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.
| Original language | English |
|---|---|
| Pages (from-to) | 194-207 |
| Number of pages | 14 |
| Journal | Immunity |
| Volume | 35 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 26 2011 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Infectious Diseases
- Immunology
Cite this
Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome. / Sharma, Shruti; DeOliveira, Rosane B.; Kalantari, Parisa; Parroche, Peggy; Goutagny, Nadege; Jiang, Zhaozhao; Chan, Jennie; Bartholomeu, Daniella C.; Lauw, Fanny; Hall, J. Perry; Barber, Glen N; Gazzinelli, Ricardo T.; Fitzgerald, Katherine A.; Golenbock, Douglas T.
In: Immunity, Vol. 35, No. 2, 26.08.2011, p. 194-207.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=80051880722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80051880722&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2011.05.016
DO - 10.1016/j.immuni.2011.05.016
M3 - Article
VL - 35
SP - 194
EP - 207
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 2
ER -