ABSTRACT
The infection of the host cell with Toxoplasma gondii involves the regulated secretion of microneme proteins (TgMICs). The complex formed by TgMIC1/4/6 on the T. gondii surface participates in the adhesion and invasion processes. Here, we show that TgMIC1-and TgMIC4-stimulated dendritic cells and macrophages produce proinflammatory cytokines through TLR2 and TLR4 signalling. This process depends on sugar recognition, since it was shown to be inhibited by point mutations introduced in the TgMIC1 and TgMIC4 carbohydrate-recognition domains. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to TgMICs. Following parasite infection, phagocytes lacking TLR2 and TLR4 failed to generate an early IL-12 response in contrast to wild type cells. Moreover, TgMIC1-KO and TgMIC1/TgMIC4-DKO parasites stimulated a lower IL-12 response than wild type parasites. Together, our data reveal that TgMIC1 and TgMIC4 interact physically with TLR2 and TLR4 N-glycans to trigger an early IL-12 response to T. gondii, which may contribute to acute control of infection.
AUTHOR SUMMARY Toxoplasmosis is caused by the protozoan Toxoplasma gondii, of the Apicomplexa phylum. It comprises important parasites able to infect a broad diversity of animals, including humans. A particularity of T. gondii is the ability to invade all nucleated cells of its hosts through an active process, which depends on the expression of surface adhesion proteins. These proteins are secreted by specialized organelles localized in the parasite apical region, such as micronemes. We show, in this study, that two of the microneme proteins from T. gondii play a function that goes beyond the adhesion activity. These microneme proteins denoted TgMIC1 and TgMIC4 have the ability to recognize sugars. Through this property, they bind to sugars contained in receptors on mammalian cells surface. This binding starts the process of activation of innate immune cells and secretion of cytokines, which may act by making more efficient the host defence mechanisms against the parasite, especially in the beginning of the infection. It results in an appropriate response because it helps to control the parasite replication during the acute infection and favours host healthy.