Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function.
Malaria-induced sepsis is associated with an intense proinflammatory cytokinemia for which the underlying mechanisms are poorly understood. It has been demonstrated that experimental infection of humans with Plasmodium falciparum primes Toll-like receptor (TLR)-mediated proinflammatory responses. Nevertheless, the relevance of this phenomenon during natural infection and, more importantly, the mechanisms by which malaria mediates TLR hyperresponsiveness are unclear. Here we show that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes involving TLR signaling, had sites for IFN-inducible transcription factors. To further define the mechanism involved in malaria-mediated "priming," we infected mice with Plasmodium chabaudi. The human data were remarkably predictive of what we observed in the rodent malaria model. Malaria-induced priming of TLR responses correlated with increased expression of TLR mRNA in a TLR9-, MyD88-, and IFNgamma-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while TLR9(-/-), IL12(-/-) and to a greater extent, IFNgamma(-/-) mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFNgamma responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.
Franklin
Bernardo S
BS
Immunopathology Laboratory, René Rachou Institute, Fundaçao Oswaldo Cruz, Avenue Augusto de Lima 1715, MG 30190, Belo Horizonte, Brazil.
Parroche
Peggy
P
Ataíde
Marco Antonio
MA
Lauw
Fanny
F
Ropert
Catherine
C
de Oliveira
Rosane B
RB
Pereira
Dhelio
D
Tada
Mauro Shugiro
MS
Nogueira
Paulo
P
da Silva
Luiz Hildebrando Pereira
LH
Bjorkbacka
Harry
H
Golenbock
Douglas T
DT
Gazzinelli
Ricardo T
RT
D000818:Animals; D016207:Cytokines; D005334:Fever; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D016788:Plasmodium chabaudi; D010963:Plasmodium falciparum; D018805:Sepsis / Q000469:parasitology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics
D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma