A dichotomous role for nitric oxide in protection against blood stage malaria infection

Nitric oxide (NO) is cytotoxic and cytostatic to blood stage malaria parasites in vitro, but the precise mechanism(s) by which it mediates an effect in vivo is not known. In particular, whether or not control of acute parasitemia depends on the presence of NO is unclear. We have shown previously that blocking NO synthesis at the time of its induction may cause an increase in peak primary parasitemia during infection of mice with Plasmodium chabaudi, suggesting that NO may be parasiticidal in vivo. However, as recent data indicate that NO suppresses Th1 cell proliferation in vitro by downregulating IL-2 production, we have investigated whether this immunoregulatory function of NO affects its capacity for anti-malarial activity. Treatment of P. chabaudi-infected mice with the iNOS inhibitor aminoguanidine hemisulfate (AG) starting just prior to the peak of primary parasitemia caused a significant elevation and extension of the acute infection and led to a partial but significant abrogation of the suppression of spleen cell proliferation to both mitogen and specific antigen observed when NO synthesis was not blocked. In the absence of NO, levels of IL-2, but not of IFN-gamma, TNF-alpha, or of any Th2-regulated cytokines examined, increased significantly. However, when AG treatment was brought forward to the early ascending phase of primary parasitemia, significantly increased levels of IFN-gamma and TNF-alpha, as well as of IL-2, were observed over those for infected control mice similarly treated with phosphate-buffered saline. Moreover, despite the absence of NO, parasitemias of AG-treated mice were not significantly elevated. The effect of AG therefore appeared to be dependent upon the timing of its administration in vivo. We propose that during malaria infections, there is a dynamic balance between the regulatory and anti-parasitic roles of NO. While the immunosuppressive function of NO leads to a downregulation in vivo of production of IL-2, and indirectly of IFN-gamma and TNF-alpha, this perceived weakening of the host cell-mediated immune response is in part masked by the protective anti-malarial effects of NO itself.