Home LiteratureArticle Details
PMID: 21820332 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Immunity ·Vol. 35 ·No. 2 ·2011-08-26 ·Pages 194-207

Sharma S, DeOliveira RB, Kalantari P, Parroche P, Goutagny N, Jiang Z, Chan J, Bartholomeu DC, Lauw F, Hall JP, Barber GN, Gazzinelli RT, Fitzgerald KA, Golenbock DT

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.

MeSH Terms
AT Rich Sequence/genetics Animals DNA, Protozoan/genetics,metabolism Gene Expression Profiling Humans Immunity, Innate/genetics Interferon Regulatory Factor-3/metabolism Interferon Regulatory Factor-7/metabolism Interferon Type I/genetics,metabolism Malaria, Falciparum/immunology,parasitology,physiopathology Membrane Proteins/metabolism Mice Mice, Knockout Oligonucleotides/genetics,metabolism Plasmodium falciparum/pathogenicity,physiology Protein Serine-Threonine Kinases/metabolism Receptor, Interferon alpha-beta/genetics Signal Transduction/genetics
Chemicals
DNA, Protozoan Interferon Regulatory Factor-3 Interferon Regulatory Factor-7 Interferon Type I Irf3 protein, mouse Irf7 protein, mouse Membrane Proteins Oligonucleotides Sting1 protein, mouse Receptor, Interferon alpha-beta Tbk1 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Sharma Shruti
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
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
References (63)
63 references, click to expand
  1. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.
    Nat Immunol. 2008 Aug;9(8):847-56 PMID: 18604214
  2. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.
    Immunity. 2006 Jan;24(1):93-103 PMID: 16413926
  3. Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice.
    Parasitology. 1992 Oct;105 ( Pt 2):165-75 PMID: 1280805
  4. IFNGR1 polymorphisms in Thai malaria patients.
    Infect Genet Evol. 2009 Dec;9(6):1406-9 PMID: 19712753
  5. Genome sequence of the human malaria parasite Plasmodium falciparum.
    Nature. 2002 Oct 3;419(6906):498-511 PMID: 12368864
  6. Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia.
    Genes Immun. 2003 Jun;4(4):275-82 PMID: 12761564
  7. Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice.
    J Immunol. 2007 May 15;178(10):6416-25 PMID: 17475871
  8. Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A.
    J Clin Invest. 2009 Jul;119(7):1931-9 PMID: 19603548
  9. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors.
    Nat Rev Immunol. 2006 Sep;6(9):644-58 PMID: 16932750
  10. Natural killer cell and macrophage cooperation in MyD88-dependent innate responses to Plasmodium falciparum.
    Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14747-52 PMID: 16203971
  11. Pathogenesis of malaria and clinically similar conditions.
    Clin Microbiol Rev. 2004 Jul;17(3):509-39, table of contents PMID: 15258091
  12. Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function.
    Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5789-94 PMID: 19297619
  13. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.
    Immunity. 2008 Oct 17;29(4):538-50 PMID: 18818105
  14. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9.
    Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1919-24 PMID: 17261807
  15. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.
    EMBO J. 2000 Sep 15;19(18):4976-85 PMID: 10990461
  16. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.
    PLoS Pathog. 2009 Aug;5(8):e1000559 PMID: 19696895
  17. Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
    PLoS One. 2009 Aug 04;4(8):e6510 PMID: 19652710
  18. Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.
    J Exp Med. 2010 Feb 15;207(2):327-37 PMID: 20123961
  19. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.
    Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20842-6 PMID: 19926846
  20. RNA recognition and signal transduction by RIG-I-like receptors.
    Immunol Rev. 2009 Jan;227(1):54-65 PMID: 19120475
  21. TLR-independent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA.
    Cell Host Microbe. 2008 Dec 11;4(6):543-54 PMID: 19064255
  22. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.
    Nature. 2007 Jul 26;448(7152):501-5 PMID: 17618271
  23. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling.
    Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2986-91 PMID: 15710892
  24. Classical CD11c+ dendritic cells, not plasmacytoid dendritic cells, induce T cell responses to Plasmodium chabaudi malaria.
    Int J Parasitol. 2010 May;40(6):711-9 PMID: 19968996
  25. Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid.
    J Immunol. 2009 Oct 15;183(8):5208-20 PMID: 19783673
  26. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis.
    J Exp Med. 2007 Jul 9;204(7):1559-69 PMID: 17562815
  27. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.
    Nat Immunol. 2008 Aug;9(8):857-65 PMID: 18604209
  28. Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria.
    Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):177-82 PMID: 16371473
  29. Peroxisomes are signaling platforms for antiviral innate immunity.
    Cell. 2010 May 14;141(4):668-81 PMID: 20451243
  30. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.
    Nat Immunol. 2010 May;11(5):395-402 PMID: 20351692
  31. An atomic model of the interferon-beta enhanceosome.
    Cell. 2007 Jun 15;129(6):1111-23 PMID: 17574024
  32. Haemozoin: from melatonin pigment to drug target, diagnostic tool, and immune modulator.
    Lancet Infect Dis. 2007 Oct;7(10):675-85 PMID: 17897610
