title: The critical role of Notch ligand Delta-like 1 in the pathogenesis of influenza A virus (H1N1) infection.
abstract: Influenza A viral infections have been identified as the etiologic agents for historic pandemics, and contribute to the annual mortality associated with acute viral pneumonia. While both innate and acquired immunity are important in combating influenza virus infection, the mechanism connecting these arms of the immune system remains unknown. Recent data have indicated that the Notch system is an important bridge between antigen-presenting cells (APCs) and T cell communication circuits and plays a central role in driving the immune system to overcome disease. In the present study, we examine the role of Notch signaling during influenza H1N1 virus infection, focusing on APCs. We demonstrate here that macrophages, but not dendritic cells (DCs), increased Notch ligand Delta-like 1 (Dll1) expression following influenza virus challenge. Dll1 expression on macrophages was dependent on retinoic acid-inducible gene-I (RIG-I) induced type-I IFN pathway, and not on the TLR3-TRIF pathway. We also found that IFNα-Receptor knockout mice failed to induce Dll1 expression on lung macrophages and had enhanced mortality during influenza virus infection. Our results further showed that specific neutralization of Dll1 during influenza virus challenge induced higher mortality, impaired viral clearance, and decreased levels of IFN-γ. In addition, we blocked Notch signaling by using γ-secretase inhibitor (GSI), a Notch signaling inhibitor. Intranasal administration of GSI during influenza infection also led to higher mortality, and higher virus load with excessive inflammation and an impaired production of IFN-γ in lungs. Moreover, Dll1 expression on macrophages specifically regulates IFN-γ levels from CD4(+)and CD8(+)T cells, which are important for anti-viral immunity. Together, the results of this study show that Dll1 positively influences the development of anti-viral immunity, and may provide mechanistic approaches for modifying and controlling the immune response against influenza H1N1 virus infection.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Allen
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
authors.forename: Matthew
authors.initials: M
authors.lastname: Schaller
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cavassani
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002135:Calcium-Binding Proteins; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016898:Interferon-alpha; D051880:Receptors, Notch; D007371:Interferon-gamma; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
references.citation: J Immunol. 2009 Mar 15;182(6):3380-9
references.pmid: 19265115
references.citation: Science. 2003 Nov 28;302(5650):1519-22
references.pmid: 14645836
references.citation: J Interferon Cytokine Res. 2004 Aug;24(8):439-54
references.pmid: 15320958
references.citation: Cell Microbiol. 2006 Jun;8(6):907-22
references.pmid: 16681834
references.citation: J Exp Med. 1993 Nov 1;178(5):1725-32
references.pmid: 8228818
references.citation: J Clin Invest. 2009 Jan;119(1):33-46
references.pmid: 19075396
references.citation: J Leukoc Biol. 2004 Feb;75(2):163-89
references.pmid: 14525967
references.citation: Immunity. 2010 Jan 29;32(1):14-27
references.pmid: 20152168
references.citation: Immunity. 2003 Oct;19(4):549-59
references.pmid: 14563319
references.citation: J Leukoc Biol. 2006 May;79(5):913-6
references.pmid: 16641136
references.citation: J Biol Chem. 2005 Feb 18;280(7):5571-80
references.pmid: 15579900
references.citation: J Clin Invest. 2009 Jul;119(7):1899-909
references.pmid: 19509469
references.citation: Microbes Infect. 2010 Jan;12(1):81-7
references.pmid: 19782761
references.citation: J Interferon Cytokine Res. 2009 Sep;29(9):549-57
references.pmid: 19708812
references.citation: J Exp Med. 2007 Jul 9;204(7):1525-31
references.pmid: 17576775
references.citation: Mt Sinai J Med. 2010 Jan-Feb;77(1):103-13
references.pmid: 20101715
references.citation: Nat Rev Immunol. 2009 Feb;9(2):116-24
references.pmid: 19165228
references.citation: Am J Pathol. 2000 Jun;156(6):1951-9
references.pmid: 10854218
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: PLoS Pathog. 2006 Jun;2(6):e53
references.pmid: 16789835
references.citation: J Exp Med. 2007 Nov 26;204(12):2925-34
references.pmid: 17998388
references.citation: Biochem J. 2009 Apr 28;420(1):1-16
references.pmid: 19382893
references.citation: J Exp Med. 1998 Oct 19;188(8):1541-6
references.pmid: 9782132
references.citation: J Virol. 2009 Jun;83(11):5825-34
references.pmid: 19297490
references.citation: Blood. 2009 Oct 8;114(15):3244-54
references.pmid: 19567879
references.citation: J Immunol. 2005 Sep 1;175(5):2851-8
references.pmid: 16116171
references.citation: Semin Cell Dev Biol. 2008 Aug;19(4):311-8
references.pmid: 18765289
references.citation: Clin Infect Dis. 2008 Dec 15;47(12):1575-8
references.pmid: 18990065
references.citation: J Leukoc Biol. 2004 Oct;76(4):886-95
references.pmid: 15240757
references.citation: J Interferon Cytokine Res. 2009 Jun;29(6):313-26
references.pmid: 19441883
references.citation: J Immunol. 2009 Jun 15;182(12):7795-802
references.pmid: 19494303
references.citation: J Virol. 2010 Feb;84(4):2027-37
references.pmid: 19939913
references.citation: Nat Med. 2004 Dec;10(12 Suppl):S82-7
references.pmid: 15577936
references.citation: J Clin Microbiol. 2001 Jan;39(1):196-200
references.pmid: 11136770
references.citation: Nature. 2006 May 4;441(7089):101-5
references.pmid: 16625202
references.citation: Viral Immunol. 2006 Summer;19(2):147-55
references.pmid: 16817757
references.citation: Vaccine. 1985 Sep;3(3 Suppl):277-80
references.pmid: 4060858