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The Journal of Immunology, 2007, 179, 162 -171
Copyright © 2007 by The American Association of Immunologists, Inc.
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*Compound via MeSH
*Substance via MeSH

Plasmodium falciparum Infection Causes Proinflammatory Priming of Human TLR Responses1

Matthew B. B. McCall*, Mihai G. Netea{dagger}, Cornelus C. Hermsen*, Trees Jansen{dagger}, Liesbeth Jacobs{dagger}, Douglas Golenbock{ddagger}, André J. A. M. van der Ven{dagger} and Robert W. Sauerwein2,*

* Department of Medical Microbiology and {dagger} Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and {ddagger} Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This experimental human malaria study was supported by a grant from the DioRaphte Foundation. M.B.B.M. is supported by a FP6 European Network of Excellence (BioMalPar) fellowship. M.G.N. is supported by a VIDI Grant from the Netherlands Organization for Scientific Research.

2 Address correspondence and reprint requests to Prof. Robert W. Sauerwein, Department Medical Microbiology 268, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address: r.sauerwein{at}mmb.umcn.nl

3 Abbreviations used in this paper: P.f., Plasmodium falciparum; pRBC, parasitized RBC; uRBC, uninfected RBC; QT-NASBA, quantitative nucleic acid sequence-based amplification.




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