Association of early interferon-γ production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children

Abstract

Background. Elucidating the cellular and molecular basis of naturally acquired immunity to Plasmodium falciparum infection would assist in developing a rationally based malaria vaccine. Innate, intermediate, and adaptive immune mechanisms are all likely to contribute to immunity. Interferon-g (IFN-g) has been implicated in both protection against and the pathogenesis of malaria in humans. In addition, considerable heterogeneity exists among rapid IFN-g responses to P. falciparum in malaria-naive donors. The question remains whether similar heterogeneity is observed in malaria-exposed individuals and whether high, medium, or low IFN-g responsiveness is differentially associated with protective immunity or morbidity. Methods. A 6-month longitudinal cohort study involving 206 school-aged Papua New Guinean children was performed. Peripheral blood mononuclear cells collected at baseline were exposed to live P. falciparum–infected erythrocytes. Early IFN-g responses were measured, and IFN-g–expressing cells were characterized by flow cytometry. IFN-g responsiveness was then tested for associations with parasitological and clinical outcome variables. Results. Malaria-specific heterogeneity in early IFN-g responsiveness was observed among children. High-level early IFN-g responses were associated with protection from high-density and clinical P. falciparum infections. Parasite-induced early IFN-g was predominantly derived from gd T cells (68% of which expressed the natural killer marker CD56) and ab T cells, whereas natural killer cells and other cells made only minor contributions. The expression of CD56 in malaria-responsive, IFN-g–expressing gd T cells correlated with IFN-g responsiveness. Conclusions. High, early IFN-g production by live parasite–stimulated peripheral blood mononuclear cells is a correlate of immunity to symptomatic malaria in Papua New Guinean children, and natural killer–like gd T cells may contribute to protection.