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Annual Review of Immunology

Volume 35, 2017

Protective and Harmful Immunity to RSV Infection

Abstract

Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.

Keyword(s): bronchiolitis, immunoregulation, mucosal immunity, pediatric infections, viral lung disease
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/content/journals/10.1146/annurev-immunol-051116-052206
2017-04-26
2024-04-24
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Literature Cited

  1. Smyth RL, Openshaw PJ. 1.  2006. Bronchiolitis. Lancet 368:9532312–22 [Google Scholar]
  2. Meissner HC. 2.  2016. Viral bronchiolitis in children. N. Engl. J. Med. 374:162–72 [Google Scholar]
  3. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA. 3.  et al. 2010. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375:97251545–555 [Google Scholar]
  4. Geoghegan S, Erviti A, Caballero MT, Vallone F, Zanone SM. 4.  et al. 2016. Mortality due to respiratory syncytial virus: burden and risk factors. Am. J. Respir. Crit. Care Med. 195:96–103 [Google Scholar]
  5. El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, Devincenzo JP. 5.  2011. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J. Infect. Dis. 204:7996–1002 [Google Scholar]
  6. DeVincenzo JP, El Saleeby CM, Bush AJ. 6.  2005. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J. Infect. Dis. 191:111861–68 [Google Scholar]
  7. Welliver TP, Reed JL, Welliver RC. 7.  2008. Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases. Pediatr. Infect. Dis. J. 27:10 Suppl.S92–96 [Google Scholar]
  8. Welliver TP, Garofalo RP, Hosakote Y, Hintz KH, Avendano L. 8.  et al. 2007. Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J. Infect. Dis. 195:81126–36 [Google Scholar]
  9. Hall CB, Powell KR, MacDonald NE, Gala CL, Menegus ME. 9.  et al. 1986. Respiratory syncytial viral infection in children with compromised immune function. N. Engl. J. Med. 315:277–81 [Google Scholar]
  10. Heidema J, Lukens MV, van Maren WW, van Dijk ME, Otten HG. 10.  et al. 2007. CD8+ T cell responses in bronchoalveolar lavage fluid and peripheral blood mononuclear cells of infants with severe primary respiratory syncytial virus infections. J. Immunol. 179:128410–17 [Google Scholar]
  11. Lambert L, Sagfors AM, Openshaw PJ, Culley FJ. 11.  2014. Immunity to RSV in early-life. Front. Immunol. 5:466 [Google Scholar]
  12. Openshaw PJ, Chiu C. 12.  2013. Protective and dysregulated T cell immunity in RSV infection. Curr. Opin. Virol. 3:4468–474 [Google Scholar]
  13. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. 13.  2007. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod. Pathol. 20:1108–19 [Google Scholar]
  14. Faber TE, Groen H, Welfing M, Jansen KJ, Bont LJ. 14.  2012. Specific increase in local IL-17 production during recovery from primary RSV bronchiolitis. J. Med. Virol 84:71084–88 [Google Scholar]
  15. McNamara PS, Flanagan BF, Hart CA, Smyth RL. 15.  2005. Production of chemokines in the lungs of infants with severe respiratory syncytial virus bronchiolitis. J. Infect. Dis. 191:81225–32 [Google Scholar]
  16. McNamara PS, Flanagan BF, Selby AM, Hart CA, Smyth RL. 16.  2004. Pro- and anti-inflammatory responses in respiratory syncytial virus bronchiolitis. Eur. Respir. J. 23:1106–12 [Google Scholar]
  17. Mobbs KJ, Smyth RL, O'Hea U, Ashby D, Ritson P, Hart CA. 17.  2002. Cytokines in severe respiratory syncytial virus bronchiolitis. Pediatr. Pulmonol. 33:6449–52 [Google Scholar]
  18. Openshaw PJ. 18.  2013. The mouse model of respiratory syncytial virus disease. Curr. Top. Microbiol. Immunol. 372:359–69 [Google Scholar]
  19. Carroll KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD. 19.  et al. 2009. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J. Allergy Clin. Immunol. 123:51055–61.e1 [Google Scholar]
  20. Sigurs N, Aljassim F, Kjellman B, Robinson PD, Sigurbergsson F. 20.  et al. 2010. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65:121045–52 [Google Scholar]
  21. Zanin M, Baviskar P, Webster R, Webby R. 21.  2016. The interaction between respiratory pathogens and mucus. Cell Host Microbe 19:2159–68 [Google Scholar]
  22. Currier MG, Lee S, Stobart CC, Hotard AL, Villenave R. 22.  et al. 2016. EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression. PLOS Pathog 12:5e1005622 [Google Scholar]
  23. Stokes KL, Currier MG, Sakamoto K, Lee S, Collins PL. 23.  et al. 2013. The respiratory syncytial virus fusion protein and neutrophils mediate the airway mucin response to pathogenic respiratory syncytial virus infection. J. Virol. 87:1810070–82 [Google Scholar]
  24. Smith CM, Kulkarni H, Radhakrishnan P, Rutman A, Bankart MJ. 24.  et al. 2014. Ciliary dyskinesia is an early feature of respiratory syncytial virus infection. Eur. Respir. J. 43:2485–96 [Google Scholar]
  25. Currie SM, Gwyer Findlay E, McFarlane AJ, Fitch PM, Böttcher B. 25.  et al. 2016. Cathelicidins have direct antiviral activity against respiratory syncytial virus in vitro and protective function in vivo in mice and humans. J. Immunol. 196:62699–710 [Google Scholar]
  26. Sano H, Nagai K, Tsutsumi H, Kuroki Y. 26.  2003. Lactoferrin and surfactant protein A exhibit distinct binding specificity to F protein and differently modulate respiratory syncytial virus infection. Eur. J. Immunol. 33:102894–902 [Google Scholar]
  27. LeVine AM, Gwozdz J, Stark J, Bruno M, Whitsett J, Korfhagen T. 27.  1999. Surfactant protein-A enhances respiratory syncytial virus clearance in vivo. J. Clin. Investig. 103:71015–21 [Google Scholar]
  28. Kerr MH, Paton JY. 28.  1999. Surfactant protein levels in severe respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 159:4 Part 11115–18 [Google Scholar]
  29. Ampuero S, Luchsinger V, Tapia L, Palomino MA, Larrañaga CE. 29.  2011. SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants. Infect. Genet. Evol. 11:61368–77 [Google Scholar]
  30. Lahti M. 30.  2002. Surfactant protein D gene polymorphism associated with severe respiratory syncytial virus infection. Pediatr. Res. 51:6696–99 [Google Scholar]
  31. Johnson SM, McNally BA, Ioannidis I, Flano E, Teng MN. 31.  et al. 2015. Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures. PLOS Pathog 11:12e1005318 [Google Scholar]
  32. Wright PF, Ikizler MR, Gonzales RA, Carroll KN, Johnson JE, Werkhaven JA. 32.  2005. Growth of respiratory syncytial virus in primary epithelial cells from the human respiratory tract. J. Virol. 79:138651–654 [Google Scholar]
