title: Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with Plasmodium berghei (ANKA) than do naive wild-type mice.
abstract: BALB/c interleukin-4 (IL-4(-/-)) or IL-4 receptor-alpha (IL-4ralpha(-/-)) 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-4ralpha(-/-) 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-gamma) production in the liver. These results suggest that IFN-gamma-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.
authors.affiliation: Section of Immunology, Bernhard Nocht Institute for Tropical Medicine, D-20359 Hamburg, Germany. saeftel@bni.uni-hamburg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Saeftel
authors.forename: Andreas
authors.initials: A
authors.lastname: Krueger
authors.forename: Sandra
authors.initials: S
authors.lastname: Arriens
authors.forename: Volker
authors.initials: V
authors.lastname: Heussler
authors.forename: Paul
authors.initials: P
authors.lastname: Racz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleischer
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
mesh_terms: D000818:Animals; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008288:Malaria / Q000276:immunology* / Q000401:mortality / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018512:Parasitemia / Q000276:immunology / Q000401:mortality / Q000469:parasitology; D010962:Plasmodium berghei / Q000254:growth & development / Q000472:pathogenicity*; D019948:Receptors, Interleukin-4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D034101:Sporozoites / Q000472:pathogenicity*
chemical_list: D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse