The inflammatory response triggered by Influenza virus: a two edged sword

Inflammation Research

Volumn 66, Issue 4, 2017, Pages 283-302

  Tavares, Luciana P ^a   Teixeira, Mauro M ^a   Garcia, Cristiana C ^a,b  

^a FEDERAL UNIVERSITY OF MINAS GERAIS   (Brazil)

^b INSTITUTO OSWALDO CRUZ   (Brazil)

Author keywords

Immunopathology; Inflammation; Influenza; Secondary infection

Indexed keywords

ANTIINFLAMMATORY AGENT; AUTACOID;

BACTERIAL INFECTION; HUMAN; IMMUNOMODULATION; INFLAMMATION; INFLUENZA A; INFLUENZA A VIRUS; INNATE IMMUNITY; LEUKOCYTE; NONHUMAN; REVIEW; SECONDARY INFECTION; VIRUS IDENTIFICATION; ANIMAL; BACTERIAL INFECTIONS; COMPLICATION; HOST PATHOGEN INTERACTION; IMMUNOLOGY; ORTHOMYXOVIRIDAE INFECTIONS; PHYSIOLOGY;

ANIMALS; ANTI-INFLAMMATORY AGENTS; BACTERIAL INFECTIONS; HOST-PATHOGEN INTERACTIONS; HUMANS; INFLAMMATION MEDIATORS; INFLUENZA A VIRUS; LEUKOCYTES; ORTHOMYXOVIRIDAE INFECTIONS;

EID: 84991407485     PISSN: 10233830     EISSN: 1420908X     Source Type: Journal    
DOI: 10.1007/s00011-016-0996-0     Document Type: Review

References (227)

