Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome

Immunity. 2011 Aug 26;35(2):194-207. doi: 10.1016/j.immuni.2011.05.016. Epub 2011 Aug 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AT Rich Sequence / genetics*
  • Animals
  • DNA, Protozoan / genetics*
  • DNA, Protozoan / metabolism
  • Gene Expression Profiling
  • Humans
  • Immunity, Innate / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / physiopathology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Oligonucleotides / genetics*
  • Oligonucleotides / metabolism
  • Plasmodium falciparum / pathogenicity
  • Plasmodium falciparum / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Signal Transduction / genetics

Substances

  • DNA, Protozoan
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Irf3 protein, mouse
  • Irf7 protein, mouse
  • Membrane Proteins
  • Oligonucleotides
  • Sting1 protein, mouse
  • Receptor, Interferon alpha-beta
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE15221