth factor 1 (IGF1), and thrombospondin 1 (TSP1) expression that were observed in the cell line, primary retinal pigment epithelial cell isolates, prepared separately from two human cadaveric donor eye pairs, were infected and interrogated, with consistent results (Figure 3B). These findings suggest that increased production of VEGF and IGF1, and decreased production of TSP1, by infected human retinal pigment epithelial cells might be responsible for the proliferation of adjacent uninfected cells
Summary
When a human is infected with the protozoan parasite, Toxoplasma gondii, the most common clinical manifestation is an inflammatory eye condition known as ocular toxoplasmosis [1]. Ocular toxoplasmosis involves the posterior eye and is characterized by recurrent necrotizing retinitis, with frequent extension of the inflammation and tissue destruction into the choroid, which encapsulates the retina. Recurrences of retinitis occur at the edge of the pigment ring This clinical picture is sufficiently characteristic that it is referred to in the ophthalmic medical literature as “typical ocular toxoplasmosis” [4]; most ophthalmologists diagnose the condition and initiate treatment with anti-parasitic and corticosteroid drugs on the basis of the clinical appearance alone, without the need to sample and test ocular fluids [5]
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