1. WHO. Influenza (Seasonal) - Fact sheet N°211. http://www.who.int/mediacentre/factsheets/fs211/en/ (2014). Accessed 02 Feb 2016.
2. Berri F, et al. Switch from protective to adverse inflammation during influenza: viral determinants and hemostasis are caught as culprits. Cell Mol Life Sci. 2014;71(5):885–98.
3. Hutchinson EC, Fodor E. Transport of the influenza virus genome from nucleus to nucleus. Viruses. 2013;5(10):2424–46.
4. Yoon SW, Webby RJ, Webster RG. Evolution and ecology of influenza A viruses. Curr Top Microbiol Immunol. 2014;385:359–75.
5. Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315–28.
6. Kuiken T, et al. Pathogenesis of influenza virus infections: the good, the bad and the ugly. Curr Opin Virol. 2012;2(3):276–86.
7. WHO. Influenza update N°258. http://www.who.int/influenza/surveillance_monitoring/updates/2016_03_07_surveillance_update_258.pdf?ua=1 (2016). Accessed 08 Mar 2016.
8. Edinger TO, Pohl MO, Stertz S. Entry of influenza A virus: host factors and antiviral targets. J Gen Virol. 2014;95(Pt 2):263–77.
9. Kohlmeier JE, Woodland DL. Immunity to respiratory viruses. Annu Rev Immunol. 2009;27:61–82.
10. Hendrickson CM, Matthay MA. Viral pathogens and acute lung injury: investigations inspired by the SARS epidemic and the 2009 H1N1 influenza pandemic. Semin Respir Crit Care Med. 2013;34(4):475–86.
11. Bruder D, Srikiatkhachorn A, Enelow RI. Cellular immunity and lung injury in respiratory virus infection. Viral Immunol. 2006;19(2):147–55.
12. de Jong MD, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203–7.
13. Peiris JS, et al. Innate immune responses to influenza A H5N1: friend or foe? Trends Immunol. 2009;30(12):574–84.
14. Baskin CR, et al. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc Natl Acad Sci USA. 2009;106(9):3455–60.
15. Perrone LA, et al. 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. J Infect Dis. 2010;202(8):1161–70.
16. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.
17. Xagorari A, Chlichlia K. Toll-like receptors and viruses: induction of innate antiviral immune responses. Open Microbiol J. 2008;2:49–59.
18. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–50.
19. Imai Y, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133(2):235–49.
20. Le Goffic R, et al. Cutting edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol. 2007;178(6):3368–72.
21. Le Goffic R, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2006;2(6):e53.
22. Guillot L, et al. 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. 2005;280(7):5571–80.
23. Diebold SS, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529–31.
24. Lee SM, et al. Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Natl Acad Sci USA. 2014;111(10):3793–8.
25. Owen DM, Gale M Jr. Fighting the flu with inflammasome signaling. Immunity. 2009;30(4):476–8.
26. Allen IC, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30(4):556–65.
27. McAuley JL, et al. Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. PLoS Pathog. 2013;9(5):e1003392.
28. Rehwinkel J, et al. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell. 2010;140(3):397–408.
29. Kato H, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity. 2005;23(1):19–28.
30. Kandasamy M, et al. RIG-I signaling Is critical for efficient polyfunctional T cell responses during influenza virus infection. PLoS Pathog. 2016;12(7):e1005754.
31. Tisoncik JR, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16–32.
32. Walsh KB, et al. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci USA. 2011;108(29):12018–23.
33. Damjanovic D, et al. Immunopathology in influenza virus infection: uncoupling the friend from foe. Clin Immunol. 2012;144(1):57–69.
34. Tscherne DM, Garcia-Sastre A. Virulence determinants of pandemic influenza viruses. J Clin Invest. 2011;121(1):6–13.
35. Arankalle VA, et al. Role of host immune response and viral load in the differential outcome of pandemic H1N1 (2009) influenza virus infection in Indian patients. PLoS One. 2010;5(10) pii: e13099.
36. Cheng XW, et al. Three fatal cases of pandemic 2009 influenza A virus infection in Shenzhen are associated with cytokine storm. Respir Physiol Neurobiol. 2011;175(1):185–7.
37. Li N, et al. Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration. Cell Mol Life Sci. 2015.
38. Ng HH, et al. Doxycycline treatment attenuates acute lung injury in mice infected with virulent influenza H3N2 virus: involvement of matrix metalloproteinases. Exp Mol Pathol. 2012;92(3):287–95.
39. Reshi ML, Su YC, Hong JR. RNA viruses: ROS-mediated cell death. Int J Cell Biol. 2014;2014:467452.
40. Kash JC, Taubenberger JK. Infectious disease theme issue: the role of viral, host, and secondary bacterial factors in influenza pathogenesis. Am J Pathol. 2015;185(6):1528–36.
