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

• Published in: Infection and Immunity 2008-11, Vol.76 (11), p.5149-5157
• Main Authors: Hartgers, Franca C, Obeng, Benedicta B, Voskamp, Astrid, Larbi, Irene A, Amoah, Abena S, Luty, Adrian J.F, Boakye, Daniel, Yazdanbakhsh, Maria
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Antigens, Protozoan - immunology; Biological and medical sciences; Child; Cytokines - immunology; Cytokines - metabolism; Enzyme Activation - immunology; Female; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Host Response and Inflammation; Humans; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Life cycle. Host-agent relationship. Pathogenesis; Malaria, Falciparum - enzymology; Malaria, Falciparum - immunology; Male; Microbiology; Mitogen-Activated Protein Kinases - immunology; Mitogen-Activated Protein Kinases - metabolism; Plasmodium falciparum; Plasmodium falciparum - immunology; Protozoa; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.01579-07

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.