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Infection and Immunity, November 2008, p. 5149-5157, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Enhanced Toll-Like Receptor Responsiveness Associated with Mitogen-Activated Protein Kinase Activation in Plasmodium falciparum-Infected Children{triangledown}

Franca C. Hartgers,1* Benedicta B. Obeng,1,3 Astrid Voskamp,1 Irene A. Larbi,3 Abena S. Amoah,3 Adrian J. F. Luty,2 Daniel Boakye,3 and Maria Yazdanbakhsh1

Department of Parasitology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands,1 Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands,2 Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG581, Legon, Accra, Ghana3

Received 30 November 2007/ Returned for modification 29 January 2008/ Accepted 7 August 2008

Acute Plasmodium falciparum infection is associated with strongly upregulated cytokine responses that are at least partly the result of activation of Toll-like receptors (TLRs). Whether and how TLR expression/responsiveness changes upon malarial infection is, however, currently not well understood. To assess this, we examined expression of TLRs and used the TLR ligand lipopolysaccharide (LPS) and Pam3Cys to stimulate peripheral blood mononuclear cells (PBMCs) from Ghanaian schoolchildren who live in a rural area where P. falciparum is endemic. Expression of TLR2 was higher, and responses to its ligand, Pam3Cys, were enhanced in P. falciparum-infected children compared to their uninfected counterparts. In cells from the same children, stimulation by Pam3Cys resulted in higher p38 mitogen-activated protein kinase activation and higher cytokine production. In vitro experiments confirmed that preincubation of PBMCs with P. falciparum-infected red blood cells enhanced responsiveness to TLR ligands. Taken together, the data indicate that P. falciparum-infected children in areas where malaria is endemic have an altered innate immune system, which might be important for the balance between immunity and pathology when new infections are encountered or when novel vaccines are introduced.

* Corresponding author. Mailing address: Department of Parasitology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: 31 71 5265066. Fax: 31 71 5266907. E-mail: F.C.Hartgers{at}lumc.nl

{triangledown} Published ahead of print on 18 August 2008.

Editor: J. F. Urban, Jr.

Infection and Immunity, November 2008, p. 5149-5157, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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