Central Role of Endogenous Gamma Interferon in Protective Immunity against Blood-StagePlasmodium chabaudiAS Infection

Abstract

The role of endogenous gamma interferon (IFN-␥) in protective immunity against blood-stage Plasmodium chabaudi AS malaria was studied using IFN-␥ gene knockout (GKO) and wild-type (WT) C57BL/6 mice. Following infection with 10 6 parasitized erythrocytes, GKO mice developed significantly higher parasitemia during acute infection than WT mice and had severe mortality. In infected GKO mice, production of interleukin 12 (IL-12) p70 and tumor necrosis factor alpha in vivo and IL-12 p70 in vitro by splenic macrophages was significantly reduced compared to that in WT mice and the enhanced nitric oxide (NO) production observed in infected WT mice was completely absent. WT and GKO mice had comparable numbers of total nucleated spleen cells and B220؉ and Mac-1 ؉ spleen cells both before and after infection. Infected WT mice, however, had significantly more F4/80 ؉ , NK1.1 ؉ , and F4/80 ؉ Ia ؉ spleen cells than infected GKO mice; male WT had more CD3؉ cells than male GKO mice. In comparison with those from WT mice, splenocytes from infected GKO mice had significantly higher proliferation in vitro in response to parasite antigen or concanavalin A stimulation and produced significantly higher levels of IL-10 in response to parasite antigen. Infected WT mice produced more parasite-specific immunoglobulin M (IgM), IgG2a, and IgG3 and less IgG1 than GKO mice. Significant gender differences in both GKO and WT mice in peak parasitemia levels, mortality, phenotypes of spleen cells, and proliferation of and cytokine production by splenocytes in vitro were apparent during infection. These results thus provide unequivocal evidence for the central role of endogenous IFN-␥ in the development of protective immunity against blood-stage P. chabaudi AS.Studies of experimental murine models as well as humans suggest an important role for gamma interferon (IFN-␥) in protective immune responses to blood-stage malaria (19,22). Treatment of mice with exogenous IFN-␥ delays the onset of parasitemia and decreases the number of infected erythrocytes during Plasmodium chabaudi adami infection (4). Shear and her colleagues (31) demonstrated that daily treatment with recombinant IFN-␥ resulted in a less severe course of infection and increased survival in mice infected with the lethal strain of Plasmodium yoelii 17x. Furthermore, these investigators found a correlation between the timing and level of IFN-␥ production in vitro by spleen cells and the outcome of infection with lethal versus nonlethal strains of P. yoelii 17x. These observations were confirmed in a recent study demonstrating that endogenous levels of IFN-␥ in the spleen during blood-stage malaria infection differ between nonlethal and lethal Plasmodium species at 24 h after infection (5). Studies in our laboratory of resistant C57BL/6 and susceptible A/J mice demonstrated a correlation between the level of resistance to blood-stage P. chabaudi AS infection and IFN-␥ mRNA expression and protein production by spleen cells (15,27,34). In addition, treatment of P. chabaudi AS-infected C57BL...

STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

“…26 Evidence indicates that IL-4, but not IL-13, acts via a STAT6-dependent mechanism to induce IFN-γ production by natural killer cells and natural killer T cells; 44 IL-4-induced IFN-γ production has been demonstrated in mice infected with Candida albicans and Leishmania major. 45,46 As observed in STAT6 -/-mice, IL-4 neutralization in P. chabaudi-infected WT mice resulted in a similar course of anemia despite a significantly higher peak parasitemia compared to that in isotype control WT mice.…”

“…26 IL-13 levels were determined using a DuoSet ELISA kit (R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions.…”

Involvement of CD8+ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

“…IFN-g is a pro-inflammatory cytokine that is intimately involved in the innate and acquired immune responses. This cytokine has important roles in immunity against blood-stage malaria, because a previous study has demonstrated that IFN-g KO mice are highly susceptible to infection with Plasmodium chabaudi AS-pRBC [20]. First, the irradiated recipients transferred with CD8 1 T cells from immune mice were treated with neutralizing antibodies to IFN-g prior to infection with PyL.…”

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…Numerous studies have revealed the importance of the cytokine balance in immune protection against malaria. A Th1/pro-inflammatory cytokine (IFN-γ, IL-12 and TNF-α) response during the early stage of infection mediates protective immunity and the resolution of parasite infection (1)(2)(3)(4)(5)(6). The initial pro-inflammatory response may switch to a predominant anti-inflammatory response that is mediated by immunoregulatory cytokines, such as TGF-β and IL-10 which down-regulate proinflammatory cytokine production to avoid malaria-associated pathology (7)(8)(9)(10)(11)(12).…”