  33. Pastey MK, Crowe JE, Graham BS. 33.  1999. RhoA interacts with the fusion glycoprotein of respiratory syncytial virus and facilitates virus-induced syncytium formation. J. Virol. 73:97262–270 [Google Scholar]
  34. Goritzka M, Makris S, Kausar F, Durant LR, Pereira C. 34.  et al. 2015. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J. Exp. Med. 212:5699–714 [Google Scholar]
  35. Bhoj VG, Sun Q, Bhoj EJ, Somers C, Chen X. 35.  et al. 2008. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. PNAS 105:3714046–51 [Google Scholar]
  36. Demoor T, Petersen BC, Morris S, Mukherjee S, Ptaschinski C. 36.  et al. 2012. IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus. J. Immunol. 189:125942–53 [Google Scholar]
  37. Marr N, Turvey SE, Grandvaux N. 37.  2013. Pathogen recognition receptor crosstalk in respiratory syncytial virus sensing: a host and cell type perspective. Trends Microbiol 21:11568–74 [Google Scholar]
  38. Borchers AT, Chang C, Gershwin ME, Gershwin LJ. 38.  2013. Respiratory syncytial virus—a comprehensive review. Clin. Rev. Allergy Immunol. 45:3331–79 [Google Scholar]
  39. Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ. 39.  et al. 2007. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J. Infect. Dis. 196:6826–34 [Google Scholar]
  40. Siezen CL, Bont L, Hodemaekers HM, Ermers MJ, Doornbos G. 40.  et al. 2009. Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes. Pediatr. Infect. Dis. J. 28:4333–35 [Google Scholar]
  41. Goritzka M, Durant LR, Pereira C, Salek-Ardakani S, Openshaw PJ, Johansson C. 41.  2014. Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection. J. Virol. 88:116128–136 [Google Scholar]
  42. Durbin RK, Kotenko SV, Durbin JE. 42.  2013. Interferon induction and function at the mucosal surface. Immunol. Rev. 255:125–39 [Google Scholar]
  43. Sun Y, Jain D, Koziol-White CJ, Genoyer E, Gilbert M. 43.  et al. 2015. Immunostimulatory defective viral genomes from respiratory syncytial virus promote a strong innate antiviral response during infection in mice and humans. PLOS Pathog 11:9e1005122 [Google Scholar]
  44. Villenave R, Broadbent L, Douglas I, Lyons JD, Coyle PV. 44.  et al. 2015. Induction and antagonism of antiviral responses in respiratory syncytial virus-infected pediatric airway epithelium. J. Virol. 89:2412309–18 [Google Scholar]
  45. McNamara PS, Fonceca AM, Howarth D, Correia JB, Slupsky JR. 45.  et al. 2013. Respiratory syncytial virus infection of airway epithelial cells, in vivo and in vitro, supports pulmonary antibody responses by inducing expression of the B cell differentiation factor BAFF. Thorax 68:176–81 [Google Scholar]
  46. Hussell T, Bell TJ. 46.  2014. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14:281–93 [Google Scholar]
  47. Reed JL, Brewah YA, Delaney T, Welliver T, Burwell T. 47.  et al. 2008. Macrophage impairment underlies airway occlusion in primary respiratory syncytial virus bronchiolitis. J. Infect. Dis. 198:121783–93 [Google Scholar]
  48. Pribul PK, Harker J, Wang B, Wang H, Tregoning JS. 48.  et al. 2008. Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development. J. Virol. 82:94441–48 [Google Scholar]
  49. Kolli D, Gupta MR, Sbrana E, Velayutham TS, Chao H. 49.  et al. 2014. Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. Am. J. Respir. Cell Mol. Biol. 51:4502–15 [Google Scholar]
  50. Makris S, Bajorek M, Culley FJ, Goritzka M, Johansson C. 50.  2016. Alveolar macrophages can control respiratory syncytial virus infection in the absence of type I interferons. J. Innate Immun. 8:452–63 [Google Scholar]
  51. Gill MA, Palucka AK, Barton T, Ghaffar F, Jafri H. 51.  et al. 2005. Mobilization of plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. J. Infect. Dis. 191:71105–15 [Google Scholar]
  52. Smit JJ, Rudd BD, Lukacs NW. 52.  2006. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. J. Exp. Med. 203:51153–59 [Google Scholar]
  53. Wang H, Peters N, Schwarze J. 53.  2006. Plasmacytoid dendritic cells limit viral replication, pulmonary inflammation, and airway hyperresponsiveness in respiratory syncytial virus infection. J. Immunol. 177:96263–70 [Google Scholar]
  54. Schijf MA, Lukens MV, Kruijsen D, van Uden NO, Garssen J. 54.  et al. 2013. Respiratory syncytial virus induced type I IFN production by pdc is regulated by RSV-infected airway epithelial cells, RSV-exposed monocytes and virus specific antibodies. PLOS ONE 8:11e81695 [Google Scholar]
  55. Owczarczyk AB, Schaller MA, Reed M, Rasky AJ, Lombard DB, Lukacs NW. 55.  2015. Sirtuin 1 regulates dendritic cell activation and autophagy during respiratory syncytial virus-induced immune responses. J. Immunol. 195:41637–46 [Google Scholar]
  56. Reed M, Morris SH, Owczarczyk AB, Lukacs NW. 56.  2015. Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung pathology during respiratory viral infection via ER stress-associated IL-1. Mucosal Immunol. 8:51118–30 [Google Scholar]
  57. Reed M, Morris SH, Jang S, Mukherjee S, Yue Z, Lukacs NW. 57.  2013. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection. J. Immunol. 191:52526–37 [Google Scholar]
  58. Ptaschinski C, Mukherjee S, Moore ML, Albert M, Helin K. 58.  et al. 2015. RSV-induced H3K4 demethylase KDM5B leads to regulation of dendritic cell-derived innate cytokines and exacerbates pathogenesis in vivo. PLOS Pathog 11:6e1004978 [Google Scholar]
  59. Yao S, Jiang L, Moser EK, Jewett LB, Wright J. 59.  et al. 2015. Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection. Mucosal Immunol 8:4746–59 [Google Scholar]
  60. Cannon MJ, Openshaw PJ, Askonas BA. 60.  1988. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J. Exp. Med. 168:31163–68 [Google Scholar]
  61. Davidson S, Crotta S, McCabe TM, Wack A. 61.  2014. Pathogenic potential of interferon αβ in acute influenza infection. Nat. Commun. 5:3864 [Google Scholar]
  62. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R. 62.  et al. 2008. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J. Exp. Med. 205:133065–77 [Google Scholar]
  63. Kaiko GE, Phipps S, Angkasekwinai P, Dong C, Foster PS. 63.  2010. NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25. J. Immunol. 185:84681–90 [Google Scholar]
  64. Huang H, Saravia J, You D, Shaw AJ, Cormier SA. 64.  2015. Impaired gamma delta T cell-derived IL-17a and inflammasome activation during early respiratory syncytial virus infection in infants. Immunol. Cell Biol. 93:2126–35 [Google Scholar]
  65. Dodd J, Riffault S, Kodituwakku JS, Hayday AC, Openshaw PJ. 65.  2009. Pulmonary Vγ4+ γδ T cells have proinflammatory and antiviral effects in viral lung disease. J. Immunol. 182:21174–81 [Google Scholar]
