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dc.contributor.authorFranklin, Bernardo S.
dc.contributor.authorParroche, Peggy
dc.contributor.authorAtaide, Marco Antonio
dc.contributor.authorLauw, Fanny
dc.contributor.authorRopert, Catherine
dc.contributor.authorDeOliveira, Rosane B.
dc.contributor.authorPereira, Dhelio
dc.contributor.authorTada, Mauro Shugiro.
dc.contributor.authorNogueira, Paulo
dc.contributor.authorda Silva, Luiz Hildebrando Pereira
dc.contributor.authorBjorkbacka, Harry
dc.contributor.authorGolenbock, Douglas T.
dc.contributor.authorGazzinelli, Ricardo T
dc.date2022-08-11T08:09:10.000
dc.date.accessioned2022-08-23T16:19:57Z
dc.date.available2022-08-23T16:19:57Z
dc.date.issued2009-04-07
dc.date.submitted2018-04-17
dc.identifier.citation<p>Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5789-94. doi:10.1073/pnas.0809742106. Epub 2009 Mar 18. <a href="https://doi.org/10.1073/pnas.0809742106">Link to article on publisher's site</a></p>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.0809742106
dc.identifier.pmid19297619
dc.identifier.urihttp://hdl.handle.net/20.500.14038/35173
dc.description.abstractMalaria-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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=19297619&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1073/pnas.0809742106
dc.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.
dc.subjectmalaria
dc.subjectinnate immunity
dc.subjecttoll-like receptor
dc.subjectTLR
dc.subjectImmunity
dc.subjectImmunology and Infectious Disease
dc.subjectImmunology of Infectious Disease
dc.subjectInfectious Disease
dc.titleMalaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume106
dc.source.issue14
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1396&amp;context=infdis_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/395
dc.identifier.contextkey11977001
refterms.dateFOA2022-08-23T16:19:58Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathinfdis_pp/395
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages5789-94


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