A Critical Role of Fc Receptor-Mediated Antibody-Dependent Phagocytosis in the Host Resistance to Blood-Stage Plasmodium berghei XAT Infection

Abstract

Plasmodium berghei XAT is an irradiation-induced attenuated variant derived from the lethal strain P. berghei NK65, and its blood-stage parasites are spontaneously cleared in immune competent mice. In the present study, we studied the mechanism of host resistance to blood-stage malaria infection using P. berghei XAT. Infection enhanced Ab-dependent phagocytosis of PRBC by splenic macrophages in wild-type C57BL/6 mice. In contrast, FcR γ-chain knockout (FcRγ−/−) mice, which lack the ability to mediate Ab-dependent phagocytosis and Ab-dependent cell-mediated cytotoxicity through FcγRI, FcγRII, and FcγRIII, could not induce Ab-dependent phagocytic activity. These FcRγ−/− mice showed increased susceptibility to the P. berghei XAT infection, with eventually fatal results, although they produced comparable amounts of IFN-γ by spleen cells and anti-XAT Abs in serum. In addition, passive transfer of anti-XAT IgG obtained from wild-type mice that had recovered from infection into FcRγ−/− mice could not suppress the increase in parasitemia, and almost all of these mice died after marked parasitemia. In contrast, passive transfer of anti-XAT IgG into control wild-type mice inhibited the increase in parasitemia. IFN-γ−/− mice, which were highly susceptible to the P. berghei XAT infection, failed to induce Ab-dependent phagocytic activity and also showed reduced production of serum anti-XAT IgG2a isotype compared with control wild-type mice. These results suggest that FcR-mediated Ab-dependent phagocytosis, which is located downstream of IFN-γ production, is important as an effector mechanism to eliminate PRBC in blood-stage P. berghei XAT infection.

Growth-Inhibitory Antibodies Are Not Necessary for Protective Immunity to Malaria Infection

“…The in vitro inhibitory assay measures the functional activity of antibodies independent of complement or other cellular mediators, and our results suggest they are important in this model system. Evidence has been accumulating to suggest that antibody action via the Fc interaction with monocytes/macrophages plays an important role in protective immunity (2,26,31,40). Such a mechanism is compatible with the results we have obtained in this experiment, and the anti-MSP1 19 antibodies we induced may act in vivo by cooperating with monocytes and/or macrophages.…”

Augmentation of Effector CD8+ T Cell Generation with Enhanced Granzyme B Expression by IL-27

“…For measurement of IFN-␥ production, purified naive CD8 ϩ T cells (2 ϫ 10 5 cells/200 l) were stimulated with plate-coated anti-CD3 (6 g/ml) in the absence of rIL-27 and/or rIL-12 and anti-IL-2 (100 g/ml) for 72 h, and culture supernatants were collected and assayed for IFN-␥ production by ELISA, as described (20). For measurement of proliferation, purified naive CD8 ϩ T cells (2 ϫ 10 5 cells/200 l) were stimulated with plate-coated anti-CD3 (6 g/ml) in the presence of rIL-27 and/or rIL-12 and anti-IL-2 (100 g/ml) for 72 h and pulsed with [ 3 H]thymidine for last 24 h.…”

Mice Deficient in Interleukin-4 (IL-4) or IL-4 Receptor α Have Higher Resistance to Sporozoite Infection withPlasmodium berghei(ANKA) than Do Naive Wild-Type Mice

“…These defense mechanisms largely depend on early innate responses and antigen-specific T helper (Th) cell activation. The importance of the Th1 cytokine gamma interferon (IFN-␥) for protection against malaria has been shown in murine models of malaria (1,11,47,50,54,55,57), with vaccinated animals lacking IFN-␥ showing greatly increased susceptibility, increased parasitemia, and a shorter life span.The role of nitric oxide (NO) in the defense against malaria infection seems to be dependent on the stage of the malaria parasite. In a blood-stage infection with Plasmodium berghei, it was shown that neither NO nor NK cells were important for the control of parasitemia (12, 55).…”