Details

Autor(en) / Beteiligte

• Franklin, Bernardo S
• Parroche, Peggy
• Ataide, Marco Antonio
• Lauw, Fanny
• Ropert, Catherine
• De Oliveira, Rosane B
• Pereira, Dhelio
• Tada, Mauro Shugiro
• Nogueira, Paulo
• Da Silva, Luiz Hildebrando Pereira
• Bjorkbacka, Harry
• Golenbock, Douglas T
• Gazzinelli, Ricardo T

Titel

Malaria primes the innate immune response due to interferon-g induced enhancement of toll-like receptor expression and function

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-04, Vol.106 (14), p.5789-5794

Erscheinungsjahr

2009

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 IFNg-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while TLR9 super(-/-), IL12 super(-/-) and to a greater extent, IFNg super(-/-) mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFNg responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.