INDUCIBLE NITRIC-OXIDE IS ESSENTIAL FOR HOST CONTROL OF PERSISTENT BUT NOT ACUTE INFECTION WITH THE INTRACELLULAR PATHOGEN TOXOPLASMA-GONDII

The induction by IFN-gamma of reactive nitrogen intermediates has been postulated as a major mechanism of host resistance to intracellular p athogens. To formally test this hypothesis in vivo, the course of Toxo plasma gondii infection was assessed in nitric oxide synthase (iNOS) - /- mice. As expected, macrophages from these animals displayed defecti ve microbicidal activity against the parasite in vitro. Nevertheless, in contrast to IFN-gamma-/- or IL-12 p40-/- animals, iNOS-deficient mi ce survived acute infection and controlled parasite growth at the site of inoculation. This early resistance was ablated by neutralization o f IFN-gamma or IL-12 in vivo and markedly diminished by depletion of n eutrophils, demonstrating the existence of previously unappreciated NO independent mechanisms operating against the parasite during early in fection. By 3-4 wk post infection, however, iNOS knockout mice did suc cumb to T. gondii. At that stage parasite expansion and pathology were evident in the central nervous system but not the periphery suggestin g that the protective role of nitric oxide against this intracellular infection is tissue specific rather than systemic.