title: Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function.
abstract: 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.
authors.affiliation: Immunopathology Laboratory, René Rachou Institute, Fundaçao Oswaldo Cruz, Avenue Augusto de Lima 1715, MG 30190, Belo Horizonte, Brazil.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.forename: Peggy
authors.initials: P
authors.lastname: Parroche
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Ataíde
authors.forename: Fanny
authors.initials: F
authors.lastname: Lauw
authors.forename: Catherine
authors.initials: C
authors.lastname: Ropert
authors.forename: Rosane B
authors.initials: RB
authors.lastname: de Oliveira
authors.forename: Dhelio
authors.initials: D
authors.lastname: Pereira
authors.forename: Mauro Shugiro
authors.initials: MS
authors.lastname: Tada
authors.forename: Paulo
authors.initials: P
authors.lastname: Nogueira
authors.forename: Luiz Hildebrando Pereira
authors.initials: LH
authors.lastname: da Silva
authors.forename: Harry
authors.initials: H
authors.lastname: Bjorkbacka
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: 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
chemical_list: 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