Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

Abstract

In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain ofPlasmodium yoelii(17XL) might be due to failure to activate a sufficient inflammatory response. Here we have compared the adaptive CD4⁺T-cell and innate immune response toP. yoelii17XL with that induced by the self-resolving, nonlethal strain ofP. yoelii, 17X(NL). During the first 7 to 9 days of infection, splenic effector CD4⁺T-cell responses were similar in mice with lethal and nonlethal infections with similar levels of activation in vivo and equivalent proliferation in vitro following mitogenic stimulation. Nonspecific T-cell hyporesponsiveness was observed at similar levels during both infections and was due, in part, to suppression mediated by CD11b⁺cells. Importantly, however, RAG^−/−mice were able to control the initial growth phase of nonlethalP. yoeliiinfection as effectively as wild-type mice, indicating that T cells and/or B cells play little, if any, role in control of the primary peak of parasitemia. Somewhat unexpectedly, we could find no clear role for either NK cells or gamma interferon (IFN-γ) in controlling primaryP. yoeliiinfection. In contrast, depletion of monocytes/macrophages exacerbated parasite growth and anemia during both lethal and nonlethal acuteP. yoeliiinfections, indicating that there is an IFN-γ-, NK cell-, and T-cell-independent pathway for induction of effector macrophages during acute malaria infection.