Factors determining resistance and susceptibility to infection with Toxoplasma gondii

Toxoplasma gondii is an intracellular protozoan parasite that invades a variety of host cells in various organs including the central nervous system. IFN-γ-dependent, cell-mediated immunity is crucial for controlling the parasites during the acute stage of infection and for preventing development of toxoplasmic encephalitis (TE) during the later stage of infection. Multiple populations of both T and non-T cells are important sources of IFN-γ in the resistance. IL-12, IL-18, Bcl-3, NF-κB(2), and CD40-CD40L ligand interaction upregulate the IFN-γ production. Down-regulation of IFN-γ-mediated immune responses is also important for host resistance to prevent development of immunopathology caused by overly stimulated responses. IL-10. TGF-β and lipoxin A4 are involved in such down-regulation. IFN-γ-mediated immune responses control tachyzoitesin both phagocytic and non-phagocytic cells through at least five different mechanisms, most likely depending on the types of cells responding to IFN-γ. Such effector functions involve production of nitric oxide by inducible nitric oxide synthase, tryptophan degradation by indolamine 2,3-dioxygenase, unidentified IFN-γ responsive gene family, limiting the availability of intracellular iron to the parasite, and production of reactive oxygen intermediates. Host genes affect resistance/susceptibility to infection with this parasite. Genes that regulate resistance against acute infection differ from those that regulate resistance to development of TE during the late stage of infection. In mouse, at least five genes are involved in determining survival during the acute stage whereas the L d gene within the D region of the major histocompatibility (H-2) complex confers resistance to development of TE. In AIDS patients, HLA-DQ3 appears to be a genetic marker of susceptibility to development of TE, and HLA-DQ1 appears to be a resistance marker. Strains (genetic variation) of T. gondii are another factor that affects the susceptibility of the host to both acute and late stages of infection. The genotypes of the parasite are important for determining the susceptibility. Some combination of alleles at two or more loci appears to be pivotal to determine virulence of the parasite during acute stage of infection. It is possible that the genes of the host and genetic variation of T. gondii affect immune response of the host to the parasite, thereby contribute to determining resistance to the infection.