  66. Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L. 66.  et al. 2015. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J. Clin. Investig. 125:2571–82 [Google Scholar]
  67. Blum JS, Wearsch PA, Cresswell P. 67.  2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443–73 [Google Scholar]
  68. Chiu C, Openshaw PJ. 68.  2015. Antiviral B cell and T cell immunity in the lungs. Nat. Immunol. 16:118–26 [Google Scholar]
  69. Christiaansen AF, Knudson CJ, Weiss KA, Varga SM. 69.  2014. The CD4 T cell response to respiratory syncytial virus infection. Immunol. Res. 59:1–3109–17 [Google Scholar]
  70. Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A. 70.  et al. 2015. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat. Commun. 6:10224 [Google Scholar]
  71. Liu J, Haddad EK, Marceau J, Morabito KM, Rao SS. 71.  et al. 2016. A numerically subdominant CD8 T cell response to matrix protein of respiratory syncytial virus controls infection with limited immunopathology. PLOS Pathog 12:3e1005486 [Google Scholar]
  72. De Bree GJ, Heidema J, van Leeuwen EM, van Bleek GM, Jonkers RE. 72.  et al. 2005. Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons. J. Infect. Dis. 191:101710–18 [Google Scholar]
  73. Knudson CJ, Weiss KA, Hartwig SM, Varga SM. 73.  2014. The pulmonary localization of virus-specific T lymphocytes is governed by the tissue tropism of infection. J. Virol. 88:169010–16 [Google Scholar]
  74. DiNapoli JM, Murphy BR, Collins PL, Bukreyev A. 74.  2008. Impairment of the CD8+ T cell response in lungs following infection with human respiratory syncytial virus is specific to the anatomical site rather than the virus, antigen, or route of infection. Virol. J. 5:105 [Google Scholar]
  75. Ruckwardt TJ, Bonaparte KL, Nason MC, Graham BS. 75.  2009. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. J. Virol. 83:73019–28 [Google Scholar]
  76. Fulton RB, Meyerholz DK, Varga SM. 76.  2010. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J. Immunol. 185:42382–92 [Google Scholar]
  77. Durant LR, Makris S, Voorburg CM, Loebbermann J, Johansson C, Openshaw PJ. 77.  2013. Regulatory T cells prevent Th2 immune responses and pulmonary eosinophilia during respiratory syncytial virus infection in mice. J. Virol. 87:2010946–54 [Google Scholar]
  78. Loebbermann J, Thornton H, Durant L, Sparwasser T, Webster KE. 78.  et al. 2012. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol. 5:2161–72 [Google Scholar]
  79. Lee DC, Harker JA, Tregoning JS, Atabani SF, Johansson C. 79.  et al. 2010. CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection. J. Virol. 84:178790–98 [Google Scholar]
  80. Delgado MF, Coviello S, Monsalvo AC, Melendi GA, Hernandez JZ. 80.  et al. 2009. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 15:134–41 [Google Scholar]
  81. Polack FP, Teng MN, Collins PL, Prince GA, Exner M. 81.  et al. 2002. A role for immune complexes in enhanced respiratory syncytial virus disease. J. Exp. Med. 196:6859–65 [Google Scholar]
  82. Loebbermann J, Durant L, Thornton H, Johansson C, Openshaw PJ. 82.  2013. Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells. PNAS 110:82987–92 [Google Scholar]
  83. Krishnamoorthy N, Khare A, Oriss TB, Raundhal M, Morse C. 83.  et al. 2012. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18:101525–30 [Google Scholar]
  84. Loebbermann J, Schnoeller C, Thornton H, Durant L, Sweeney NP. 84.  et al. 2012. IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice. PLOS ONE 7:2e32371 [Google Scholar]
  85. Sun L, Cornell TT, LeVine A, Berlin AA, Hinkovska-Galcheva V. 85.  et al. 2013. Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation. Clin. Exp. Immunol. 172:2263–79 [Google Scholar]
  86. Weiss KA, Christiaansen AF, Fulton RB, Meyerholz DK, Varga SM. 86.  2011. Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. J. Immunol. 187:63145–54 [Google Scholar]
  87. Sun J, Cardani A, Sharma AK, Laubach VE, Jack RS. 87.  et al. 2011. Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLOS Pathog 7:8e1002173 [Google Scholar]
  88. Shao HY, Huang JY, Lin YW, Yu SL, Chitra E. 88.  et al. 2015. Depletion of regulatory T-cells leads to moderate B-cell antigenicity in respiratory syncytial virus infection. Int. J. Infect. Dis. 41:56–64 [Google Scholar]
  89. Nagata DE, Ting HA, Cavassani KA, Schaller MA, Mukherjee S. 89.  et al. 2015. Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal Immunol. 8:51131–43 [Google Scholar]
  90. Habibi MS, Jozwik A, Makris S, Dunning J, Paras A. 90.  et al. 2015. Impaired antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. Am. J. Respir. Crit. Care Med. 191:91040–49 [Google Scholar]
  91. Chiu C, Ellebedy AH, Wrammert J, Ahmed R. 91.  2015. B cell responses to influenza infection and vaccination. Curr. Top. Microbiol. Immunol. 386:381–98 [Google Scholar]
  92. Couch RB, Kasel JA. 92.  1983. Immunity to influenza in man. Annu. Rev. Microbiol. 37:529–49 [Google Scholar]
  93. Barclay WS, al-Nakib W, Higgins PG, Tyrrell DA. 93.  1989. The time course of the humoral immune response to rhinovirus infection. Epidemiol. Infect. 103:3659–69 [Google Scholar]
  94. Agoti CN, Mwihuri AG, Sande CJ, Onyango CO, Medley GF. 94.  et al. 2012. Genetic relatedness of infecting and reinfecting respiratory syncytial virus strains identified in a birth cohort from rural Kenya. J. Infect. Dis. 206:101532–41 [Google Scholar]
  95. Hall CB, Walsh EE, Long CE, Schnabel KC. 95.  1991. Immunity to and frequency of reinfection with respiratory syncytial virus. J. Infect. Dis. 163:4693–98 [Google Scholar]
  96. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G. 96.  et al. 2016. Trained immunity: a program of innate immune memory in health and disease. Science 352:6284aaf1098 [Google Scholar]
  97. Crouse J, Kalinke U, Oxenius A. 97.  2015. Regulation of antiviral T cell responses by type I interferons. Nat. Rev. Immunol. 15:4231–42 [Google Scholar]
  98. Spann KM, Tran KC, Collins PL. 98.  2005. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NK-κb, and proinflammatory cytokines. J. Virol. 79:95353–62 [Google Scholar]
  99. Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. 99.  2004. Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages. J. Virol 78:84363–69 Erratum. 2004. J. Virol. 78(12):6705 [Google Scholar]
  100. Ling Z, Tran KC, Teng MN. 100.  2009. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J. Virol. 83:83734–42 [Google Scholar]