41. La Gruta NL, et al. A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol. 2007;85(2):85–92.
42. Hsieh YC, et al. Influenza pandemics: past, present and future. J Formos Med Assoc. 2006;105(1):1–6.
43. Kaiser L, et al. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol. 2001;64(3):262–8.
44. Hayden FG, et al. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest. 1998;101(3):643–9.
45. Julkunen I, et al. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev. 2001;12(2–3):171–80.
46. Jewell NA, et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol. 2010;84(21):11515–22.
47. Wareing MD, et al. Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J Leukoc Biol. 2004;76(4):886–95.
48. To KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol. 2001;63(3):242–6.
49. Lee N, et al. Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults. PLoS One. 2011;6(10):e26050.
50. Fensterl V, Sen GC. Interferons and viral infections. BioFactors. 2009;35(1):14–20.
51. Chelbi-Alix MK, Wietzerbin J. Interferon, a growing cytokine family: 50 years of interferon research. Biochimie. 2007;89(6–7):713–8.
52. Price GE, Gaszewska-Mastarlarz A, Moskophidis D. The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice. J Virol. 2000;74(9):3996–4003.
53. Szretter KJ, et al. Early control of H5N1 influenza virus replication by the type I interferon response in mice. J Virol. 2009;83(11):5825–34.
54. Davidson S, et al. Pathogenic potential of interferon alphabeta in acute influenza infection. Nat Commun. 2014;5:3864.
55. Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol. 2008;89(Pt 1):1–47.
56. Shahangian A, et al. Type I IFNs mediate development of post influenza bacterial pneumonia in mice. J Clin Invest. 2009;119(7):1910–20.
57. Stifter SA, et al. Functional interplay between type I and II interferons is essential to limit influenza A virus-induced tissue inflammation. PLoS Pathog. 2016;12(1):e1005378.
58. Heise MT, Virgin HWT. The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol. 1995;69(2):904–9.
59. Stanton GJ, et al. Nondetectable levels of interferon gamma is a critical host defense during the first day of herpes simplex virus infection. Microb Pathog. 1987;3(3):179–83.
60. Boehm U, et al. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–95.
61. Verhoeven D, Perry S, Pryharski K. Control of influenza infection is impaired by diminished interferon-gamma secretion by CD4 T cell in the lungs of toddlers. J Leukoc Biol. 2016;100(1):203–12.
62. + T cell homeostasis in the absence of IFN-gamma signaling. J Immunol. 2007;178(12):7616–22.
63. + T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways. Am J Physiol Lung Cell Mol Physiol. 2015;308(7):L650–7.
64. Baumgarth N, Kelso A. In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue. J Virol. 1996;70(7):4411–8.
65. Sommereyns C, et al. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017.
66. Mordstein M, et al. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog. 2008;4(9):e1000151.
67. van de Sandt CE, Kreijtz JH, Rimmelzwaan GF. Evasion of influenza A viruses from innate and adaptive immune responses. Viruses. 2012;4(9):1438–76.
68. Crotta S, et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLoS Pathog. 2013;9(11):e1003773.
69. Acosta-Rodriguez EV, et al. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8(9):942–9.
70. Luft T, et al. IL-1 beta enhances CD40 ligand-mediated cytokine secretion by human dendritic cells (DC): a mechanism for T cell-independent DC activation. J Immunol. 2002;168(2):713–22.
71. Ichinohe T, et al. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206(1):79–87.
72. Schmitz N, et al. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol. 2005;79(10):6441–8.
73. Liu Y, et al. Genetic variants in IL1A and IL1B contribute to the susceptibility to 2009 pandemic H1N1 influenza A virus. BMC Immunol. 2013;14:37.
74. Robinson KM, et al. Influenza A exacerbates Staphylococcus aureus pneumonia by attenuating IL-1beta production in mice. J Immunol. 2013;191(10):5153–9.
75. Guarda G, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34(2):213–23.
76. Chiaretti A, et al. IL-1 beta and IL-6 upregulation in children with H1N1 influenza virus infection. Mediat Inflamm. 2013;2013:495848.
77. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014;32:659–702.
78. Yamaya M, et al. Magnitude of influenza virus replication and cell damage is associated with interleukin-6 production in primary cultures of human tracheal epithelium. Respir Physiol Neurobiol. 2014;202:16–23.
79. Shi X, et al. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice. Crit Care. 2013;17(6):R301.
80. Szretter KJ, et al. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol. 2007;81(6):2736–44.
