TY - JOUR
T1 - Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome
AU - Sharma, Shruti
AU - DeOliveira, Rosane B.
AU - Kalantari, Parisa
AU - Parroche, Peggy
AU - Goutagny, Nadege
AU - Jiang, Zhaozhao
AU - Chan, Jennie
AU - Bartholomeu, Daniella C.
AU - Lauw, Fanny
AU - Hall, J. Perry
AU - Barber, Glen N.
AU - Gazzinelli, Ricardo T.
AU - Fitzgerald, Katherine A.
AU - Golenbock, Douglas T.
PY - 2011/8/26
Y1 - 2011/8/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2011.05.016
DO - 10.1016/j.immuni.2011.05.016
M3 - Article
C2 - 21820332
AN - SCOPUS:80051880722
VL - 35
SP - 194
EP - 207
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 2
ER -