  101. Elliott J, Lynch OT, Suessmuth Y, Qian P, Boyd CR. 101.  et al. 2007. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J. Virol. 81:73428–36 [Google Scholar]
  102. Whelan JN, Tran KC, van Rossum DB, Teng MN. 102.  2016. Identification of respiratory syncytial virus nonstructural protein 2 residues essential for exploitation of the host ubiquitin system and inhibition of innate immune responses. J. Virol. 90:6453–63 [Google Scholar]
  103. Ren J, Liu T, Pang L, Li K, Garofalo RP. 103.  et al. 2011. A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein. J. Gen. Virol. 92:Part 92153–59 [Google Scholar]
  104. Krug RM. 104.  2015. Functions of the influenza A virus NS1 protein in antiviral defense. Curr. Opin. Virol. 12:1–6 [Google Scholar]
  105. Teijaro JR. 105.  2016. Type I interferons in viral control and immune regulation. Curr. Opin. Virol. 16:31–40 [Google Scholar]
  106. Munir S, Le Nouen C, Luongo C, Buchholz UJ, Collins PL, Bukreyev A. 106.  2008. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J. Virol. 82:178780–96 [Google Scholar]
  107. Agarwal P, Raghavan A, Nandiwada SL, Curtsinger JM, Bohjanen PR. 107.  et al. 2009. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J. Immunol. 183:31695–704 [Google Scholar]
  108. González PA, Prado CE, Leiva ED, Carreño LJ, Bueno SM. 108.  et al. 2008. Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells. PNAS 105:3914999–5004 [Google Scholar]
  109. Rallabhandi P, Phillips RL, Boukhvalova MS, Pletneva LM, Shirey KA. 109.  et al. 2012. Respiratory syncytial virus fusion protein-induced Toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. mBio 3:4e00218–12 [Google Scholar]
  110. Oshansky CM, Zhang W, Moore E, Tripp RA. 110.  2009. The host response and molecular pathogenesis associated with respiratory syncytial virus infection. Future Microbiol 4:3279–97 [Google Scholar]
  111. Chirkova T, Lin S, Oomens AG, Gaston KA, Boyoglu-Barnum S. 111.  et al. 2015. CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells. J. Gen. Virol. 96:92543–56 [Google Scholar]
  112. Jeong KI, Piepenhagen PA, Kishko M, DiNapoli JM, Groppo RP. 112.  et al. 2015. CX3CR1 is expressed in differentiated human ciliated airway cells and co-localizes with respiratory syncytial virus on cilia in a G protein-dependent manner. PLOS ONE 10:6e0130517 [Google Scholar]
  113. Moore EC, Barber J, Tripp RA. 113.  2008. Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15). Virol. J. 5:116 [Google Scholar]
  114. Chirkova T, Boyoglu-Barnum S, Gaston KA, Malik FM, Trau SP. 114.  et al. 2013. Respiratory syncytial virus G protein CX3C motif impairs human airway epithelial and immune cell responses. J. Virol. 87:2413466–79 [Google Scholar]
  115. Haynes LM, Caidi H, Radu GU, Miao C, Harcourt JL. 115.  et al. 2009. Therapeutic monoclonal antibody treatment targeting respiratory syncytial virus (RSV) G protein mediates viral clearance and reduces the pathogenesis of RSV infection in BALB/c mice. J. Infect. Dis. 200:3439–47 [Google Scholar]
  116. Céspedes PF, Bueno SM, Ramírez BA, Gomez RS, Riquelme SA. 116.  et al. 2014. Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. PNAS 111:31E3214–23 [Google Scholar]
  117. Bosch AA, Biesbroek G, Trzcinski K, Sanders EA, Bogaert D. 117.  2013. Viral and bacterial interactions in the upper respiratory tract. PLOS Pathog 9:1e1003057 [Google Scholar]
  118. Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH. 118.  et al. 2014. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am. J. Respir. Crit. Care Med. 190:3298–308 [Google Scholar]
  119. Biesbroek G, Tsivtsivadze E, Sanders EA, Montijn R, Veenhoven RH. 119.  et al. 2014. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am. J. Respir. Crit. Care Med. 190:111283–92 [Google Scholar]
  120. Pendse M, Hooper LV. 120.  2016. Immunology: Mum's microbes boost baby's immunity. Nature 533:760142–43 [Google Scholar]
  121. Gomez de Agüero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y. 121.  et al. 2016. The maternal microbiota drives early postnatal innate immune development. Science 351:62791296–302 [Google Scholar]
  122. Teo SM, Mok D, Pham K, Kusel M, Serralha M. 122.  et al. 2015. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17:5704–15 [Google Scholar]
  123. Vissing NH, Chawes BL, Bisgaard H. 123.  2013. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am. J. Respir. Crit. Care Med. 188:101246–52 [Google Scholar]
  124. Hasegawa K, Linnemann RW, Mansbach JM, Ajami NJ, Espinola JA. 124.  et al. 2016. The fecal microbiota profile and bronchiolitis in infants. Pediatrics 138:1e20160218 [Google Scholar]
  125. de Steenhuijsen Piters WA, Heinonen S, Hasrat R, Bunsow E, Smith B. 125.  et al. 2016. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 194:91104–15 [Google Scholar]
  126. Stensballe LG, Hjuler T, Andersen A, Kaltoft M, Ravn H. 126.  et al. 2008. Hospitalization for respiratory syncytial virus infection and invasive pneumococcal disease in Danish children aged <2 years: a population-based cohort study. Clin. Infect. Dis. 46:81165–71 [Google Scholar]
  127. Stark JM, Stark MA, Colasurdo GN, LeVine AM. 127.  2006. Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection. J. Med. Virol 78:6829–38 [Google Scholar]
  128. Goulding J, Godlee A, Vekaria S, Hilty M, Snelgrove R, Hussell T. 128.  2011. Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. J. Infect. Dis. 204:71086–94 [Google Scholar]
  129. Didierlaurent A, Goulding J, Patel S, Snelgrove R, Low L. 129.  et al. 2008. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205:2323–29 [Google Scholar]
  130. Mella C, Suarez-Arrabal MC, Lopez S, Stephens J, Fernandez S. 130.  et al. 2013. Innate immune dysfunction is associated with enhanced disease severity in infants with severe respiratory syncytial virus bronchiolitis. J. Infect. Dis. 207:4564–73 [Google Scholar]
  131. García C, Soriano-Fallas A, Lozano J, Leos N, Gomez AM. 131.  et al. 2012. Decreased innate immune cytokine responses correlate with disease severity in children with respiratory syncytial virus and human rhinovirus bronchiolitis. Pediatr. Infect. Dis. J. 31:186–89 [Google Scholar]
  132. Tulic MK, Hurrelbrink RJ, Prêle CM, Laing IA, Upham JW. 132.  et al. 2007. Tlr4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J. Immunol. 179:1132–40 [Google Scholar]
  133. Mandelberg A, Tal G, Naugolny L, Cesar K, Oron A. 133.  et al. 2006. Lipopolysaccharide hyporesponsiveness as a risk factor for intensive care unit hospitalization in infants with respiratory syncitial virus bronchiolitis. Clin. Exp. Immunol. 144:148–52 [Google Scholar]
