ArticleProceedings of the National Academy of Sciences of the United States of America2011
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 125 citations in OpenAlex.
- Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.PLoS pathogens · 2014Trial
- TLR9/NF-κB-mediated dendritic cell activation by neutrophil extracellular traps drives pathogenesis in experimental cerebral malaria.Journal of neuroinflammation · 2025Article
- DNA fromMicroorganisms · 2025Article
- Essential role of pre-existing humoral immunity in TLR9-mediated type I IFN response to recombinant AAV vectors in human whole blood.Frontiers in immunology · 2024Article
- Small molecule modulators of immune pattern recognition receptors.RSC chemical biology · 2023Review
- Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis.Cell communication and signaling : CCS · 2023Article
- Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis.Journal of translational medicine · 2023Article
- Antimalarial potential ofThe journal of venomous animals and toxins including tropical diseases · 2023Article
- Diagnosis of cerebral malaria: Tools to reduceFrontiers in cellular and infection microbiology · 2023Review
- Rutin ameliorates malaria pathogenesis by modulating inflammatory mechanism: an in vitro and in vivo study.Inflammopharmacology · 2022Article
- Network-driven analysis of human-Plasmodium falciparum interactome: processes for malaria drug discovery and extracting in silico targets.Malaria journal · 2021Article
- Chronic Inhibition of Toll-Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats.Journal of the American Heart Association · 2021Article
- Disrupted Iron Metabolism and Mortality during Co-infection with Malaria and an Intestinal Gram-Negative Extracellular Pathogen.Cell reports · 2021Article
- Identification of Key Immune-Related Genes in the Progression of Septic Shock.Frontiers in genetics · 2021Article
- TLR-9 Plays a Role inFrontiers in immunology · 2021Article
- Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches.Signal transduction and targeted therapy · 2020Review
- Clostridioides difficile Toxin A Remodels Membranes and Mediates DNA Entry Into Cells to Activate Toll-Like Receptor 9 Signaling.Gastroenterology · 2020Article
- Integrative analysis of microRNA and mRNA expression profiles of monocyte-derived dendritic cells differentiation during experimental cerebral malaria.Journal of leukocyte biology · 2020Article
- Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes.European journal of medicinal chemistry · 2020Review
- Genetic diversity of toll-like receptor genes in the vulnerable Chinese egret (Egretta eulophotes).PloS one · 2020Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.