Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome
Department of Medicine, Division of Infectious Diseases and Immunology
AT Rich Sequence; Animals; DNA, Protozoan; Gene Expression Profiling; Humans; Immunity, Innate; Interferon Regulatory Factor-3; Interferon Regulatory Factor-7; Interferon Type I; Malaria, Falciparum; Membrane Proteins; Mice; Mice, Knockout; Oligonucleotides; Plasmodium falciparum; Protein-Serine-Threonine Kinases; Receptor, Interferon alpha-beta; Signal Transduction
Immunology and Infectious Disease
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.
DOI of Published Version
Immunity. 2011 Aug 26;35(2):194-207. Epub 2011 Aug 4. Link to article on publisher's site
Sharma S, DeOliveira RB, Kalantari P, Parroche P, Goutagny N, Jiang Z, Chan J, Bartholomeu DC, Lauw FN, Hall JP, Barber GN, Gazzinelli RT, Fitzgerald KA, Golenbock DT. (2011). Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Infectious Diseases and Immunology Publications. https://doi.org/10.1016/j.immuni.2011.05.016. Retrieved from https://escholarship.umassmed.edu/infdis_pp/138