  33. Strong immunostimulatory activity of AT-oligodeoxynucleotide requires a six-base loop with a self-stabilized 5'-C...G-3' stem structure.
    Cell Microbiol. 2006 Mar;8(3):485-95 PMID: 16469059
  34. Differential gene induction by type I and type II interferons and their combination.
    J Interferon Cytokine Res. 2006 Jul;26(7):462-72 PMID: 16800785
  35. MyD88-dependent activation of dendritic cells and CD4(+) T lymphocytes mediates symptoms, but is not required for the immunological control of parasites during rodent malaria.
    Microbes Infect. 2007 Jun;9(7):881-90 PMID: 17537666
  36. Type I interferon production enhances susceptibility to Listeria monocytogenes infection.
    J Exp Med. 2004 Aug 16;200(4):437-45 PMID: 15302901
  37. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines.
    Nature. 2008 Feb 7;451(7179):725-9 PMID: 18256672
  38. Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.
    J Leukoc Biol. 2010 Dec;88(6):1171-80 PMID: 20651301
  39. Protein-DNA complex is the exclusive malaria parasite component that activates dendritic cells and triggers innate immune responses.
    J Immunol. 2010 Apr 15;184(8):4338-48 PMID: 20231693
  40. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.
    Nature. 2009 Mar 26;458(7237):514-8 PMID: 19158675
  41. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.
    Nat Genet. 2007 Apr;39(4):523-8 PMID: 17322885
  42. The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease.
    J Immunol. 2009 Dec 15;183(12):7975-83 PMID: 19923465
  43. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
    Nature. 2009 Oct 8;461(7265):788-92 PMID: 19776740
  44. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.
    Nat Immunol. 2005 Oct;6(10):981-8 PMID: 16127453
  45. Role of the Toll/interleukin-1 receptor signaling pathway in host resistance and pathogenesis during infection with protozoan parasites.
    Immunol Rev. 2004 Oct;201:9-25 PMID: 15361229
  46. Cell type-specific recognition of human metapneumoviruses (HMPVs) by retinoic acid-inducible gene I (RIG-I) and TLR7 and viral interference of RIG-I ligand recognition by HMPV-B1 phosphoprotein.
    J Immunol. 2010 Feb 1;184(3):1168-79 PMID: 20042593
  47. IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria.
    J Infect Dis. 2002 Jun 1;185(11):1684-7 PMID: 12023780
  48. Activation of innate immune antiviral responses by Nod2.
    Nat Immunol. 2009 Oct;10(10):1073-80 PMID: 19701189
  49. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism.
    J Immunol. 2001 Nov 15;167(10):5928-34 PMID: 11698470
  50. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I.
    J Immunol. 2005 Oct 15;175(8):5260-8 PMID: 16210631
  51. Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria.
    J Immunol. 2007 May 15;178(10):6033-7 PMID: 17475826
  52. Murine cerebral malaria development is independent of toll-like receptor signaling.
    Am J Pathol. 2007 May;170(5):1640-8 PMID: 17456769
  53. A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis.
    J Infect Dis. 2006 Oct 15;194(8):1127-1134 PMID: 16991088
  54. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate.
    Nat Immunol. 2009 Oct;10(10):1065-72 PMID: 19609254
  55. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: the requirement of extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase and NF-kappaB pathways for the expression of proinflammatory cytokines and nitric oxide.
    J Biol Chem. 2005 Mar 4;280(9):8617-27 PMID: 15611045
  56. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
    Nature. 2008 Oct 2;455(7213):674-8 PMID: 18724357
  57. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway.
    J Immunol. 2004 Apr 15;172(8):4926-33 PMID: 15067072
  58. PfCG2, a Plasmodium falciparum protein peripherally associated with the parasitophorous vacuolar membrane, is expressed in the period of maximum hemoglobin uptake and digestion by trophozoites.
    Mol Biochem Parasitol. 2005 Dec;144(2):167-76 PMID: 16183150
  59. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.
    Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8 PMID: 9861020
  60. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.
    Cell. 2009 Aug 7;138(3):576-91 PMID: 19631370
  61. A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts.
    J Immunol. 2008 Dec 1;181(11):7917-24 PMID: 19017982
  62. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.
    Nature. 2005 Oct 20;437(7062):1167-72 PMID: 16177806
  63. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.
    Nat Immunol. 2003 May;4(5):491-6 PMID: 12692549
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2011.05.016
Published
2011-08-26
Epub
2011-00-04
Pages
194-207
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3162998
Subset
IM
Grants
NIAID NIH HHS · R01 AI067497-05 · United States
NIAID NIH HHS · R01 AI079293 · United States
NIAID NIH HHS · R01 AI083713 · United States
NIAID NIH HHS · R01 AI067497 · United States
NIAID NIH HHS · R21AI80907 · United States
NIAID NIH HHS · R56 AI067497 · United States
NIAID NIH HHS · AI067497 · United States
NIAID NIH HHS · R21 AI080907 · United States
NIAID NIH HHS · R01 AI083641-01 · United States
NIAID NIH HHS · AI079293 · United States
NIAID NIH HHS · R01 AI083713-04 · United States
NIAID NIH HHS · R37 AI067497 · United States
Databases
GEO
GSE15221
Corrections
CommentIn
PMID: 21866165
CommentIn
PMID: 21867921
External Links
PubMed source DOI: 10.1016/j.immuni.2011.05.016 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2