Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

ludc webb

Harry Björkbacka

Researcher

ludc webb

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

Author

  • 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

Summary, in English

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.

Department/s

  • Cardiovascular Research - Immunity and Atherosclerosis

Publishing year

2009

Language

English

Pages

5789-5794

Publication/Series

Proceedings of the National Academy of Sciences

Volume

106

Issue

14

Document type

Journal article

Publisher

National Acad Sciences

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis

ISBN/ISSN/Other

  • ISSN: 1091-6490