81. Hamada H, et al. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J Immunol. 2009;182(6):3469–81.
82. McKinstry KK, et al. IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol. 2009;182(12):7353–63.
83. Wang X, et al. A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection. Cell Mol Immunol. 2011;8(6):462–8.
84. Crowe CR, et al. Critical role of IL-17RA in immunopathology of influenza infection. J Immunol. 2009;183(8):5301–10.
85. Bermejo-Martin JF, et al. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Crit Care. 2009;13(6):R201.
86. Liu FD, et al. Timed action of IL-27 protects from immunopathology while preserving defense in influenza. PLoS Pathog. 2014;10(5):e1004110.
87. Mayer KD, et al. Cutting edge: T-bet and IL-27R are critical for in vivo IFN-gamma production by CD8 T cells during infection. J Immunol. 2008;180(2):693–7.
88. Liu L, et al. Influenza A virus induces interleukin-27 through cyclooxygenase-2 and protein kinase A signaling. J Biol Chem. 2012;287(15):11899–910.
89. Ivanov S, et al. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection. J Virol. 2013;87(12):6911–24.
90. Pociask DA, et al. IL-22 is essential for lung epithelial repair following influenza infection. Am J Pathol. 2013;182(4):1286–96.
91. Uhlig S, Goggel R, Engel S. Mechanisms of platelet-activating factor (PAF)-mediated responses in the lung. Pharmacol Rep. 2005;57(Suppl):206–21.
92. Ishii S, Shimizu T. Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice. Prog Lipid Res. 2000;39(1):41–82.
93. Weijer S, et al. Host response of platelet-activating factor receptor-deficient mice during pulmonary tuberculosis. Immunology. 2003;109(4):552–6.
94. Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev. 2000;80(4):1669–99.
95. Chao W, Olson MS. Platelet-activating factor: receptors and signal transduction. Biochem J. 1993;292(Pt 3):617–29.
96. Garcia CC, et al. Platelet-activating factor receptor plays a role in lung injury and death caused by influenza A in mice. plos Pathog. 2010;6(11):e1001171.
97. van der Sluijs KF, et al. Involvement of the platelet-activating factor receptor in host defense against Streptococcus pneumoniae during postinfluenza pneumonia. Am J Physiol Lung Cell Mol Physiol. 2006;290(1):L194–9.
98. McCarthy MK, Weinberg JB. Eicosanoids and respiratory viral infection: coordinators of inflammation and potential therapeutic targets. Mediat Inflamm. 2012;2012:236345.
99. Yokomizo T, et al. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature. 1997;387(6633):620–4.
100. Yokomizo T, et al. A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med. 2000;192(3):421–32.
101. Tager AM, Luster AD. BLT1 and BLT2: the leukotriene B(4) receptors. Prostaglandins Leukot Essent Fatty Acids. 2003;69(2–3):123–34.
102. Gaudreault E, Gosselin J. Leukotriene B4 induces release of antimicrobial peptides in lungs of virally infected mice. J Immunol. 2008;180(9):6211–21.
103. Widegren H, et al. LTB4 increases nasal neutrophil activity and conditions neutrophils to exert antiviral effects. Respir Med. 2011;105(7):997–1006.
104. Ricklin D, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.
105. Sun S, et al. Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol. 2013;49(2):221–30.
106. Tong HH, et al. Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice. PLoS One. 2014;9(4):e95160.
107. Xu GL, et al. C5a/C5aR pathway is essential for the pathogenesis of murine viral fulminant hepatitis by way of potentiating Fgl2/fibroleukin expression. Hepatology. 2014;60(1):114–24.
108. Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005;23:821–52.
109. Garcia CC, et al. Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury. PLoS One. 2013;8(5):e64443.
110. Monsalvo AC, et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med. 2011;17(2):195–9.
111. O’Brien KB, et al. A protective role for complement C3 protein during pandemic 2009 H1N1 and H5N1 influenza A virus infection. PLoS ONE. 2011;6(3):e17377.
112. Sun S, et al. Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. Clin Infect Dis. 2015;60(4):586–95.
113. Turner MD, et al. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843(11):2563–82.
114. Gao R, et al. Cytokine and chemokine profiles in lung tissues from fatal cases of 2009 pandemic influenza A (H1N1): role of the host immune response in pathogenesis. Am J Pathol. 2013;183(4):1258–68.
115. van Helden MJ, Zaiss DM, Sijts AJ. CCR2 defines a distinct population of NK cells and mediates their migration during influenza virus infection in mice. PLoS One. 2012;7(12):e52027.
116. Maelfait J, et al. A20 deficiency in lung epithelial cells protects against influenza A virus infection. PLoS Pathog. 2016;12(1):e1005410.
117. Ellis GT, et al. TRAIL + monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection. EMBO Rep. 2015;16(9):1203–18.
118. + monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180(4):2562–72.
119. Dessing MC, et al. Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia. Clin Immunol. 2007;125(3):328–36.
120. Narasaraju T, et al. MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. Am J Respir Cell Mol Biol. 2010;42(6):732–43.
121. Sakai S, et al. Therapeutic effect of anti-macrophage inflammatory protein 2 antibody on influenza virus-induced pneumonia in mice. J Virol. 2000;74(5):2472–6.
122. Wareing MD, et al. CXCR2 is required for neutrophil recruitment to the lung during influenza virus infection, but is not essential for viral clearance. Viral Immunol. 2007;20(3):369–78.
123. + T cells is required for severe T-cell-mediated lung injury. PLoS One. 2013;8(11):e79340.
124. Tate MD, et al. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol. 2010;84(15):7569–80.
125. Zhao X, et al. PI3 K/Akt signaling pathway modulates influenza virus induced mouse alveolar macrophage polarization to M1/M2b. PLoS One. 2014;9(8):e104506.
126. Schneider C, et al. Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLoS Pathog. 2014;10(4):e1004053.
127. Tumpey TM, et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol. 2005;79(23):14933–44.
128. Hogner K, et al. Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLoS Pathog. 2013;9(2):e1003188.
129. Hashimoto Y, et al. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol. 2007;178(4):2448–57.
130. Brandes M, et al. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell. 2013;154(1):197–212.
131. Zhang Z, et al. Infectious progeny of 2009 A (H1N1) influenza virus replicated in and released from human neutrophils. Sci Rep. 2015;5:17809.
132. Fujisawa H. Inhibitory role of neutrophils on influenza virus multiplication in the lungs of mice. Microbiol Immunol. 2001;45(10):679–88.
133. Perrone LA, et al. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 2008;4(8):e1000115.
134. Fujisawa H. Neutrophils play an essential role in cooperation with antibody in both protection against and recovery from pulmonary infection with influenza virus in mice. J Virol. 2008;82(6):2772–83.
135. Daley JM, et al. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol. 2008;83(1):64–70.
136. Narasaraju T, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011;179(1):199–210.
137. Zhang RH, et al. N-acetyl-l-cystine (NAC) protects against H9N2 swine influenza virus-induced acute lung injury. Int Immunopharmacol. 2014;22(1):1–8.
138. Vlahos R, et al. Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation. PLoS Pathog. 2011;7(2):e1001271.
139. Shi X, et al. PEGylated human catalase elicits potent therapeutic effects on H1N1 influenza-induced pneumonia in mice. Appl Microbiol Biotechnol. 2013;97(23):10025–33.
140. Geiler J, et al. N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol. 2010;79(3):413–20.
141. Hwang I, et al. Activation mechanisms of natural killer cells during influenza virus infection. PLoS One. 2012;7(12):e51858.
142. Gazit R, et al. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol. 2006;7(5):517–23.
143. + T cells. Virology. 2010;407(2):325–32.
144. Vanderven HA, et al. What lies beneath: antibody dependent natural killer cell activation by antibodies to internal influenza virus proteins. EBioMedicine. 2016;8:277–90.
145. Jansen CA, et al. Differential lung NK cell responses in avian influenza virus infected chickens correlate with pathogenicity. Sci Rep. 2013;3:2478.
146. Zhou G, Juang SW, Kane KP. NK cells exacerbate the pathology of influenza virus infection in mice. Eur J Immunol. 2013;43(4):929–38.
147. Abdul-Careem MF, et al. Critical role of natural killer cells in lung immunopathology during influenza infection in mice. J Infect Dis. 2012;206(2):167–77.
148. Chang YJ, et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol. 2011;12(7):631–8.
149. Gorski SA, Hahn YS, Braciale TJ. Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog. 2013;9(9):e1003615.
150. Monticelli LA, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–54.
151. Shim DH, et al. Pandemic influenza virus, pH1N1, induces asthmatic symptoms via activation of innate lymphoid cells. Pediatr Allergy Immunol. 2015;26(8):780–8.
152. Monticelli LA, Sonnenberg GF, Artis D. Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung. Curr Opin Immunol. 2012;24(3):284–9.
153. Ho LP, et al. Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection. Eur J Immunol. 2008;38(7):1913–22.
154. De Santo C, et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest. 2008;118(12):4036–48.
155. + T cell response during acute influenza A virus H3N2 pneumonia. J Immunol. 2011;186(10):5590–602.
