Enhanced Toll-like receptor responsiveness associated with mitogen-activated protein kinase activation in Plasmodium falciparum-infected children.
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 Pam(3)Cys 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, Pam(3)Cys, were enhanced in P. falciparum-infected children compared to their uninfected counterparts. In cells from the same children, stimulation by Pam(3)Cys 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.
Hartgers
Franca C
FC
Department of Parasitology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. F.C.Hartgers@lumc.nl
Obeng
Benedicta B
BB
Voskamp
Astrid
A
Larbi
Irene A
IA
Amoah
Abena S
AS
Luty
Adrian J F
AJ
Boakye
Daniel
D
Yazdanbakhsh
Maria
M
D000293:Adolescent; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D016778:Malaria, Falciparum / Q000201:enzymology / Q000276:immunology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
D000953:Antigens, Protozoan; D016207:Cytokines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases