IFN-gamma-dependent nitric oxide production is not linked to resistance inexperimental African trypanosomiasis

Resistance to African trypanosomes is dependent on B cell and Th1 cell resp onses to the variant surface glycoprotein (VSG). While B cell responses to VSG control levels of parasitemia, the cytokine responses of Th1 cells to V SG appear to be linked to the control of parasites in extravascular tissues . We have recently shown that IFN-gamma knockout (IFN-gamma KO) mice are hi ghly susceptible to infection and have reduced levels of macrophage activat ion compared to the wild-type C57BL/6 (WT) parent strain, even though paras itemias were controlled by VSG-specific antibody responses in both strains. In the present work, we examine the role of IFN-gamma in the induction of nitric oxide (NO) production and host resistance and in the development of suppressor macrophage activity in mice infected with Trypanosoma brucei rho desiense. In contrast to WT mice, susceptible IFN-gamma RO mice did not pro duce NO during infection and did not develop suppressor macrophage activity , suggesting that NO might be linked to resistance but that suppressor cell activity was not associated with resistance or susceptibility to trypanoso me infection. To further examine the consequence of inducible NO production in infection, we monitored survival, parasitemia, and Th cell cytokine pro duction in iNOS KO mice. While survival times and parasitemia of iNOS KO mi ce did not differ significantly from WT mice, VSG-specific Th1 cells from i NOS KO mice produced higher levels of IFN-gamma and IL-2 than cells from WT mice. Together, these results show for the first time that inducible NO pr oduction is not the central defect associated with susceptibility of IFN-ga mma KO mice to African trypanosomes, that IFN gamma-induced factors other t han iNOS may be important for resistance to the trypanosomes, and that supp ressor macrophage activity is not linked to either the resistance or the su sceptibility phenotypes. (C) 1999 Academic Press.