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Enhanced Toll-like receptor responsiveness associated with mitogen-activated protein kinase activation in Plasmodium
Franca C Hartgers1, Benedicta B Obeng, Astrid Voskamp
1Department of Parasitology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. F.C.Hartgers@lumc.nl
Abstract:
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.
Insights
Children with acute Plasmodium falciparum malaria show increased Toll-like receptor 2 (TLR2) expression and heightened responses to its ligand. This altered innate immune system may impact malaria immunity and vaccine effectiveness.
Area of Science:
- Immunology
- Infectious Diseases
- Malariology
Background:
- Acute Plasmodium falciparum infection triggers significant cytokine responses, partly via Toll-like receptor (TLR) activation.
- The impact of malarial infection on TLR expression and responsiveness remains poorly understood.
Purpose of the Study:
- To investigate changes in TLR expression and responsiveness in children with endemic Plasmodium falciparum malaria.
- To assess the functional consequences of altered TLR signaling on immune cell activation and cytokine production.
Main Methods:
- Examined TLR expression in peripheral blood mononuclear cells (PBMCs) from Ghanaian schoolchildren.
- Stimulated PBMCs with TLR ligands (lipopolysaccharide and Pam(3)Cys) to assess responsiveness.
- Measured p38 mitogen-activated protein kinase activation and cytokine production.
- Conducted in vitro experiments using P. falciparum-infected red blood cells.
Main Results:
- Children with P. falciparum infection exhibited higher TLR2 expression compared to uninfected children.
- Pam(3)Cys stimulation led to enhanced TLR2 responses, including increased p38 MAPK activation and cytokine production.
- In vitro preincubation with infected red blood cells boosted PBMC responsiveness to TLR ligands.
Conclusions:
- P. falciparum infection alters the innate immune system in endemic populations.
- Upregulated TLR2 expression and responsiveness may play a role in malaria-associated immunity and pathology.
- Findings have implications for understanding host-parasite interactions and developing malaria vaccines.
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