title: Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.
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.
authors.affiliation: Laboratory of Immunopathology, René Rachou Research Center, Oswaldo Cruz Foundation, Belo Horizonte, 30190-002, Minas Gerais, Brazil.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.forename: Sally T
authors.initials: ST
authors.lastname: Ishizaka
authors.forename: Marc
authors.initials: M
authors.lastname: Lamphier
authors.forename: Fabian
authors.initials: F
authors.lastname: Gusovsky
authors.forename: Hans
authors.initials: H
authors.lastname: Hansen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rose
authors.forename: Wanjun
authors.initials: W
authors.lastname: Zheng
authors.forename: Marco Antônio
authors.initials: MA
authors.lastname: Ataíde
authors.forename: Rosane B
authors.initials: RB
authors.lastname: de Oliveira
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016779:Malaria, Cerebral / Q000139:chemically induced / Q000469:parasitology / Q000517:prevention & control* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009696:Nucleic Acids / Q000378:metabolism*; D016788:Plasmodium chabaudi / Q000187:drug effects / Q000502:physiology; D012772:Shock, Septic / Q000139:chemically induced / Q000150:complications; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D006841:Hydrocarbons, Aromatic; D008070:Lipopolysaccharides; D009696:Nucleic Acids; D051193:Toll-Like Receptors