| The intracellular protozoan Toxoplasma gondii is an opportunistic pathogen capable of causing severe disease and sometimes death. Nevertheless, in most cases the parasite successfully establishes asymptomatic infection. This is achieved by the parasite's ability to both stimulate appropriate immunity and downregulate specific immune functions. The interaction between pathogen and host leading to this successful outcome is the main theme of this dissertation. In particular, my study focuses on intracellular signaling pathways activated or suppressed during macrophage infection with Toxoplasma.; T. gondii induces IL-12 production, which through its ability to stimulate cell-mediated immunity, is a key cytokine in host resistance to the parasite. I found that the parasite utilizes host p38 mitogen-activated protein kinase (MAPK) to trigger IL-12 induction and that it employs autophosphorylation as a mechanism to activate this MAPK.; Signaling leading to IL-12 production during virulent and avirulent parasite infection was compared. In particular, the role of MyD88, a common adaptor of Toll-like receptor signaling, was examined. I found that MyD88 plays a role only in avirulent strain infection in terms of IL-12 induction and p38 MAPK activation. In contrast, the virulent RH strain uses MyD88-independent pathways to trigger IL-12 production and MAPK activation.; Toxoplasma downregulates LPS-triggered cytokine responses. I found that Toxoplasma inhibited LPS-induced MAPK phosphorylation, an activity required for endotoxin-induced proinflammatory cytokine production. Moreover, Toxoplasma infection renders macrophages resistant to apoptosis inducers. I found Gi protein-coupled receptors-mediated phosphatidylinositol 3-kinase (PI3-K) activation is a mechanism used by the parasite to prevent apoptosis.; This dissertation shows that Toxoplasma stimulates host signaling pathways leading to IL-12 production, at the same time blocking inflammatory cytokine production and apoptosis triggered by other mediators. The study provides an understanding of the mechanisms underlying these responses, and elucidates the basic nature of the molecular interaction between Toxoplasma and its host. |
