Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance.

Raul Ramos Furtado Dias,Roberto Carlos Tedesco,Eulógio Carlos Queiroz De Carvalho,Antonio Carlos Silva,Carla Cristina Da Silva Leite,Katia Da Silva Calabrese,Maria De Fatima Sarro-Silva,Renato Augusto Damatta,Ira J Blader

doi:10.1371/journal.pone.0113374

Abstract

Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

Highlights

Infection with Toxoplasma gondii is acquired by direct contact with food through ingestion of undercooked or raw meat containing the parasite cysts, congenitally through the placenta [1], or from oocyst contamination of soil or water [2]
Considering the divergent tolerance resistant (TR) and tolerance susceptible (TS) inflammatory and immuno-tolerogenic profiles produced by genetic selection for extreme phenotypes of oral tolerance, and for their influence on infections, we aimed to know if TR and TS mice orally infected by T. gondii may be useful models to study inflammatory diseases caused by this parasite
When infected with 50 cysts 100% of the C57BL/6 survived after the second week, while TS mice attained 95% survival and TR mice 60% (Figure 1a)

Summary

Introduction

Infection with Toxoplasma gondii is acquired by direct contact with food through ingestion of undercooked or raw meat containing the parasite cysts, congenitally through the placenta [1], or from oocyst contamination of soil or water [2]. In C57BL/6 mice infected with high T. gondii burdens, IBD – like is observed with similar morphopathologic characteristics of human IBD [7]. This inflammatory process results in early mortality of the susceptible hosts. A more sophisticated model such as TLR4-deficient mice (C57BL/10ScN, carrying a deletion of the TLR4) presents 60% survival after oral infection but reduced immunopathology [12] This murine ileal immunopathology resembling acute episodes in human IBD [7, 13] suggests that T. gondii is involved in the etiopathogeny, especially in human Crohn’s disease [14]. Intestinal chronic pathology investigation in mice orally infected with T. gondii is relevant

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