156. Barthelemy A, et al. Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection. Mucosal Immunol. 2016; doi:10.1038/mi.2016.49.
157. Kreijtz JH, Fouchier RA, Rimmelzwaan GF. Immune responses to influenza virus infection. Virus Res. 2011;162(1–2):19–30.
158. Hillaire ML, Rimmelzwaan GF, Kreijtz JH. Clearance of influenza virus infections by T cells: risk of collateral damage? Curr Opin Virol. 2013;3(4):430–7.
159. McCormick S, et al. Control of pathogenic CD4 T cells and lethal immunopathology by signaling immunoadaptor DAP12 during influenza infection. J Immunol. 2011;187(8):4280–92.
160. + T cells. J Immunol. 2004;173(2):721–5.
161. Duan S, Thomas PG. Balancing immune protection and immune pathology by CD8(+) T-cell responses to influenza infection. Front Immunol. 2016;7:25.
162. Enelow RI, et al. Structural and functional consequences of alveolar cell recognition by CD8(+) T lymphocytes in experimental lung disease. J Clin Invest. 1998;102(9):1653–61.
163. + regulatory T cell response. J Virol. 2012;86(5):2817–25.
164. + T cell-responses by IL-10-dependent mechanism during H5N1 influenza virus infection. Eur J Immunol. 2014;44(1):103–14.
165. Simonsen L. The global impact of influenza on morbidity and mortality. Vaccine. 1999;17(Suppl 1):S3–10.
166. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis. 2008;198(7):962–70.
167. McCullers JA. Do specific virus-bacteria pairings drive clinical outcomes of pneumonia? Clin Microbiol Infect. 2013;19(2):113–8.
168. Ramphal R, et al. Adherence of Pseudomonas aeruginosa to tracheal cells injured by influenza infection or by endotracheal intubation. Infect Immun. 1980;27(2):614–9.
169. McCullers JA. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat Rev Microbiol. 2014;12(4):252–62.
170. McAuley JL, et al. Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe. 2007;2(4):240–9.
171. McCullers JA, Rehg JE. Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor. J Infect Dis. 2002;186(3):341–50.
172. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev. 2006;19(3):571–82.
173. Siegel SJ, Roche AM, Weiser JN. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe. 2014;16(1):55–67.
174. Pittet LA, et al. Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae. Am J Respir Cell Mol Biol. 2010;42(4):450–60.
175. Kudva A, et al. Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol. 2011;186(3):1666–74.
176. Sun K, Metzger DW. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med. 2008;14(5):558–64.
177. McNamee LA, Harmsen AG. Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect Immun. 2006;74(12):6707–21.
178. van der Sluijs KF, et al. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol. 2004;172(12):7603–9.
179. Kosai K, et al. Increase of apoptosis in a murine model for severe pneumococcal pneumonia during influenza A virus infection. Jpn J Infect Dis. 2011;64(6):451–7.
180. Wilson HE, et al. Reactions of Monkeys to experimental mixed influenza and Streptococcus Infections: an analysis of the relative roles of humoral and cellular immunity, with the description of an intercurrent nephritic syndrome. J Exp Med. 1947;85(2):199–215.
181. Speshock JL, et al. Filamentous influenza A virus infection predisposes mice to fatal septicemia following superinfection with Streptococcus pneumoniae serotype 3. Infect Immun. 2007;75(6):3102–11.
182. Smith MW, et al. Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia after influenza. Comp Med. 2007;57(1):82–9.
183. Wu Y, et al. Successive influenza virus infection and Streptococcus pneumoniae stimulation alter human dendritic cell function. BMC Infect Dis. 2011;11:201.
184. Kuri T, et al. Influenza A virus-mediated priming enhances cytokine secretion by human dendritic cells infected with Streptococcus pneumoniae. Cell Microbiol. 2013;15(8):1385–400.
185. Centers for Disease C. and Prevention. Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)—United States, May–August 2009. MMWR Morb Mortal Wkly Rep. 2009;58(38):1071–4.
186. Robinson KM, et al. Influenza A virus exacerbates Staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production. J Infect Dis. 2014;209(6):865–75.
187. Warshauer D, et al. Effect of influenza viral infection on the ingestion and killing of bacteria by alveolar macrophages. Am Rev Respir Dis. 1977;115(2):269–77.
188. Martin RR, et al. Effects of infection with influenza virus on the function of polymorphonuclear leukocytes. J Infect Dis. 1981;144(3):279–80.
189. Didierlaurent A, et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J Exp Med. 2008;205(2):323–9.
190. Goulding J, et al. Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. J Infect Dis. 2011;204(7):1086–94.
191. Kash JC, et al. Lethal synergism of 2009 pandemic H1N1 influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses. MBio. 2011; 2(5).
