Toxoplasma gondii is an obligate intracellular parasite capable of infecting most warm-blooded vertebrates and many nucleated cell types. Parasite transmission occurs orally through ingestion of tissue cysts or sporozoites from feline feces in contaminated soil, food, and water. Infection typically results in an asymptomatic primary infection that leads to a chronic latent infection affecting 30% of the world's population.
Dartmouth researchers have now generated attenuated uracil auxotroph mutants of T. gondii that lack enzymes of pyrimidine biosynthesis. Uracil auxotroph mutants provide long-term protection against infection by inducing potent Th-1 immune responses with little systemic inflammation. In addition, strains (KU80 knockouts) of T. gondii that exhibit a high percentage of homologous recombination have been produced that enable a precise genetic definition to genetically modified strains. KU80 knockouts can now be used to efficiently produce gene knockouts and gene replacements for the identification of drug targets, vaccine candidates, and characterization of virulence factors.
High-throughput knockout of T. gondii genes is now possible thereby enabling a genome-wide knockout approach. These mutants are useful, e.g., to construct crippled strains of T. gondii that, in addition to being severely attenuated in their virulence, also exhibit other desirable defects such as loss of ability to develop into tissue cysts, loss of sexual stages, loss of oocyst formation, or other developmental or phenotypic defects or changes that would enhance the efficacy or safety of vaccines.
In addition, these strains find use in high-throughput drug screens to identify inhibitors of exogenous proteins from other parasites. Similarly, such strains enable the rapid design of T. gondii strains carrying and expressing (single or multiple) foreign antigens representing components of vaccines that are capable of vaccination against both T. gondii as well as many non-T. gondii diseases.
Several naturally evolved biological properties of the T. gondii vaccine platform make this technology a potentially superior platform for the development of therapeutics and vaccines against infectious diseases, cancer, and other human diseases. This platform is remarkably well suited to deliver superior Th1 immune responses.
This technology is claimed in the published United Sates Patent Application Nos. 11/962,584 and 12/394,365. We are seeking an industrial partner interested in its commercialization. (Ref: J392, J423)
Last Updated: 7/24/12