IAI Accepts, published online ahead of print on 18 August 2008

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Infect. Immun. doi:10.1128/IAI.01579-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Enhanced TLR responsiveness associated with MAPK activation in Plasmodium falciparum-infected children

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

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

^* To whom correspondence should be addressed. Email: F.C.Hartgers{at}lumc.nl.

Acute Plasmodium falciparum infection is associated with strongly up-regulated cytokine responses that are at least partly the result of activation of Toll-like receptors (TLR). 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 ligands LPS and Pam3Cys to stimulate peripheral blood mononuclear cells (PBMC) from Ghanaian schoolchildren who live in a rural area where P. falciparum is endemic. Expression of TRL2 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 Pam3Cys resulted in higher p38 mitogen activated protein kinase (MAPK) activation and higher cytokine production. In vitro experiments confirmed that pre-incubation of PBMC with P. falciparum-infected red blood cells enhanced responsiveness to TLR ligands. Taken together the data indicate that P. falciparum-infected children in malaria-endemic areas 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.

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