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.
Vyšlo v časopise: The Critical Role of Notch Ligand Delta-like 1 in the Pathogenesis of Influenza A Virus (H1N1) Infection. PLoS Pathog 7(11): e32767. doi:10.1371/journal.ppat.1002341 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002341
1. PaleseP 2004 Influenza: old and new threats. Nat Med 10 S82 87
2. WebbyRJWebsterRG 2003 Are we ready for pandemic influenza? Science 302 1519 1522
3. SwedishKAConenelloGFactorSH 2010 First Season of 2009 H1N1 Influenza. Mt Sinai J Med 77 103 113
4. Le GofficRBalloyVLagranderieMAlexopoulouLEscriouN 2006 Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2 e53
5. KumarHKawaiTAkiraS 2009 Pathogen recognition in the innate immune response. Biochem J 420 1 16
6. GoodmanAGZengHProllSCPengXCillonizC 2010 The alpha/beta interferon receptor provides protection against influenza virus replication but is dispensable for inflammatory response signaling. J Virol 84 2027 2037
7. GuillotLLe GofficRBlochSEscriouNAkiraS 2005 Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J Biol Chem 280 5571 5580
8. YoneyamaMKikuchiMMatsumotoKImaizumiTMiyagishiM 2005 Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175 2851 2858
9. TakeuchiOAkiraS 2010 Pattern recognition receptors and inflammation. Cell 140 805 820
10. WolffTLudwigS 2009 Influenza viruses control the vertebrate type I interferon system: factors, mechanisms, and consequences. J Interferon Cytokine Res 29 549 557
11. TakaokaAYanaiH 2006 Interferon signalling network in innate defence. Cell Microbiol 8 907 922
12. SchroderKHertzogPJRavasiTHumeDA 2004 Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75 163 189
13. MalmgaardL 2004 Induction and regulation of IFNs during viral infections. J Interferon Cytokine Res 24 439 454
14. RadtkeFFasnachtNMacdonaldHR 2010 Notch signaling in the immune system. Immunity 32 14 27
15. AmsenDAntovAFlavellRA 2009 The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 9 116 124
16. ItoTSchallerMHogaboamCMStandifordTJSandorM 2009 TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4. J Clin Invest 119 33 46
17. SchallerMANeupaneRRuddBDKunkelSLKallalLE 2007 Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines. J Exp Med 204 2925 2934
18. ZhangZClarkeTBWeiserJN 2009 Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest 119 1899 1909
19. EhrhardtCSeyerRHrinciusEREierhoffTWolffT 2010 Interplay between influenza A virus and the innate immune signaling. Microbes Infect 12 81 87
20. SchindlerCPlumleeC 2008 Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol 19 311 318
21. KatoHTakeuchiOSatoSYoneyamaMYamamotoM 2006 Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441 101 105
22. SzretterKJGangappaSBelserJAZengHChenH 2009 Early control of H5N1 influenza virus replication by the type I interferon response in mice. J Virol 83 5825 5834
23. MaekawaYTsukumoSChibaSHiraiHHayashiY 2003 Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity 19 549 559
24. ChoOHShinHMMieleLGoldeTEFauqA 2009 Notch regulates cytolytic effector function in CD8+ T cells. J Immunol 182 3380 3389
25. FotiMGranucciFPelizzolaMBerettaORicciardi-CastagnoliP 2006 Dendritic cells in pathogen recognition and induction of immune responses: a functional genomics approach. J Leukoc Biol 79 913 916
26. SkokosDNussenzweigMC 2007 CD8 - DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med 204 1525 1531
27. BruderDSrikiatkhachornAEnelowRI 2006 Cellular immunity and lung injury in respiratory virus infection. Viral Immunol 19 147 155
28. KarupiahGChenJHMahalingamSNathanCFMacMickingJD 1998 Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. J Exp Med 188 1541 1546
29. KhoufacheKLeBouderFMorelloELaurentFRiffaultS 2009 Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway. J Immunol 182 7795 7802
30. GrahamMBDaltonDKGiltinanDBracialeVLStewartTA 1993 Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178 1725 1732
31. TannockGAPaulJABarryRD 1985 Immunization against influenza by the ocular route. Vaccine 3 277 280
32. WareingMDLyonABLuBGerardCSarawarSR 2004 Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J Leukoc Biol 76 886 895
33. DeshmaneSLKremlevSAminiSSawayaBE 2009 Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29 313 326
34. ZhaoYLuMLauLTLuJGaoZ 2008 Neutrophils may be a vehicle for viral replication and dissemination in human H5N1 avian influenza. Clin Infect Dis 47 1575 1578
35. DawsonTCBeckMAKuzielWAHendersonFMaedaN 2000 Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol 156 1951 1959
36. IshiiMWenHCorsaCALiuTCoelhoAL 2009 Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114 3244 3254
37. van EldenLJNijhuisMSchipperPSchuurmanRvan LoonAM 2001 Simultaneous detection of influenza viruses A and B using real-time quantitative PCR. J Clin Microbiol 39 196 200
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
