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

Abstract

BALB/c interleukin-4 (IL-4؊/؊ ) or IL-4 receptor-␣ (IL-4r␣ ؊/؊ ) knockout (KO) mice were used to assess the roles of the IL-4 and IL-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. Intraperitoneal infection with the blood-stage erythrocytes of Plasmodium berghei (ANKA) resulted in 100% mortality within 24 days in BALB/c mice, as well as in the mutant mouse strains. However, when infected intravenously with the sporozoite liver stage, 60 to 80% of IL-4 ؊/؊ and IL-4r␣ ؊/؊ mice survived, whereas all BALB/c mice succumbed with high parasitemia. Compared to infected BALB/c controls, the surviving KO mice showed increased NK cell numbers and expression of inducible nitric oxide synthase (iNOS) in the liver and were able to eliminate parasites early during infection. In vivo blockade of NO resulted in 100% mortality of sporozoite-infected KO mice. In vivo depletion of NK cells also resulted in 80 to 100% mortality, with a significant reduction in gamma interferon (IFN-␥) production in the liver. These results suggest that IFN-␥-producing NK cells are critical in host resistance against the sporozoite liver stage by inducing NO production, an effective killing effector molecule against Plasmodium. The absence of IL-4-mediated functions increases the protective innate immune mechanism identified above, which results in immunity against P. berghei infection in these mice, with no major role for IL-13.Both cell-mediated immunity and humoral immunity play important roles in the mechanisms of defense against human and animal malaria. 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). In contrast, compared to the liver-phase stage of sporozoite infection, NK cells were shown to be activated by sporozoites (37) and produced IFN-␥ (31, 37). A clear role for NO as a defense mechanism against the liver stage of P. berghei was found only in vaccinated animals (25,36,45,48).Concerning Th2 response, it was shown that a lack of interleukin-4 (IL-4) in the murine infection with Plasmodium chabaudi chabaudi results in a course of infection similar to that seen in the wild-type mice (2, 50, 51), with slightly different parasitemia kinetics. Moreover the in vitro Th1 immune responses were sustained in the IL-4-deficient mice (51). All of these studies were done by infection of mice with parasitized erythrocytes, but no study has been performed that focused on the role of I...

Invariant Vα14 Chain NKT Cells PromotePlasmodium bergheiCircumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8+T Cells in the Liver after Poxvirus Vaccination of Mice

“…The slightly better protection of KO mice might be due to the absence of IL-4-producing V␣14iNKT cells, promoting a Th1-polarized liver environment, indicated by higher numbers of NK cells as well as of CD8 ϩ T and CD3 Ϫ cells expressing IFN-␥ or TNF-␣ intracellularly. In line with this, a shift toward protective IFN-␥ responses in the liver occurs in naive infected IL-4 KO or IL-4 receptor KO BALB/c mice (40).…”

NK Cell Responses toPlasmodiumInfection and Control of Intrahepatic Parasite Development

“…It has been suggested that NK cells are involved in the development of protective innate immunity through their production of IFN-␥ (15,(42)(43)(44)(45). However, most studies on the role of NK cells in the immune response to malaria in mice have been conducted with irradiated sporozoites or blood-stage parasites.…”

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

“…Real-time PCR for Foxp3 was performed in a 20-l reaction volume containing 2 l of 10ϫ reaction buffer: 4 mM Mg2 ϩ , 200 nM of each primer; for ␤-actin: 3 mM Mg2 ϩ , 300 nM of each primer, 0.2 l of SYBR Green (diluted 1/1000 in DMSO), 0.5 U of Hotstar Taq (Qiagen), and 2 l of cDNA, using the Rotorgene 6000 (Corbett Research), as already described (39). Reaction conditions were 15 min at 95°C, followed by 45 cycles of 10 s at 94°C, 20 s at 58°C, and 20 s at 72°C.…”