192. Jamieson AM, et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science. 2013;340(6137):1230–4.
193. Fedson DS. Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza Other Respir Viruses. 2009;3(4):129–42.
194. Garcia CC, et al. The development of anti-inflammatory drugs for infectious diseases. Discov Med. 2010;10(55):479–88.
195. Han K, et al. Early use of glucocorticoids was a risk factor for critical disease and death from pH1N1 infection. Clin Infect Dis. 2011;53(4):326–33.
196. Kim SH, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med. 2011;183(9):1207–14.
197. Kudo K, et al. Systemic corticosteroids and early administration of antiviral agents for pneumonia with acute wheezing due to influenza A(H1N1)pdm09 in Japan. PLoS ONE. 2012;7(2):e32280.
198. Abeles AM, Pillinger MH. Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum. 2006;54(2):393–407.
199. Kwong JC, Li P, Redelmeier DA. Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One. 2009;4(11):e8087.
200. Frost FJ, et al. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;131(4):1006–12.
201. Vandermeer ML, et al. Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study. J Infect Dis. 2012;205(1):13–9.
202. Brett SJ, et al. Pre-admission statin use and in-hospital severity of 2009 pandemic influenza A(H1N1) disease. PLoS One. 2011;6(4):e18120.
203. Kumaki Y, Morrey JD, Barnard DL. Effect of statin treatments on highly pathogenic avian influenza H5N1, seasonal and H1N1pdm09 virus infections in BALB/c mice. Future Virol. 2012;7(8):801–18.
204. Liu Z, et al. Evaluation of the efficacy and safety of a statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB/c mice. Eur J Pharm Sci. 2009;38(3):215–23.
205. Mehrbod P, et al. Simvastatin modulates cellular components in influenza A virus-infected cells. Int J Mol Med. 2014;34(1):61–73.
206. Rocca B, FitzGerald GA. Cyclooxygenases and prostaglandins: shaping up the immune response. Int Immunopharmacol. 2002;2(5):603–30.
207. Darwish I, Mubareka S, Liles WC. Immunomodulatory therapy for severe influenza. Expert Rev Anti Infect Ther. 2011;9(7):807–22.
208. Lee SM, et al. Hyperinduction of cyclooxygenase-2-mediated proinflammatory cascade: a mechanism for the pathogenesis of avian influenza H5N1 infection. J Infect Dis. 2008;198(4):525–35.
209. Zheng BJ, et al. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci USA. 2008;105(23):8091–6.
210. Lauder SN, et al. Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity. Thorax. 2011;66(5):368–74.
211. Carey MA, et al. Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection. J Immunol. 2005;175(10):6878–84.
212. Bassaganya-Riera J, et al. PPAR-gamma activation as an anti-inflammatory therapy for respiratory virus infections. Viral Immunol. 2010;23(4):343–52.
213. Budd A, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother. 2007;51(8):2965–8.
214. Moseley CE, Webster RG, Aldridge JR. Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza Other Respir Viruses. 2010;4(5):307–11.
215. Russell CD, Schwarze J. The role of pro-resolution lipid mediators in infectious disease. Immunology. 2014;141(2):166–73.
216. Morita M, et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013;153(1):112–25.
217. Winter C, et al. Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis. J Immunol. 2007;178(9):5828–38.
218. Lin KL, et al. CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection. J Immunol. 2011;186(1):508–15.
219. Iwasaki A, Medzhitov R. A new shield for a cytokine storm. Cell. 2011;146(6):861–2.
220. Marsolais D, et al. A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc Natl Acad Sci USA. 2009;106(5):1560–5.
221. Teijaro JR, et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell. 2011;146(6):980–91.
222. Sato K, et al. Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice. Am J Respir Crit Care Med. 1998;157(3 Pt 1):853–7.
223. Karlstrom A, et al. Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. J Infect Dis. 2009;199(3):311–9.
224. Higashi F, et al. Additional treatment with clarithromycin reduces fever duration in patients with influenza. Respir Investig. 2014;52(5):302–9.
225. Planz O. Development of cellular signaling pathway inhibitors as new antivirals against influenza. Antiviral Res. 2013;98(3):457–68.
226. Aeffner F, Woods PS, Davis IC. Activation of A1-adenosine receptors promotes leukocyte recruitment to the lung and attenuates acute lung injury in mice infected with influenza A/WSN/33 (H1N1) virus. J Virol. 2014;88(17):10214–27.
227. Sharma G, et al. Reduction of influenza virus-induced lung inflammation and mortality in animals treated with a phosophodisestrase-4 inhibitor and a selective serotonin reuptake inhibitor. Emerging Microbes Infect 2013;2,e54; doi:10.1038/emi.2013.52.