  134. Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E. 134.  et al. 2004. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J. Infect. Dis. 189:112057–63 [Google Scholar]
  135. Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB. 135.  et al. 2007. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J. Immunol. 179:53171–77 [Google Scholar]
  136. Paulus SC, Hirschfeld AF, Victor RE, Brunstein J, Thomas E, Turvey SE. 136.  2007. Common human Toll-like receptor 4 polymorphisms—role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin. Immunol. 123:3252–57 [Google Scholar]
  137. Kresfelder TL, Janssen R, Bont L, Pretorius M, Venter M. 137.  2011. Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children. J. Med. Virol 83:101834–40 [Google Scholar]
  138. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP. 138.  et al. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1:5398–401 [Google Scholar]
  139. Kallal LE, Hartigan AJ, Hogaboam CM, Schaller MA, Lukacs NW. 139.  2010. Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology. J. Immunol. 185:74137–47 [Google Scholar]
  140. Goritzka M, Pereira C, Makris S, Durant LR, Johansson C. 140.  2015. T cell responses are elicited against respiratory syncytial virus in the absence of signalling through TLRs, RLRs and IL-1R/IL-18R. Sci. Rep. 5:18533 [Google Scholar]
  141. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC. 141.  et al. 2013. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLOS Med 10:11e1001549 [Google Scholar]
  142. Marr N, Wang TI, Kam SH, Hu YS, Sharma AA. 142.  et al. 2014. Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children. J. Immunol. 192:3948–57 [Google Scholar]
  143. Cormier SA, Shrestha B, Saravia J, Lee GI, Shen L. 143.  et al. 2014. Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection. J. Virol. 88:169350–60 [Google Scholar]
  144. Remot A, Descamps D, Jouneau L, Laubreton D, Dubuquoy C. 144.  et al. 2016. Flt3 ligand improves the innate response to respiratory syncytial virus and limits lung disease upon RSV reexposure in neonate mice. Eur. J. Immunol. 46:4874–84 [Google Scholar]
  145. Han J, Dakhama A, Jia Y, Wang M, Zeng W. 145.  et al. 2012. Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. J. Allergy Clin. Immunol. 130:51175–86.e9 [Google Scholar]
  146. Yamaguchi Y, Harker JA, Wang B, Openshaw PJ, Tregoning JS, Culley FJ. 146.  2012. Preexposure to CpG protects against the delayed effects of neonatal respiratory syncytial virus infection. J. Virol. 86:1910456–61 [Google Scholar]
  147. Chu HY, Steinhoff MC, Magaret A, Zaman K, Roy E. 147.  et al. 2014. Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh. J. Infect. Dis. 210:101582–89 [Google Scholar]
  148. Vissers M, Ahout IM, de Jonge MI, Ferwerda G. 148.  2015. Mucosal IgG levels correlate better with respiratory syncytial virus load and inflammation than plasma IgG levels. Clin. Vaccine Immunol. 23:3243–45 [Google Scholar]
  149. Ogilvie MM, Vathenen AS, Radford M, Codd J, Key S. 149.  1981. Maternal antibody and respiratory syncytial virus infection in infancy. J. Med. Virol 7:4263–71 [Google Scholar]
  150. Glezen WP, Paredes A, Allison JE, Taber LH, Frank AL. 150.  1981. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. J. Pediatr. 98:5708–15 [Google Scholar]
  151. Ochola R, Sande C, Fegan G, Scott PD, Medley GF. 151.  et al. 2009. The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya. PLOS ONE 4:12e8088 [Google Scholar]
  152. Piedra PA, Jewell AM, Cron SG, Atmar RL, Glezen WP. 152.  2003. Correlates of immunity to respiratory syncytial virus (RSV) associated-hospitalization: establishment of minimum protective threshold levels of serum neutralizing antibodies. Vaccine 21:243479–82 [Google Scholar]
  153. Stensballe LG, Ravn H, Kristensen K, Agerskov K, Meakins T. 153.  et al. 2009. Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. J. Allergy Clin. Immunol. 123:2398–403 [Google Scholar]
  154. Nyiro JU, Sande C, Mutunga M, Kiyuka PK, Munywoki PK. 154.  et al. 2015. Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya. Vaccine 33:151797–801 [Google Scholar]
  155. Dunn SR, Ryder AB, Tollefson SJ, Xu M, Saville BR, Williams JV. 155.  2013. Seroepidemiologies of human metapneumovirus and respiratory syncytial virus in young children, determined with a new recombinant fusion protein enzyme-linked immunosorbent assay. Clin. Vaccine Immunol. 20:101654–56 [Google Scholar]
  156. De Sierra TM, Kumar ML, Wasser TE, Murphy BR, Subbarao EK. 156.  1993. Respiratory syncytial virus-specific immunoglobulins in preterm infants. J. Pediatr. 122:5 Part 1787–91 [Google Scholar]
  157. Okoko BJ, Wesumperuma LH, Ota MO, Pinder M, Banya W. 157.  et al. 2001. The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a rural West African population. J. Infect. Dis. 184:5627–32 [Google Scholar]
  158. Atwell JE, Thumar B, Robinson LJ, Tobby R, Yambo P. 158.  et al. 2016. Impact of placental malaria and hypergammaglobulinemia on transplacental transfer of respiratory syncytial virus antibody in Papua New Guinea. J. Infect. Dis. 213:3423–31 [Google Scholar]
  159. McIntosh K, McQuillin J, Gardner PS. 159.  1979. Cell-free and cell-bound antibody in nasal secretions from infants with respiratory syncytial virus infection. Infect. Immun. 23:2276–81 [Google Scholar]
  160. McIntosh K, Masters HB, Orr I, Chao RK, Barkin RM. 160.  1978. The immunologic response to infection with respiratory syncytial virus in infants. J. Infect. Dis. 138:124–32 [Google Scholar]
  161. Sande CJ, Cane PA, Nokes DJ. 161.  2014. The association between age and the development of respiratory syncytial virus neutralising antibody responses following natural infection in infants. Vaccine 32:374726–29 [Google Scholar]
  162. Shinoff JJ, O'Brien KL, Thumar B, Shaw JB, Reid R. 162.  et al. 2008. Young infants can develop protective levels of neutralizing antibody after infection with respiratory syncytial virus. J. Infect. Dis. 198:71007–15 [Google Scholar]
  163. Williams JV, Weitkamp JH, Blum DL, LaFleur BJ, Crowe JE. 163.  2009. The human neonatal B cell response to respiratory syncytial virus uses a biased antibody variable gene repertoire that lacks somatic mutations. Mol. Immunol. 47:2–3407–14 [Google Scholar]
  164. Ohuma EO, Okiro EA, Ochola R, Sande CJ, Cane PA. 164.  et al. 2012. The natural history of respiratory syncytial virus in a birth cohort: the influence of age and previous infection on reinfection and disease. Am. J. Epidemiol. 176:9794–802 [Google Scholar]
