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Infection and Immunity, January 2004, p. 322-331, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.322-331.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Michael Saeftel,1,2* Andreas Krueger,3 Sandra Arriens,1 Volker Heussler,3 Paul Racz,4 Bernhard Fleischer,1 Frank Brombacher,5 and Achim Hoerauf1,2

Section of Immunology,1 Section of Molecular Parasitology,3 Section of Pathology, Bernhard Nocht Institute for Tropical Medicine, D-20359 Hamburg,4 Institute for Medical Parasitology, Friedrich Wilhelm University Bonn, 53105 Bonn, Germany,2 Division of Immunology, Faculty of Health Science, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa5

Received 14 February 2003/ Returned for modification 19 May 2003/ Accepted 3 October 2003

BALB/c interleukin-4 (IL-4-/-) or IL-4 receptor-{alpha} (IL-4r{alpha}-/-) 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{alpha}-/- 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.

* Corresponding author. Mailing address: Institute for Medical Parasitology, Friedrich Wilhelm University Bonn, 53105 Bonn, Germany. Phone: (49) 228-287 5673. Fax: (49) 228-287 9573. E-mail: saeftel{at}bni.uni-hamburg.de.

Editor: J. M. Mansfield

Infection and Immunity, January 2004, p. 322-331, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.322-331.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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