MECHANISMS OF INNATE RESISTANCE TO TOXOPLASMA-GONDII INFECTION

The interaction of protozoan parasites with innate host defences is cr itical in determining the character of the subsequent infection. The i nitial steps in the encounter of Toxoplasma gondii with the vertebrate immune system provide a striking example of this important aspect of the host-parasite relationship. In immunocompetent individuals this in tracellular protozoan produces an asymptomatic chronic infection as pa rt of its strategy for transmission. Nevertheless, T. gondii is inhere ntly a highly virulent pathogen. The rapid induction by the parasite o f a potent cell-mediated immune response that both limits its growth a nd drives conversion to a dormant cyst stage explains this apparent pa radox. Studies with gene-deficient mice have demonstrated the interleu kin-12 (IL-12)-dependent production of interferon gamma (IFN-gamma) to be of paramount importance in controlling early parasite growth. Howe ver, this seems to be independent of nitric oxide production as mice d eficient in inducible nitric oxide synthase (iNOS) and tumour necrosis factor receptor were able to control early growth of T. gondii, altho ugh they later succumbed to infection. Nitric oxide does, however, see m to be important in controlling persistent infection; treating chroni c infection with iNOS metabolic inhibitors results in disease reactiva tion. Preliminary evidence implicates neutrophils in effector pathways against this parasite distinct from that described for macrophages. O nce initiated, IL-12-dependent IFN-gamma production in synergy with ot her proinflammatory cytokines can positively feed back on itself to in duce 'cytokine shock'. Regulatory cytokines, particularly IL-10, are e ssential to down-regulate inflammation and limit host pathology.