INDUCTION OF NITRIC-OXIDE SYNTHASE PROTECTS AGAINST MALARIA IN MICE EXPOSED TO IRRADIATED PLASMODIUM-BERGHEI-INFECTED MOSQUITOS - INVOLVEMENT OF INTERFERON-GAMMA AND CD8-CELLS( T)

Exposure of BALB/c mice to mosquitoes infected with irradiated Plasmod ium berghei confers protective immunity against subsequent sporozoite challenge. Immunized mice challenged with viable sporozoites develop p arasitemia when treated orally with substrate inhibitors of nitric oxi de synthase (NOS). This suggests that the production of nitric oxide ( NO) prevents the development of exoerythrocytic stages of malaria in l iver. Liver tissue from immunized mice expressed maximal levels of mRN A for inducible NOS (iNOS) between 12 and 24 h after challenge with sp orozoites. Intraperitoneal injection of neutralizing monoclonal antibo dy against interferon gamma (IFN-gamma) or in vivo depletion of CD8(+) T cells, but not CD4(+) T cells, at the time of challenge blocked exp ression of iNOS mRNA and ablated protection in immunized mice. These r esults show that both CD8(+) T cells and IFN-gamma are important compo nents in the regulation of iNOS in liver which contributes to the prot ective response of mice immunized with irradiated malaria sporozoites. IFN-gamma, likely provided by malaria-specific CD8(+) T cells, induce s liver cells, hepatocytes and/or Kupffer cells, to produce NO for the destruction of infected hepatocytes or the parasite within these cell s.