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Published on: January 3, 2012
Plasmodium falciparum infection causes proinflammatory priming of human TLR responses
Matthew B B McCall1, Mihai G Netea, Cornelus C Hermsen
1Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
Abstract:
TLRs are a major group of pattern recognition receptors that are crucial in initiating innate immune responses and are capable of recognizing Plasmodium ligands. We have investigated TLR responses during acute experimental P. falciparum (P.f.) infection in 15 malaria-naive volunteers. TLR-4 responses in whole blood ex vivo stimulations were characterized by significantly (p < 0.01) up-regulated proinflammatory cytokine production during infection compared with baseline, whereas TLR-2/TLR-1 responses demonstrated increases in both proinflammatory and anti-inflammatory cytokine production. Responses through other TLRs were less obviously modified by malaria infection. The degree to which proinflammatory TLR responses were boosted early in infection was partially prognostic of clinical inflammatory parameters during the subsequent clinical course. Although simultaneous costimulation of human PBMC with P.f. lysate and specific TLR stimuli in vitro did not induce synergistic effects on cytokine synthesis, PBMC started to respond to subsequent TLR-4 and TLR-2 stimulation with significantly (p < 0.05) increased TNF-alpha and reduced IL-10 production following increasing periods of preincubation with P.f. Ag. In contrast, preincubation with preparations derived from other parasitic, bacterial, and fungal pathogens strongly suppressed subsequent TLR responses. Taken together, P.f. primes human TLR responses toward a more proinflammatory cytokine profile both in vitro and in vivo, a characteristic exceptional among microorganisms.
Insights
Toll-like receptor (TLR) responses in humans shift towards pro-inflammatory cytokine production during Plasmodium falciparum malaria. This TLR priming by malaria is unique among pathogens and may predict disease severity.
Area of Science:
- Immunology
- Infectious Diseases
- Malariology
Background:
- Toll-like receptors (TLRs) are key pattern recognition receptors initiating innate immunity.
- Plasmodium falciparum (P.f.) ligands are recognized by TLRs, influencing immune responses.
- Understanding TLRs' role in acute malaria is crucial for immune response modulation.
Purpose of the Study:
- To investigate Toll-like receptor (TLR) responses during acute experimental Plasmodium falciparum infection.
- To characterize TLR-4, TLR-2, and TLR-1 responses in malaria-naive volunteers.
- To assess the prognostic value of TLR responses for clinical inflammatory parameters.
Main Methods:
- Ex vivo whole blood stimulation assays with Plasmodium falciparum (P.f.) antigens.
- Measurement of pro-inflammatory and anti-inflammatory cytokine production (e.g., TNF-alpha, IL-10).
- In vitro preincubation of peripheral blood mononuclear cells (PBMCs) with P.f. antigens followed by TLR stimulation.
Main Results:
- TLR-4 responses showed significantly increased pro-inflammatory cytokine production during P.f. infection.
- TLR-2/TLR-1 responses increased both pro-inflammatory and anti-inflammatory cytokines.
- Early pro-inflammatory TLR responses correlated with subsequent clinical inflammatory parameters.
- P.f. preincubation enhanced subsequent TLR-4 and TLR-2 responses, increasing TNF-alpha and reducing IL-10.
Conclusions:
- Plasmodium falciparum infection primes human TLR responses towards a pro-inflammatory cytokine profile.
- This priming effect is unique compared to other microbial pathogens.
- TLR responses during malaria may serve as a prognostic indicator for disease severity.
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