Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function
Authors
Franklin, Bernardo S.Parroche, Peggy
Ataide, Marco Antonio
Lauw, Fanny
Ropert, Catherine
DeOliveira, Rosane B.
Pereira, Dhelio
Tada, Mauro Shugiro.
Nogueira, Paulo
da Silva, Luiz Hildebrando Pereira
Bjorkbacka, Harry
Golenbock, Douglas T.
Gazzinelli, Ricardo T.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2009-04-07Keywords
malariainnate immunity
toll-like receptor
TLR
Immunity
Immunology and Infectious Disease
Immunology of Infectious Disease
Infectious Disease
Metadata
Show full item recordAbstract
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.Source
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5789-94. doi:10.1073/pnas.0809742106. Epub 2009 Mar 18. Link to article on publisher's site
DOI
10.1073/pnas.0809742106Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35173PubMed ID
19297619Related Resources
Rights
© 2009. Freely available online through the PNAS open access option. Publisher PDF posted as allowed by the publisher's license at https://www.pnas.org/page/authors/licenses.ae974a485f413a2113503eed53cd6c53
10.1073/pnas.0809742106