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.
N1 - Funding Information:
The authors would like to thank A. Cerny for animal husbandry and genotyping and O. Mulhern for her help with affinity purification assays. This work is supported by NIH grants AI067497 (to K.A.F), by AI079293 (to K.A.F and D.T.G), by R21AI80907 (to R.T.G) and FAPEMIG/CNPq/INCTV from FIOCRUZ, Brazil (to D.T.G). K.A.F and D.T.G oversaw the whole project with R.T.G and S.S. S.S. designed and conducted the experiments with help from Z.J., R.O., P.P., P.K., F.L., and N.G. D.C.B quantified the AT-rich and CpG motif frequency, R.O. and J.C. conducted the in vivo mouse models, and H.B. performed microarray analysis. G.B. made STING-deficient mice and J.P.H made the TBK1-hypomorphic mice. S.S., K.A.F., and D.T.G. wrote the manuscript.
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 -