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

Research output: Contribution to journalArticle

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

Details

Authors
  • Bernardo S. Franklin
  • Peggy Parroche
  • Marco Antonio Ataidea
  • Fanny Lauw
  • Catherine Ropert
  • Rosane B. de Oliveira
  • Dhelio Pereira
  • Mauro Shugiro Tada
  • Paulo Nogueira
  • Luiz Hildebrando Pereira da Silva
  • Harry Björkbacka
  • Douglas T. Golenbock
  • Ricardo T. Gazzinelli
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)5789-5794
JournalProceedings of the National Academy of Sciences
Volume106
Issue number14
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes