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
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.
Sharma, Shrutie; DeOliveira, Rosane B.; Kalantari, Parisa; Parroche, Peggy; Goutagny, Nadege; Jiang, Zhaozhao; Chan, Jennie; Bartholomeu, Daniella C.; Lauw, Fanny N.; Hall, J. Perry; Barber, Glen N.; Gazzinelli, Ricardo T.; Fitzgerald, Katherine A.; and Golenbock, Douglas T., "Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome" (2011). Infectious Diseases and Immunology Publications and Presentations. 138.