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PMID: 25395539 Published · ppublish English Journal Article Research Support, American Recovery and Reinvestment Act Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18.

Science (New York, N.Y.) ·Vol. 346 ·No. 6211 ·2014-11-14 ·Pages 861-5

Zhang B, Chassaing B, Shi Z, Uchiyama R, Zhang Z, Denning TL, Crawford SE, Pruijssers AJ, Iskarpatyoti JA, Estes MK, Dermody TS, Ouyang W, Williams IR, Vijay-Kumar M, Gewirtz AT

Abstract

Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.

MeSH Terms
Animals Diarrhea/immunology,therapy,virology Disease Models, Animal Feces/virology Flagellin/administration & dosage,immunology Homeodomain Proteins/genetics Immunity, Innate Interleukin-18/administration & dosage,genetics,immunology Interleukins/administration & dosage,genetics,immunology Mice Mice, Inbred C57BL Mice, Mutant Strains Mutation Rotavirus Infections/immunology,prevention & control,therapy Toll-Like Receptor 5/genetics,physiology Virus Shedding
Chemicals
Homeodomain Proteins Interleukin-18 Interleukins Toll-Like Receptor 5 Flagellin RAG-1 protein interleukin-22
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Zhang Benyue
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Chassaing Benoit
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Shi Zhenda
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Uchiyama Robin
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Zhang Zhan
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Denning Timothy L
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Crawford Sue E
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
Pruijssers Andrea J
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
Iskarpatyoti Jason A
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
Estes Mary K
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
Dermody Terence S
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pediatrics, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Ouyang Wenjun
Department of Immunology, Genentech, South San Francisco, CA, USA.
Williams Ifor R
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Vijay-Kumar Matam
Department of Nutritional Sciences and Medicine, Pennsylvania State University, University Park, PA 16802, USA.
Gewirtz Andrew T
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. agewirtz@gsu.edu.
References (25)
25 references, click to expand
  1. Protein kinase R mediates intestinal epithelial gene remodeling in response to double-stranded RNA and live rotavirus.
    J Immunol. 2005 May 15;174(10):6322-31 PMID: 15879132
  2. Flagellin is the major proinflammatory determinant of enteropathogenic Salmonella.
    J Immunol. 2003 Oct 1;171(7):3668-74 PMID: 14500664
  3. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens.
    Immunity. 2002 Aug;17(2):211-20 PMID: 12196292
  4. Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice.
    Gastroenterology. 2014 Dec;147(6):1363-77.e17 PMID: 25172014
  5. NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen.
    Mucosal Immunol. 2014 Jul;7(4):775-85 PMID: 24280936
  6. Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges.
    Mucosal Immunol. 2012 May;5(3):288-98 PMID: 22318495
  7. Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense.
    Immunity. 2012 Feb 24;36(2):276-87 PMID: 22306017
  8. NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells.
    Nat Immunol. 2012 Feb;13(2):162-9 PMID: 22231517
  9. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.
    Nature. 2011 Sep 29;477(7366):596-600 PMID: 21918512
  10. IFN-lambda determines the intestinal epithelial antiviral host defense.
    Proc Natl Acad Sci U S A. 2011 May 10;108(19):7944-9 PMID: 21518880
  11. Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity.
    Gut. 2011 May;60(5):648-57 PMID: 21199832
  12. TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin.
    Eur J Immunol. 2010 Dec;40(12):3528-34 PMID: 21072873
  13. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa.
    J Immunol. 2010 Jul 15;185(2):1177-85 PMID: 20566828
  14. IRF3 inhibition by rotavirus NSP1 is host cell and virus strain dependent but independent of NSP1 proteasomal degradation.
    J Virol. 2009 Oct;83(20):10322-35 PMID: 19656876
  15. Rotavirus NSP1 inhibits NFkappaB activation by inducing proteasome-dependent degradation of beta-TrCP: a novel mechanism of IFN antagonism.
    PLoS Pathog. 2009 Jan;5(1):e1000280 PMID: 19180189
  16. Flagellin: key target of mucosal innate immunity.
    Mucosal Immunol. 2009 May;2(3):197-205 PMID: 19242410
  17. Rotaviruses: from pathogenesis to vaccination.
    Gastroenterology. 2009 May;136(6):1939-51 PMID: 19457420
  18. Qualitative and quantitative characteristics of rotavirus-specific CD8 T cells vary depending on the route of infection.
    J Virol. 2008 Jul;82(14):6812-9 PMID: 18480435
  19. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation.
    J Immunol. 2008 Jun 15;180(12):8280-5 PMID: 18523294
  20. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models.
    Science. 2008 Apr 11;320(5873):226-30 PMID: 18403709
  21. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.
    Nat Immunol. 2006 Jun;7(6):576-82 PMID: 16648852
  22. Rotavirus and severe childhood diarrhea.
    Emerg Infect Dis. 2006 Feb;12(2):304-6 PMID: 16494759
  23. Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus.
    J Virol. 1990 Jan;64(1):361-8 PMID: 2152822
  24. Murine model of rotavirus infection.
    Adv Exp Med Biol. 1997;412:233-40 PMID: 9192019
  25. Age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein.
    Science. 1996 Apr 5;272(5258):101-4 PMID: 8600515
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1256999
Email
agewirtz@gsu.edu
Published
2014-11-14
Pages
861-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4788408
Subset
IM
Grants
NIAID NIH HHS · AI107943 · United States
NIDDK NIH HHS · R01 DK061417 · United States
NIDDK NIH HHS · R01 DK064730 · United States
NIDDK NIH HHS · DK061417 · United States
NIAID NIH HHS · R56 AI080656 · United States
NIAID NIH HHS · R01 AI080656 · United States
NIAID NIH HHS · R01 AI038296 · United States
NIDDK NIH HHS · P30 DK056338 · United States
NIAID NIH HHS · AI080656 · United States
NIDDK NIH HHS · DK56338 · United States
NIAID NIH HHS · R37 AI038296 · United States
NIAID NIH HHS · AI038296 · United States
NIDDK NIH HHS · DK064730 · United States
Databases
GEO
GSE62479
External Links
PubMed source DOI: 10.1126/science.1256999 PMC Full Text View journal details
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