Department of Medicine, Division of Infectious Diseases and Immunology
Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
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.
malaria, innate immunity, toll-like receptor, TLR
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© 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.
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Franklin BS, Parroche P, Ataide MA, Lauw F, Ropert C, DeOliveira RB, Pereira D, Tada MS, Nogueira P, da Silva LH, Bjorkbacka H, Golenbock DT, Gazzinelli RT. (2009). Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function. Infectious Diseases and Immunology Publications. https://doi.org/10.1073/pnas.0809742106. Retrieved from https://escholarship.umassmed.edu/infdis_pp/395