  165. Sande CJ, Mutunga MN, Okiro EA, Medley GF, Cane PA, Nokes DJ. 165.  2013. Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort. J. Med. Virol 85:112020–25 [Google Scholar]
  166. Murphy BR, Alling DW, Snyder MH, Walsh EE, Prince GA. 166.  et al. 1986. Effect of age and preexisting antibody on serum antibody response of infants and children to the F and G glycoproteins during respiratory syncytial virus infection. J. Clin. Microbiol. 24:5894–98 [Google Scholar]
  167. Kanswal S, Katsenelson N, Selvapandiyan A, Bram RJ, Akkoyunlu M. 167.  2008. Deficient TACI expression on B lymphocytes of newborn mice leads to defective Ig secretion in response to BAFF or APRIL. J. Immunol. 181:2976–90 [Google Scholar]
  168. Reed JL, Welliver TP, Sims GP, McKinney L, Velozo L. 168.  et al. 2009. Innate immune signals modulate antiviral and polyreactive antibody responses during severe respiratory syncytial virus infection. J. Infect. Dis. 199:81128–138 [Google Scholar]
  169. Tregoning JS, Wang BL, McDonald JU, Yamaguchi Y, Harker JA. 169.  et al. 2013. Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection. PNAS 110:145576–81 [Google Scholar]
  170. McNamara PS, Ritson P, Selby A, Hart CA, Smyth RL. 170.  2003. Bronchoalveolar lavage cellularity in infants with severe respiratory syncytial virus bronchiolitis. Arch. Dis. Child 88:10922–26 [Google Scholar]
  171. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F. 171.  et al. 2009. Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183:117150–60 [Google Scholar]
  172. Legg JP, Hussain IR, Warner JA, Johnston SL, Warner JO. 172.  2003. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis. Am. J. Respir. Crit. Care Med. 168:6633–39 [Google Scholar]
  173. Aberle JH, Aberle SW, Dworzak MN, Mandl CW, Rebhandl W. 173.  et al. 1999. Reduced interferon-gamma expression in peripheral blood mononuclear cells of infants with severe respiratory syncytial virus disease. Am. J. Respir. Crit. Care Med. 160:41263–68 [Google Scholar]
  174. Kristjansson S, Bjarnarson SP, Wennergren G, Palsdottir AH, Arnadottir T. 174.  et al. 2005. Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local Th2-like response. J. Allergy Clin. Immunol. 116:4805–11 [Google Scholar]
  175. Semple MG, Dankert HM, Ebrahimi B, Correia JB, Booth JA. 175.  et al. 2007. Severe respiratory syncytial virus bronchiolitis in infants is associated with reduced airway interferon gamma and substance P. PLOS ONE 2:10e1038 [Google Scholar]
  176. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F. 176.  et al. 2000. Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study. Am. J. Respir. Crit. Care Med. 161:51518–23 [Google Scholar]
  177. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F. 177.  et al. 2001. Local interferon-gamma levels during respiratory syncytial virus lower respiratory tract infection are associated with disease severity. J. Infect. Dis. 184:3355–58 [Google Scholar]
  178. Hoebee B, Bont L, Rietveld E, van Oosten M, Hodemaekers HM. 178.  et al. 2004. Influence of promoter variants of interleukin-10, interleukin-9, and tumor necrosis factor-αα genes on respiratory syncytial virus bronchiolitis. J. Infect. Dis. 189:2239–47 [Google Scholar]
  179. Hoebee B, Rietveld E, Bont L, Oosten MV, Hodemaekers HM. 179.  et al. 2003. Association of severe respiratory syncytial virus bronchiolitis with interleukin-4 and interleukin-4 receptor α polymorphisms. J. Infect. Dis. 187:12–11 [Google Scholar]
  180. Ermers MJ, Hoebee B, Hodemaekers HM, Kimman TG, Kimpen JL, Bont L. 180.  2007. IL-13 genetic polymorphism identifies children with late wheezing after respiratory syncytial virus infection. J. Allergy Clin. Immunol. 119:51086–91 [Google Scholar]
  181. Fonceca AM, Flanagan BF, Trinick R, Smyth RL, McNamara PS. 181.  2012. Primary airway epithelial cultures from children are highly permissive to respiratory syncytial virus infection. Thorax 67:142–48 [Google Scholar]
  182. Villenave R, Thavagnanam S, Sarlang S, Parker J, Douglas I. 182.  et al. 2012. In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo. PNAS 109:135040–45 [Google Scholar]
  183. Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K. 183.  et al. 2016. Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 138:814–24.e11 [Google Scholar]
  184. Lee HC, Headley MB, Loo YM, Berlin A, Gale M. 184.  et al. 2012. Thymic stromal lymphopoietin is induced by respiratory syncytial virus-infected airway epithelial cells and promotes a type 2 response to infection. J. Allergy Clin. Immunol. 130:51187–96.e5 [Google Scholar]
  185. Yang SH, Chu MA, Park HJ, Lee KH, Kim WT, Chung HL. 185.  2012. Increased nasal interleukin-33 in the infants with acute respiratory syncytial virus bronchiolitis. Pediatr. Allergy Respir. Dis. 22:4383 [Google Scholar]
  186. Culley FJ, Pollott J, Openshaw PJ. 186.  2002. Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J. Exp. Med. 196:101381–86 [Google Scholar]
  187. Saravia J, You D, Shrestha B, Jaligama S, Siefker D. 187.  et al. 2015. Respiratory syncytial virus disease is mediated by age-variable IL-33. PLOS Pathog 11:10e1005217 [Google Scholar]
  188. Faber TE, Schuurhof A, Vonk A, Koppelman GH, Hennus MP. 188.  et al. 2012. IL1RLl gene variants and nasopharyngeal IL1RL-alpha levels are associated with severe RSV bronchiolitis: a multicenter cohort study. PLOS ONE 7:5e34364 [Google Scholar]
  189. Geerdink RJ, Pillay J, Meyaard L, Bont L. 189.  2015. Neutrophils in respiratory syncytial virus infection: a target for asthma prevention. J. Allergy Clin. Immunol. 136:4838–47 [Google Scholar]
  190. Stoppelenburg AJ, de Roock S, Hennus MP, Bont L, Boes M. 190.  2014. Elevated Th17 response in infants undergoing respiratory viral infection. Am. J. Pathol. 184:51274–79 [Google Scholar]
  191. Stoppelenburg AJ, Salimi V, Hennus M, Plantinga M, Huis in't Veld R. 191.  et al. 2013. Local IL-17a potentiates early neutrophil recruitment to the respiratory tract during severe RSV infection. PLOS ONE 8:10e78461 [Google Scholar]
  192. Lukens MV, van de Pol AC, Coenjaerts FE, Jansen NJ, Kamp VM. 192.  et al. 2010. A systemic neutrophil response precedes robust CD8+ T-cell activation during natural respiratory syncytial virus infection in infants. J. Virol. 84:52374–83 [Google Scholar]
  193. McNamara PS, Flanagan BF, Baldwin LM, Newland P, Hart CA, Smyth RL. 193.  2004. Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet 363:94141031–37 [Google Scholar]
