title: Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome.
abstract: Although Toll-like receptor 9 (TLR9) has been implicated in cytokine and type I interferon (IFN) production during malaria in humans and mice, the high AT content of the Plasmodium falciparum genome prompted us to examine the possibility that malarial DNA triggered TLR9-independent pathways. Over 6000 ATTTTTAC ("AT-rich") motifs are present in the genome of P. falciparum, which we show here potently induce type I IFNs. Parasite DNA, parasitized erythrocytes and oligonucleotides containing the AT-rich motif induce type I IFNs via a pathway that did not involve the previously described sensors TLR9, DAI, RNA polymerase-III or IFI16/p204. Rather, AT-rich DNA sensing involved an unknown receptor that coupled to the STING, TBK1 and IRF3-IRF7 signaling pathway. Mice lacking IRF3, IRF7, the kinase TBK1 or the type I IFN receptor were resistant to otherwise lethal cerebral malaria. Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Rosane B
authors.initials: RB
authors.lastname: DeOliveira
authors.forename: Parisa
authors.initials: P
authors.lastname: Kalantari
authors.forename: Peggy
authors.initials: P
authors.lastname: Parroche
authors.forename: Nadege
authors.initials: N
authors.lastname: Goutagny
authors.forename: Zhaozhao
authors.initials: Z
authors.lastname: Jiang
authors.forename: Jennie
authors.initials: J
authors.lastname: Chan
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Bartholomeu
authors.forename: Fanny
authors.initials: F
authors.lastname: Lauw
authors.forename: J Perry
authors.initials: JP
authors.lastname: Hall
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
mesh_terms: D020856:AT Rich Sequence / Q000235:genetics*; D000818:Animals; D016054:DNA, Protozoan / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009841:Oligonucleotides / Q000235:genetics* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000472:pathogenicity / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000099197:STING Protein
chemical_list: D016054:DNA, Protozoan; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008565:Membrane Proteins; D009841:Oligonucleotides; D017346:Protein Serine-Threonine Kinases; D053633:Receptor, Interferon alpha-beta; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse