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Elise Rochet, Alexander Pfaff, Tristan Bourcier, Ermanno Candolfi; IL6: a new target for the treatment of ocular toxoplasmosis recurrence?. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2877.
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Ocular toxoplasmosis (OT), caused by Toxoplasma gondii, is a major cause of visual impairment worldwide. It is responsible for 30-50% of posterior uveitis with an estimated 800,000 cases in France and 1,400,000 in USA. The principal danger is the life-time risk of recurrence, the reactivation of previous, scarred lesions, occurring for both congenital and acquired OT. Current treatment neither eliminates the parasite from the retina, nor reduces the risk of reactivation. The underlying physiopathological mechanisms are still unknown. This is mainly due to a lack of an appropriate mouse model.
We established a murine model of recurrence through in situ reinfection. Three strains of mice with different susceptibility were evaluated in order to get insight into protective and pathological responses: the outbred Swiss-Webster, as well as the inbred C57BL/6 and CBA/J strains. Mice were intraperitoneally infected with cysts of the avirulent type II PRU strain, representative of most of human infections in Europe and North America and then intraocularly reinfected 4 weeks later with tachyzoites of the same strain. Ocular parasite load and immune regulator transcripts were quantified. We also performed histological analyses and cellular cytokine localizations. Finally, multiplex protein assay in aqueous humor allowed us to identify key cytokines and chemokines in our model.
We observed a major increase of ocular parasite load at day 7 post-reinfection in C57BL/6 and CBA/J mice, but not in Swiss-Webster mice. However, breakdown of retinal organization was only observed in C57BL/6 mice, Swiss-Webster and CBA/J conserving their retinal integrity. In C57Bl/6 mice, this retinal damage is associated with a significant increase of IFN-γ and IL-6 and the inflammatory chemokines MIP-1β, MCP-1 and RANTES. By means of neutralizing antibodies, we have confirmed the protective role of IFN-γ and the detrimental role of IL-6 for parasite elimination and retinal integrity.
We have established a useful model of OT recurrence. Our preliminary results identify protective and pathological immune response patterns. The study of cellular and molecular mechanisms of this host-pathogen interaction is in progress. Our results are a step towards identification of specific targets for clinical intervention which will reduce the risk and consequences of reactivation in patients.
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