  194. Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC. 194.  et al. 2010. Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls. Pediatr. Pulmonol. 45:6608–13 [Google Scholar]
  195. Dodd JS, Lum E, Goulding J, Muir R, Van Snick J, Openshaw PJ. 195.  2009. IL-9 regulates pathology during primary and memory responses to respiratory syncytial virus infection. J. Immunol. 183:117006–13 [Google Scholar]
  196. Raiden S, Pandolfi J, Payasliàn F, Anderson M, Rivarola N. 196.  et al. 2014. Depletion of circulating regulatory T cells during severe respiratory syncytial virus infection in young children. Am. J. Respir. Crit. Care Med. 189:7865–68 [Google Scholar]
  197. Korppi M, Nuolivirta K, Lauhkonen E, Holster A, Teräsjärvi J. 197.  et al. 2017. IL-10 gene polymorphism is associated with preschool atopy and early-life recurrent wheezing after bronchiolitis in infancy. Pediatr. Pulmonol. 52:114–20 [Google Scholar]
  198. Ruckwardt TJ, Malloy AM, Morabito KM, Graham BS. 198.  2014. Quantitative and qualitative deficits in neonatal lung-migratory dendritic cells impact the generation of the CD8+ T cell response. PLOS Pathog 10:2e1003934 [Google Scholar]
  199. Ruckwardt TJ, Malloy AM, Gostick E, Price DA, Dash P. 199.  et al. 2011. Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice. PLOS Pathog 7:12e1002377 [Google Scholar]
  200. PrabhuDas M, Adkins B, Gans H, King C, Levy O. 200.  et al. 2011. Challenges in infant immunity: implications for responses to infection and vaccines. Nat. Immunol. 12:3189–94 [Google Scholar]
  201. Sumino K, Tucker J, Shahab M, Jaffee KF, Visness CM. 201.  et al. 2012. Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life. J. Allergy Clin. Immunol. 129:51267–73.e1 [Google Scholar]
  202. De Almeida Nagata DE, Demoor T, Ptaschinski C, Ting HA, Jang S. 202.  et al. 2014. IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis. Am. J. Pathol. 184:61807–18 [Google Scholar]
  203. Dakhama A, Park JW, Taube C, Joetham A, Balhorn A. 203.  et al. 2005. The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production. J. Immunol. 175:31876–83 [Google Scholar]
  204. Tregoning JS, Yamaguchi Y, Harker J, Wang B, Openshaw PJ. 204.  2008. The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice. J. Virol. 82:84115–24 [Google Scholar]
  205. You D, Saravia J, Siefker D, Shrestha B, Cormier SA. 205.  2016. Crawling with virus: translational insights from a neonatal mouse model on the pathogenesis of respiratory syncytial virus in infants. J. Virol. 90:12–4 [Google Scholar]
  206. Harker JA, Yamaguchi Y, Culley FJ, Tregoning JS, Openshaw PJ. 206.  2014. Delayed sequelae of neonatal respiratory syncytial virus infection are dependent on cells of the innate immune system. J. Virol. 88:1604–11 [Google Scholar]
  207. Lee YM, Miyahara N, Takeda K, Prpich J, Oh A. 207.  et al. 2008. IFN-gamma production during initial infection determines the outcome of reinfection with respiratory syncytial virus. Am. J. Respir. Crit. Care Med. 177:2208–18 [Google Scholar]
  208. Eichinger KM, Egaña L, Orend JG, Resetar E, Anderson KB. 208.  et al. 2015. Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice. Respir. Res. 16:122 [Google Scholar]
  209. Harker JA, Lee DC, Yamaguchi Y, Wang B, Bukreyev A. 209.  et al. 2010. Delivery of cytokines by recombinant virus in early life alters the immune response to adult lung infection. J. Virol. 84:105294–302 [Google Scholar]
  210. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A. 210.  et al. 2013. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N. Engl. J. Med. 368:191791–99 [Google Scholar]
  211. O'Brien KL, Chandran A, Weatherholtz R, Jafri HS, Griffin MP. 211.  et al. 2015. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial. Lancet Infect. Dis. 15:121398–408 [Google Scholar]
  212. Pala P, Bjarnason R, Sigurbergsson F, Metcalfe C, Sigurs N, Openshaw PJ. 212.  2002. Enhanced IL-4 responses in children with a history of respiratory syncytial virus bronchiolitis in infancy. Eur. Respir. J. 20:2376–82 [Google Scholar]
  213. Van der Sande MA, Kidd IM, Goetghebuer T, Martynoga RA, Magnusen A. 213.  et al. 2002. Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children. Clin. Exp. Allergy 32:101430–35 [Google Scholar]
  214. Schauer U, Hoffjan S, Rothoeft T, Bartz H, Konig S. 214.  et al. 2004. Severe respiratory syncytial virus infections and reduced interferon-gamma generation in vitro. Clin. Exp. Immunol. 138:1102–9 [Google Scholar]
  215. Renzi PM, Turgeon JP, Yang JP, Drblik SP, Marcotte JE. 215.  et al. 1997. Cellular immunity is activated and a Th-2 response is associated with early wheezing in infants after bronchiolitis. J. Pediatr. 130:4584–93 [Google Scholar]
  216. Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL. 216.  2004. Reduced interferon gamma production and soluble CD14 levels in early life predict recurrent wheezing by 1 year of age. Am. J. Respir. Crit. Care Med. 169:170–76 [Google Scholar]
  217. Schuurhof A, Janssen R, de Groot H, Hodemaekers HM, de Klerk A. 217.  et al. 2011. Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze. Respir. Res. 12:121 [Google Scholar]
  218. Ermers MJ, Janssen R, Onland-Moret NC, Hodemaekers HM, Rovers MM. 218.  et al. 2011. IL10 family member genes IL19 and IL20 are associated with recurrent wheeze after respiratory syncytial virus bronchiolitis. Pediatr. Res 70:5518–23 [Google Scholar]
  219. Eberl G. 219.  2016. Immunity by equilibrium. Nat. Rev. Immunol. 16:8524–32 [Google Scholar]
  220. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N. 220.  et al. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:2179–86 [Google Scholar]
  221. Fleming DM, Taylor RJ, Lustig RL, Schuck-Paim C, Haguinet F. 221.  et al. 2015. Modelling estimates of the burden of respiratory syncytial virus infection in adults and the elderly in the United Kingdom. BMC Infect. Dis. 15:443 [Google Scholar]
  222. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. 222.  2005. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352:171749–59 [Google Scholar]
  223. Falsey AR, McElhaney JE, Beran J, van Essen GA, Duval X. 223.  et al. 2014. Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness. J. Infect. Dis. 209:121873–81 [Google Scholar]
  224. Walsh EE, Peterson DR, Falsey AR. 224.  2004. Risk factors for severe respiratory syncytial virus infection in elderly persons. J. Infect. Dis. 189:2233–38 [Google Scholar]
  225. Duncan CB, Walsh EE, Peterson DR, Lee FE, Falsey AR. 225.  2009. Risk factors for respiratory failure associated with respiratory syncytial virus infection in adults. J. Infect. Dis. 200:81242–46 [Google Scholar]
