DEVELOPMENT OF ANTIMALARIA IMMUNITY IN MICE LACKING IFN-GAMMA RECEPTOR

IFN-gamma receptor deficient (IFN-gamma R(-/-)) mice, immunized with d ifferent developmental stages of malaria parasites, were used to defin e the mechanisms of protection against the various stages of this infe ction. IFN-gamma R(-/-) mice fail to develop protective immunity again st Plasmodium yoelii sporozoites or liver stages, upon immunization wi th a single dose of irradiated sporozoites, whereas in immunized wild- type mice, parasite development was strongly inhibited. immunized wild -type mice expressed high levels of inducible nitric oxide synthase (i NOS) mRNA in their liver, upon challenge with viable sporozoites, wher eas only background levels of iNOS were detected in immunized IFN-gamm a R(-/-) mice. In contrast, after immunization with multiple doses of irradiated sporozoites, both IFN-gamma R(-/-) and wild-type mice mount ed an immune response, which strongly inhibited the development of liv er stage parasites. In both types of mice, protection occurred in the absence of appreciable expression of liver iNOS mRNA. As for the cours e of the erythrocytic phase of infection by nonlethal malaria species, P. yoelii yoelii and P. chabaudi adami, we observed only a moderately prolonged parasitemia in IFN-gamma R(-/-) mice compared with wild-typ e mice, indicating that IFN-gamma may only play a modest role in immun ity against erythrocytic stages. These results indicate that IFN-gamma is the main mediator of the protective mechanism that develops first upon immunization with sporozoites. However, the nature of the anti-pa rasite mechanism(s) changes in the course of immunization, so that mul tiple immunizing doses elicit additional protective mechanisms, which are independent of IFN-gamma and its receptor.