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

Franklin, Bernardo S.; Parroche, Peggy; Ataidea, Marco Antonio; Lauw, Fanny; Ropert, Catherine; de Oliveira, Rosane B.; Pereira, Dhelio; Tada, Mauro Shugiro; Nogueira, Paulo and Pereira da Silva, Luiz Hildebrando, et al. (2009) In Proceedings of the National Academy of Sciences 106(14). p.5789-5794
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... (More)
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. (Less)
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Proceedings of the National Academy of Sciences
volume
106
issue
14
pages
5789 - 5794
publisher
National Acad Sciences
external identifiers
  • wos:000264967500061
  • scopus:65249132344
ISSN
1091-6490
DOI
10.1073/pnas.0809742106
language
English
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yes
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9805d0bf-79c3-4f0d-8ad0-a6ea55675e55 (old id 1400494)
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2009-06-15 13:58:13
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2017-09-24 03:48:32
@article{9805d0bf-79c3-4f0d-8ad0-a6ea55675e55,
  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.},
  author       = {Franklin, Bernardo S. and Parroche, Peggy and Ataidea, Marco Antonio and Lauw, Fanny and Ropert, Catherine and de Oliveira, Rosane B. and Pereira, Dhelio and Tada, Mauro Shugiro and Nogueira, Paulo and Pereira da Silva, Luiz Hildebrando and Björkbacka, Harry and Golenbock, Douglas T. and Gazzinelli, Ricardo T.},
  issn         = {1091-6490},
  language     = {eng},
  number       = {14},
  pages        = {5789--5794},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function},
  url          = {http://dx.doi.org/10.1073/pnas.0809742106},
  volume       = {106},
  year         = {2009},
}