Host immune responses in a non replication model of Toxoplasma gondii infection

Toxoplasma gondii is a highly successful obligate intracellular parasite capable of infecting humans and poses a significant health threat to people with AIDS and who are immunosuppressed. Infection with T. gondii involves a highly complex coordination of parasite specific secretory mechanisms and proteins that lead to development of life long immunity. Only natural infection induces immunity capable of controlling T. gondii infection and no effective vaccine exists. A complete understanding of immunity to T. gondii is critical for the development of safe and more effective vaccines.;This thesis focuses on the host immune response to the novel non replicating T. gondii strain cps1-1. Immunization with cps1-1 elicits immunity capable of clearing high lethal dose Type I RH challenge. We find that in the absence of acute parasite replication and dissemination, cps1-1 infection induces a moderate Th-1 biased inflammatory response that is sufficient to induce the development of this highly effective CD8+ T cell mediated immunity. The inflammatory response is marked by the production of IL-12p70 both systemically and locally as well as a unique pattern of influx of GR1+ CD68 + monocytes. In addition, CD8+ T cells infiltrate more rapidly than CD4+ T cells into the site of infection. We also find that B cells, independent of antibody production, are required for the development of cps1-1 induced immunity. In the absence of B cells, cps1-1 immune CD8+ T cells are inhibited in their ability to recall to antigen and are present at a lower frequency. Finally, we reveal that cps1-1 induced immunity is highly effective as a vaccine against a Type II strain T. gondii infection and can completely inhibit the development of toxoplasmic encephalitis in a genetically susceptible mouse strain. In this regard we reveal the effectiveness of cps1-1 to protect against Type I and Type II challenge and prevention of TE. Our data reveals fundamental aspects of the immune response required for the development of potent immunity against T. gondii infection and highlights the significance of the cps1-1 strain as a vaccine candidate and model of study for other important Th-1 mediated diseases in humans.