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

Franklin, Bernardo S.; Parroche, Peggy; Ataide, Marco A.; Lauw, Fanny N.; Ropert, Catherine; Oliveira, Rosane B. de; Pereira, Dhélio Batista; Tada, Mauro Shugiro; Nogueira, Paulo Afonso; Silva, Luiz Hildebrando Pereira da; Björkbacka, Harry; Golenbock, Douglas T.; Gazzinelli, Ricardo T.

doi:10.1073/pnas.0809742106

Cited by 178 publications

(203 citation statements)

References 44 publications

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“…Long before TLRs were discovered and TLR4 was recognized as the receptor for LPS, it was shown that the amount of Escherichia coli LPS considered lethal to naive mice is decreased several hundredfold in mice infected with different Plasmodium species (21). This phenomenon remained unexplained until recently, when it was shown that malaria causes proinflammatory priming of innate immune responses (16,19,22). Our group has shown that TLR9 activation is a key mechanism in malaria-mediated inflammatory priming, because WT mice became extremely susceptible to low doses of LPS, whereas TLR9 −/− mice were partially protected (19).…”

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confidence: 99%

“…Although some conflicting data exist (9), the vast majority of studies (10)(11)(12)(13)(14)(15)(16)(17), including our own (18)(19)(20), indicate that Plasmodium parasites possess intrinsic TLR agonists, which are important components of the proinflammatory responses and the immune-mediated symptoms in both rodent and human malaria. In addition, we observed a hyperresponsiveness of TLRs during acute episodes of human and rodent malaria (19). Long before TLRs were discovered and TLR4 was recognized as the receptor for LPS, it was shown that the amount of Escherichia coli LPS considered lethal to naive mice is decreased several hundredfold in mice infected with different Plasmodium species (21).…”

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confidence: 99%

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Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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102

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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confidence: 99%

mentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

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“…pDC recognition of dsDNA genomic intermediates of replicating DNA viruses via TLR9 accounts for the detection of HSV and murine cytomegalovirus [51,[71][72][73]. Interestingly, TLR9-mediated recognition of the malarial byproduct hemozoin derived from Plasmodium falciparum and subsequent production of IL-12 and IFN-γ by DC have been implicated in the proinflammatory cytokinemia associated with acute disease and related sepsis by enhancing TLR expression-and 'priming'-associated signaling pathways leading to hyperresponsiveness to further bacterial or parasitic TLR activation [74,75].…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Enemy at the gates: dendritic cells and immunity to mucosal pathogens

Soloff

Barratt‐Boyes

2010

Cell Res

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“…Of the ten TLRs in humans, the most notable are TLR4 and TLR9, whose activation and changes in expression are thought to potentially affect the clinical outcome of malaria [4][5][6][7] . While TLR4 may interact with extra-cellular ligands (such as PfGPI; Plasmodium falciparum Glycosylphosphatidylinositol) as well as intracellular ligands as it is located both on the cell surface and on endosomes, TLR9 interacts only with intracellular ligands owing to its endosomal localization 8,[10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

“…The host response to malarial infection is immediate and is mediated by pattern recognition receptors of the innate immune system 3,4 . Among these, the Toll-like receptors (TLRs) are well studied in malaria [5][6][7][8][9] and are stimulated by infected red blood cells (RBCs) and/or parasite-derived metabolites, culminating in the release of pro-inflammatory cytokines such as IFN-γ, IL-12, and TNF-α, as well as nitric oxide 8,9 , which are important for controlling the acute blood-stage infection. However, an excessive or deregulated inflammatory response may result in severe malaria.…”

Section: Introductionmentioning

confidence: 99%

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

Dhangadamajhi

Kar

Rout

et al. 2017

Rev. Soc. Bras. Med. Trop.

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Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there are inconsistencies in the associations of common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) with malaria outcome. A comprehensive search was conducted to identify relevant and independent Plasmodium falciparum-infected casecontrol studies, and meta-analysis including six studies for each SNP was performed to obtain more precise estimates of the pooled effects of these variants. The results showed significant associations of the -1486C allele with the risk of severe malaria in allele contrast (T vs. C, p = 0.004, OR = 1.26) and homozygous (TT vs. CC, p = 0.03, OR = 1.51) genetic models. There was no association between the D299G or T-1237C variants and uncomplicated or severe malaria using any of the genetic models tested. However, in stratified analysis, -1237C was associated with the risk of severe malaria in Indian adults (TT vs. TC, p = 0.06, OR = 2.13; TT vs. TC+CC, p <0.00001, OR = 2.65), suggesting that our results must be considered preliminary. The robustness of -1486C as a risk factor warrants investigation into its functionality in malaria pathogenesis. Further, the lack of an association with the T-1237C variant was weak, and future studies examining more detailed individual data from different ethnic groups are essential for confirmation of its genetic contribution to malaria.

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

Cited by 178 publications

References 44 publications

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Enemy at the gates: dendritic cells and immunity to mucosal pathogens

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

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