Published online before print May 18, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060792

Accepted for publication April 5, 2007.

Article

Genetically Attenuated Plasmodium berghei Liver Stages Persist and Elicit Sterile Protection Primarily via CD8 T Cells

Ann-Kristin Mueller^*, Martina Deckert, Kirsten Heiss^*, Kristin Goetz^*, Kai Matuschewski^*@, and Dirk Schlüter

From the Department of Parasitology,* Heidelberg University School of Medicine, Heidelberg; the Department of Neuropathology, University of Cologne, Köln; and the Institute for Medical Microbiology, OvG Universität Magdeburg, Magdeburg, Germany

^@ To whom correspondence should be addressed. E-mail: kai.matuschewski{at}med.uni-heidelberg.de.

	Abstract

Live-attenuated Plasmodium liver stages remain the only experimental model that confers complete sterile protection against malaria. Irradiation-attenuated Plasmodium parasites mediate protection primarily by CD8 T cells. In contrast, it is unknown how genetically attenuated liver stage parasites provide protection. Here, we show that immunization with uis3(-) sporozoites does not cause breakthrough infection in T and B-cell-deficient rag1^-/- and IFN-^-/- mice. However, protection was abolished in these animals, suggesting a crucial role for adaptive immune responses and interferon-. Although uis3(-) immunization induced Plasmodium-specific antibodies, B- cell-deficient mice immunized with uis3(-) sporozoites were completely protected against wild-type sporozoite challenge infection. T-cell depletion experiments before parasite challenge showed that protection is primarily mediated by CD8 T cells. In good agreement, adoptive transfer of total spleen cells and enriched CD8 T cells from immunized animals conferred sterile protection against malaria transmission to recipient mice, whereas adoptive transfer of CD4 T cells was less protective. Importantly, primaquine treatment completely abolished the uis3(-)-mediated protection, indicating that persistence of uis3(-)-attenuated liver stages is crucial for their protective action. These findings establish the basic immune mechanisms underlying protection induced by genetically attenuated Plasmodium parasites and substantiate their use as vaccines against malaria.