Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome

Shruti Sharma, Rosane B. DeOliveira, Parisa Kalantari, Peggy Parroche, Nadege Goutagny, Zhaozhao Jiang, Jennie Chan, Daniella C. Bartholomeu, Fanny Lauw, J. Perry Hall, Glen N. Barber, Ricardo T. Gazzinelli, Katherine A. Fitzgerald, Douglas T. Golenbock

Research output: Contribution to journalArticle

161 Scopus citations

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 languageEnglish (US)
Pages (from-to)194-207
Number of pages14
JournalImmunity
Volume35
Issue number2
DOIs
StatePublished - Aug 26 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Sharma, S., DeOliveira, R. B., Kalantari, P., Parroche, P., Goutagny, N., Jiang, Z., Chan, J., Bartholomeu, D. C., Lauw, F., Hall, J. P., Barber, G. N., Gazzinelli, R. T., Fitzgerald, K. A., & Golenbock, D. T. (2011). Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome. Immunity, 35(2), 194-207. https://doi.org/10.1016/j.immuni.2011.05.016