Studies on the nitric oxide radical-based system for prevention of malaria infection in gene knockout mice

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To investigate the role of the nitric oxide radical (NO-) in the prevention of infection by erythrocytic malaria parasite, murine malaria parasite (Plasmodium chabaudi chabaudi AS) was injected into the abdominal cavity of interferon-γ receptor gene knockout mice (IFN-γ R-/-) and inducible Nitric Oxide Synthase gene knockout mice (iNOS-/-) to compare survival rate, peripheral red blood cell (RBC) counts, and parasitemia between the knockout mice and wild type mice (IFN-γ R+/+, iNOS+/+). Such infection experiments were also carried out with neutrophil-depleted mice which had been treated with monoclonal anti-mouse granulocyte antibodies (RB6-8C5) for depletion. Results did not show any significant difference in the changes of RBC counts nor parasitemia between them. On the other hand, as for the survival rate of the infected mice, the Logrank (Mantel-Cox) test of the Kaplan-Meter method of Nonmetric Survival Analysis suggested the following results. 1) Male mice of IFN-γ R+/+ lived loner than IFN-γ R-/- male mice when neutrophils were depleted and self-healing was observed with some of the neutrophil-depleted IFN-γ R-/- mice (P=0.0614). 2) The neutrophil-depleted IFN-γ R+/+ mice lived longer and self-healing was observed more often than in the neutrophil-depleted IFN-γ R-/- mice, namely, P=0.0148 for female and P=0.0236 for male mice. 3) When 2.5×10^5-10^6 of infected RBC were administered to iNOS-/- and iNOS+/+ mice, the iNOS+/+ mice lived longer and self-healing was observed more often than in the iNOS-/- mice. 4) The results of the neutrophil-depletion experiment did not differ between the iNOS-/- mice and the iNOS+/+ mice. The results suggested that the NO- did not directly nor significantly prevent infection of the erythrocytic malaria parasite, while the survival rate of the infected mice appeared to be somehow influenced by IFN-γ, neutrophil related various cytokines, the NO-, active oxygen, etc.