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This work was supported by the the University of Tours (to IDP and FDG), the University of Montpellier (to SD and EC), the Deutsche Forschungsgemeinschaft (to RTS), the Wellcome Trust project grant 093228 (to TKS) and the Campus France/DAAD PHC PROCOPE 24931RE (to RTS and EC). The funding source has no involvement in the conduct of the research and preparation of the article. Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs. Publisher PDF

Toxoplasma gondii is a ubiquitous parasitic protozoan, which causes congenital infectious diseases as well as severe encephalitis, a major cause of death among immune-deficient persons, such as AIDS patients. T. gondii is normally controlled by the immune system of healthy individuals, leading to an asymptomatic infection. T. gondii triggers early cytokine production, which, to a certain extent, protects the host against replication of tachyzoites, the infective form of the parasite. Glycosylphosphatidylinositols (GPIs) constitute a class of glycolipids that have various functions, the most fundamental being to link proteins to eucaryotic cell membranes. GPIs are involved in the pathogenicity of other protozoan parasites and are known to induce tumor necrosis factor-alpha (TNF alpha) production. We show that GPIs highly purified from T. gondii tachyzoites, as well as their core glycans, induce TNF alpha production in macrophages. A chemically synthesized GPI of T. gondii lacking its lipid moiety, GPIa, has the same effect as the natural GPIs, whereas a chemically synthesized molecule with dialkylglycerol instead of diacylglycerol as lipid moiety, GPIb, does not induce TNF alpha production. Moreover, GPIb inhibits the TNF alpha production induced by T. gondii GPI or by GPIa. The core glycan prepared from the two chemically synthesized molecules activates macrophages, showing that the lipid moiety may regulate signaling. Stimulation of macrophages with GPIs of T. gondii results in activation of the transcription factor NF-kappa B, which is inhibited by the chemically synthesized GPIb, suggesting the involvement of NF-kappa B in TNF alpha gene expression. Our results support the idea that T. gondii GPIs are bioactive factors that participate in the production of TNF alpha during toxoplasmal pathogenesis.