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Infection and Immunity, July 2007, p. 3621-3632, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00095-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not Require Plasmodium falciparum Erythrocyte Membrane Protein 1{triangledown}

Salenna R. Elliott,1* Timothy P. Spurck,2 Joelle M. Dodin,1 Alexander G. Maier,3 Till S. Voss,3,{dagger} Francisca Yosaatmadja,1 Paul D. Payne,1 Geoffrey I. McFadden,2 Alan F. Cowman,3 Stephen J. Rogerson,1 Louis Schofield,3 and Graham V. Brown1

Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia,1 School of Botany, The University of Melbourne, Melbourne, Victoria, Australia,2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia3

Received 18 January 2007/ Returned for modification 21 February 2007/ Accepted 20 April 2007

Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36- and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.

* Corresponding author. Present address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Phone: (613) 9345 2555. Fax: (613) 9347 0852. E-mail: elliott{at}wehi.edu.au

{triangledown} Published ahead of print on 30 April 2007.

Editor: W. A. Petri, Jr.

{dagger} Present address: Swiss Tropical Institute, Basel, Switzerland.

Infection and Immunity, July 2007, p. 3621-3632, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00095-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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