  226. Lee N, Lui GC, Wong KT, Li TC, Tse EC. 226.  et al. 2013. High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin. Infect. Dis. 57:81069–77 [Google Scholar]
  227. Lee N, Chan MC, Lui GC, Li R, Wong RY. 227.  et al. 2015. High viral load and respiratory failure in adults hospitalized for respiratory syncytial virus infections. J. Infect. Dis. 212:81237–40 [Google Scholar]
  228. Malloy AM, Falsey AR, Ruckwardt TJ. 228.  2013. Consequences of immature and senescent immune responses for infection with respiratory syncytial virus. Curr. Top. Microbiol. Immunol. 372:211–31 [Google Scholar]
  229. Kollmann TR, Levy O, Montgomery RR, Goriely S. 229.  2012. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37:5771–83 [Google Scholar]
  230. Shaw AC, Goldstein DR, Montgomery RR. 230.  2013. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13:12875–87 [Google Scholar]
  231. Pillai PS, Molony RD, Martinod K, Dong H, Pang IK. 231.  et al. 2016. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352:6284463–66 [Google Scholar]
  232. Boraschi D, Aguado MT, Dutel C, Goronzy J, Louis J. 232.  et al. 2013. The gracefully aging immune system. Sci. Transl. Med. 5:185185ps8 [Google Scholar]
  233. Looney RJ, Falsey AR, Walsh E, Campbell D. 233.  2002. Effect of aging on cytokine production in response to respiratory syncytial virus infection. J. Infect. Dis. 185:5682–85 [Google Scholar]
  234. Cherukuri A, Patton K, Gasser RA, Zuo F, Woo J. 234.  et al. 2013. Adults 65 years old and older have reduced numbers of functional memory T cells to respiratory syncytial virus fusion protein. Clin. Vaccine Immunol. 20:2239–47 [Google Scholar]
  235. Cusi MG, Martorelli B, Di Genova G, Terrosi C, Campoccia G, Correale P. 235.  2010. Age related changes in T cell mediated immune response and effector memory to respiratory syncytial virus (RSV) in healthy subjects. Immun. Ageing 7:14 [Google Scholar]
  236. Zhang Y, Wang Y, Gilmore X, Xu K, Wyde PR, Mbawuike IN. 236.  2002. An aged mouse model for RSV infection and diminished CD8+ CTL responses. Exp. Biol. Med. 227:2133–40 [Google Scholar]
  237. Wong TM, Boyapalle S, Sampayo V, Nguyen HD, Bedi R. 237.  et al. 2014. Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology. PLOS ONE 9:2e88764 [Google Scholar]
  238. Fulton RB, Weiss KA, Pewe LL, Harty JT, Varga SM. 238.  2013. Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection. J. Virol. 87:2312694–700 [Google Scholar]
  239. Falsey AR, Walsh EE. 239.  1998. Relationship of serum antibody to risk of respiratory syncytial virus infection in elderly adults. J. Infect. Dis. 177:2463–66 [Google Scholar]
  240. Luchsinger V, Piedra PA, Ruiz M, Zunino E, Martínez MA. 240.  et al. 2012. Role of neutralizing antibodies in adults with community-acquired pneumonia by respiratory syncytial virus. Clin. Infect. Dis. 54:7905–12 [Google Scholar]
  241. Walsh EE, Falsey AR. 241.  2004. Age related differences in humoral immune response to respiratory syncytial virus infection in adults. J. Med. Virol 73:2295–99 [Google Scholar]
  242. Agius G, Dindinaud G, Biggar RJ, Peyre R, Vaillant V. 242.  et al. 1990. An epidemic of respiratory syncytial virus in elderly people: clinical and serological findings. J. Med. Virol 30:2117–27 [Google Scholar]
  243. Murata Y, Lightfoote PM, Biear JN, Falsey AR, Walsh EE. 243.  2010. Humoral response to the central unglycosylated region of the respiratory syncytial virus attachment protein. Vaccine 28:386242–46 [Google Scholar]
  244. Siegrist CA, Aspinall R. 244.  2009. B-cell responses to vaccination at the extremes of age. Nat. Rev. Immunol. 9:3185–94 [Google Scholar]
  245. Mohr E, Siegrist CA. 245.  2016. Vaccination in early life: standing up to the challenges. Curr. Opin. Immunol. 41:1–8 [Google Scholar]
  246. Anderson LJ, Dormitzer PR, Nokes DJ, Rappuoli R, Roca A, Graham BS. 246.  2013. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine 31:Suppl. 2B209–15 [Google Scholar]
  247. Widjaja I, Wicht O, Luytjes W, Leenhouts K, Rottier PJ. 247.  et al. 2016. Characterization of epitope-specific anti-respiratory syncytial virus (anti-RSV) antibody responses after natural infection and after vaccination with formalin-inactivated RSV. J. Virol. 90:135965–77 [Google Scholar]
  248. Munoz FM. 248.  2015. Respiratory syncytial virus in infants: Is maternal vaccination a realistic strategy?. Curr. Opin. Infect. Dis. 28:3221–24 [Google Scholar]
  249. Anderson LJ. 249.  2013. Respiratory syncytial virus vaccine development. Semin. Immunol. 25:2160–71 [Google Scholar]
  250. Kachikis A, Englund JA. 250.  2016. Maternal immunization: optimizing protection for the mother and infant. J. Infect. 72:Suppl.S83–90 [Google Scholar]
  251. Munoz F. 251.  2003. Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant women. Vaccine 21:243465–67 [Google Scholar]
  252. Brandt C, Power UF, Plotnicky-Gilquin H, Huss T, Nguyen T. 252.  et al. 1997. Protective immunity against respiratory syncytial virus in early life after murine maternal or neonatal vaccination with the recombinant G fusion protein BBG2Na. J. Infect. Dis. 176:4884–91 [Google Scholar]
  253. Sharma A, Wendland R, Sung B, Wu W, Grunwald T, Worgall S. 253.  2014. Maternal immunization with chimpanzee adenovirus expressing RSV fusion protein protects against neonatal RSV pulmonary infection. Vaccine 32:435761–68 [Google Scholar]
  254. Graham BS. 254.  2016. Vaccines against respiratory syncytial virus: The time has finally come. Vaccine 34:303535–41 [Google Scholar]
  255. Meijboom MJ, Pouwels KB, Luytjes W, Postma MJ, Hak E. 255.  2013. RSV vaccine in development: assessing the potential cost-effectiveness in the Dutch elderly population. Vaccine 31:526254–60 [Google Scholar]
  256. Del Giudice G, Weinberger B, Grubeck-Loebenstein B. 256.  2015. Vaccines for the elderly. Gerontology 61:3203–10 [Google Scholar]
  257. Valkenburg SA, Venturi V, Dang TH, Bird NL, Doherty PC. 257.  et al. 2012. Early priming minimizes the age-related immune compromise of CD8+ T cell diversity and function. PLOS Pathog 8:2e1002544 [Google Scholar]
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Protective and Harmful Immunity to RSV Infection
Annual Review of Immunology 35, 501 (2017); https://doi.org/10.1146/annurev-immunol-051116-052206
/content/journals/10.1146/annurev-immunol-051116-052206
/content/journals/10.1146/annurev-immunol-051116-052206
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