title: Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus.
abstract: BACKGROUND
  Highly pathogenic avian influenza viruses of the H5N1 subtype continue to cross the species barrier to infect humans and cause severe disease. It has been suggested that an exaggerated immune response contributes to the pathogenesis of H5N1 virus infection in mammals. In particular, H5N1 virus infections are associated with a high expression of the proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α).
  
  
  METHODS
  We investigated the compounding affects of both cytokines on the outcome of H5N1 virus disease by using triple mutant mice deficient in 3 signaling receptors, TNF-R1, TNF-R2, and IL-1-RI.
  
  
  RESULTS
  Triple mutant mice exhibited reduced morbidity and a significant delay in mortality following lethal challenge with a lethal H5N1 virus, whereas no such differences were observed with the less virulent A/PR/8/34 (H1N1) virus. H5N1-infected triple mutant mice displayed diminished cytokine production in lung tissue and a quantifiable decrease of macrophages and neutrophils in the lungs postinfection. Moreover, morphometric analysis of airway sections revealed less extensive inflammation in H5N1-infected triple mutant mice, compared with infected wild-type mice.
  
  
  CONCLUSIONS
  The combined signaling from the TNF or IL-1 receptors promotes maximal lung inflammation that may contribute to the severity of disease caused by H5N1 virus infection.
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Perrone
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D002452:Cell Count; D016207:Cytokines / Q000172:deficiency / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality; D053124:Influenza A Virus, H5N1 Subtype; D008171:Lung Diseases / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D015398:Signal Transduction; D019562:Viral Load
chemical_list: D016207:Cytokines; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor
references.citation: Lancet. 1998 Feb 14;351(9101):467-71
references.pmid: 9482437
references.citation: Lancet. 2002 Dec 7;360(9348):1831-7
references.pmid: 12480361
references.citation: Eur J Immunol. 1997 Nov;27(11):2870-5
references.pmid: 9394812
references.citation: Science. 2006 Apr 21;312(5772):399
references.pmid: 16556800
references.citation: Semin Immunol. 2002 Apr;14(2):123-32
references.pmid: 11978084
references.citation: J Virol. 2000 Jul;74(13):6105-16
references.pmid: 10846094
references.citation: Nat Med. 2006 Oct;12(10):1203-7
references.pmid: 16964257
references.citation: J Med Microbiol. 2007 Jul;56(Pt 7):875-883
references.pmid: 17577050
references.citation: J Immunol. 1998 Jan 15;160(2):943-52
references.pmid: 9551933
references.citation: J Virol. 1998 Aug;72(8):6678-88
references.pmid: 9658115
references.citation: J Virol. 1999 Jul;73(7):5903-11
references.pmid: 10364342
references.citation: Emerg Infect Dis. 2005 Jul;11(7):1036-41
references.pmid: 16022777
references.citation: PLoS Pathog. 2008 Aug 01;4(8):e1000115
references.pmid: 18670648
references.citation: Clin Infect Dis. 2009 Jul 15;49(2):279-90
references.pmid: 19522652
references.citation: Cytokine Growth Factor Rev. 2008 Jun-Aug;19(3-4):183-6
references.pmid: 18555199
references.citation: Lancet. 1998 Feb 14;351(9101):472-7
references.pmid: 9482438
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1302-10
references.pmid: 14966082
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Jan;288(1):L3-15
references.pmid: 15591040
references.citation: Lab Invest. 2002 Sep;82(9):1155-66
references.pmid: 12218076
references.citation: Immunol Cell Biol. 2007 Feb-Mar;85(2):85-92
references.pmid: 17213831
references.citation: Semin Respir Crit Care Med. 2006 Aug;27(4):337-49
references.pmid: 16909368
references.citation: J Immunol. 2001 Mar 15;166(6):4042-8
references.pmid: 11238652
references.citation: Lancet. 2004 Feb 21;363(9409):617-9
references.pmid: 14987888
references.citation: Respir Res. 2006 Oct 11;7:125
references.pmid: 17034639
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L105-13
references.pmid: 17416740
references.citation: Nature. 2006 Mar 23;440(7083):435-6
references.pmid: 16554799
references.citation: N Engl J Med. 2004 Mar 18;350(12):1179-88
references.pmid: 14985470
references.citation: Am J Respir Crit Care Med. 2003 Dec 15;168(12):1462-70
references.pmid: 12958055
references.citation: Virology. 1999 Feb 1;254(1):115-23
references.pmid: 9927579
references.citation: Crit Care Med. 2002 Apr;30(4):781-6
references.pmid: 11940745
references.citation: J Med Virol. 2001 Mar;63(3):242-6
references.pmid: 11170064
references.citation: Respir Res. 2005 Nov 11;6:135
references.pmid: 16283933
references.citation: Lancet. 2008 Apr 26;371(9622):1464-75
references.pmid: 18440429
references.citation: Adv Immunol. 2007;93:265-78
references.pmid: 17383544
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12479-81
references.pmid: 17640882
references.citation: Am J Respir Cell Mol Biol. 2003 May;28(5):574-81
references.pmid: 12707013
references.citation: Biochem Pharmacol. 2009 Jun 15;77(12):1763-72
references.pmid: 19428331
references.citation: J Immunol. 2005 Dec 1;175(11):7530-5
references.pmid: 16301661
references.citation: Int J Biochem Cell Biol. 2009 May;41(5):998-1001
references.pmid: 18761421
references.citation: Ann N Y Acad Sci. 2008 Mar;1123:134-45
references.pmid: 18375586
references.citation: Shock. 1997 May;7(5):339-44
references.pmid: 9165668
references.citation: Eur Respir J. 2009 Apr;33(4):852-60
references.pmid: 19129272
references.citation: Pediatr Infect Dis J. 2008 Oct;27(10 Suppl):S54-6
references.pmid: 18820578
references.citation: J Virol. 2007 Mar;81(6):2736-44
references.pmid: 17182684
references.citation: Clin Sci (Lond). 2008 Mar;114(6):403-12
references.pmid: 18260828
references.citation: Front Biosci. 2008 Jan 01;13:2400-7
references.pmid: 17981721