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Elsevier, Immunity, 2(35), p. 194-207, 2011

DOI: 10.1016/j.immuni.2011.05.016

Elsevier, International Journal of Infectious Diseases, (16), p. e59-e60, 2012

DOI: 10.1016/j.ijid.2012.05.148

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Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome

Journal article published in 2011 by Shruti Sharma, Rosane B. DeOliveira, Parisa Kalantari, Peggy Parroche, Nadege Goutagny, Zhaozhao Jiang, J. Perry Hall, Jennie Chan, Daniella C. Bartholomeu, Fanny N. Lauw, J. Perry Hall, Glen N. Barber, Ricardo T. Gazzinelli ORCID, Katherine A. Fitzgerald, Douglas T. Golenbock
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Although Toll-like receptor 9 (TLR9) has been implicated in regulating 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 DNA sensing 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-r motif induce type I IFNs via a pathway that did not involve previously described sensors including TLR9, DAI, RNA polymerase-III or IFI16/p204. Rather, AT-rich DNA sensing involved an unknown receptor that coupled to STING, TBK1 and IRF3-IRF7 signaling pathway. Mice lacking both IRF3 and 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.