Protective and harmful immunity to RSV infection

Annual Review of Immunology

Volumn 35, Issue , 2017, Pages 501-532

  Openshaw, Peter J M ^a   Chiu, Chris ^a   Culley, Fiona J ^a   Johansson, Cecilia ^a  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

Bronchiolitis; Immunoregulation; Mucosal immunity; Pediatric infections; Viral lung disease

Indexed keywords

ANTIBODY; CHEMOKINE; CYTOKINE; GLYCOPROTEIN; GLYCOPROTEIN F; INTERFERON; INTERLEUKIN 10; NONSTRUCTURAL PROTEIN 1; NONSTRUCTURAL PROTEIN 2; POLYPEPTIDE ANTIBIOTIC AGENT; RESPIRATORY SYNCYTIAL VIRUS VACCINE; SURFACTANT; THROMBOSPONDIN; UNCLASSIFIED DRUG; VIRUS VACCINE;

ADAPTIVE IMMUNITY; ADULT; AGED; AIRWAY CELL; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL SURFACE; CYTOKINE PRODUCTION; DISEASE SEVERITY; HUMAN; IMMUNE EVASION; IMMUNE RESPONSE; IMMUNITY; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFANCY; INFANT; INFECTION; INNATE IMMUNITY; MICROFLORA; MUCUS SECRETION; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; RESPIRATORY SYNCYTIAL VIRUS INFECTION; REVIEW; T LYMPHOCYTE; VACCINATION; VERY ELDERLY; ANIMAL; CHILD; IMMUNOLOGY; PNEUMOVIRUS; RESPIRATORY MUCOSA; VIROLOGY;

ADULT; AGED; ANIMALS; CHILD; HUMANS; IMMUNE EVASION; IMMUNOMODULATION; RESPIRATORY MUCOSA; RESPIRATORY SYNCYTIAL VIRUS INFECTIONS; RESPIRATORY SYNCYTIAL VIRUSES; VIRAL VACCINES;

EID: 85018309713     PISSN: 07320582     EISSN: 15453278     Source Type: Book Series    
DOI: 10.1146/annurev-immunol-051116-052206     Document Type: Review

References (257)

1. Smyth RL, Openshaw PJ. 2006. Bronchiolitis. Lancet 368(9532):312-22
2. Meissner HC. 2016. Viral bronchiolitis in children. N. Engl. J. Med. 374(1):62-72
3. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, et al. 2010. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and metaanalysis. Lancet 375(9725):1545-555
4. Geoghegan S, Erviti A, Caballero MT, Vallone F, Zanone SM, et al. 2016. Mortality due to respiratory syncytial virus: burden and risk factors. Am. J. Respir. Crit. Care Med. 195:96-103
5. El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, Devincenzo JP. 2011. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J. Infect. Dis. 204(7):996-1002
6. DeVincenzo JP, El Saleeby CM, Bush AJ. 2005. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J. Infect. Dis. 191(11):1861-68
7. Welliver TP, Reed JL, Welliver RC. 2008. Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases. Pediatr. Infect. Dis. J. 27(10 Suppl.):S92-96
8. Welliver TP, Garofalo RP, Hosakote Y, Hintz KH, Avendano L, 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(8):1126-36
9. Hall CB, Powell KR, MacDonald NE, Gala CL, Menegus ME, et al. 1986. Respiratory syncytial viral infection in children with compromised immune function. N. Engl. J. Med. 315(2):77-81
10. Heidema J, Lukens MV, vanMaren WW, van Dijk ME, Otten HG, 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(12):8410-17
11. Lambert L, Sagfors AM, Openshaw PJ, Culley FJ. 2014. Immunity to RSV in early-life. Front. Immunol. 5:466
12. Openshaw PJ, Chiu C. 2013. Protective and dysregulated T cell immunity in RSV infection. Curr. Opin. Virol. 3(4):468-474
13. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. 2007. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod. Pathol. 20(1):108-19
14. Faber TE, Groen H, Welfing M, Jansen KJ, Bont LJ. 2012. Specific increase in local IL-17 production during recovery from primary RSV bronchiolitis. J. Med. Virol. 84(7):1084-88
15. McNamara PS, Flanagan BF, Hart CA, Smyth RL. 2005. Production of chemokines in the lungs of infants with severe respiratory syncytial virus bronchiolitis. J. Infect. Dis. 191(8):1225-32
16. McNamara PS, Flanagan BF, Selby AM, Hart CA, Smyth RL. 2004. Pro-and anti-inflammatory responses in respiratory syncytial virus bronchiolitis. Eur. Respir. J. 23(1):106-12
17. Mobbs KJ, Smyth RL, O'Hea U, Ashby D, Ritson P, Hart CA. 2002. Cytokines in severe respiratory syncytial virus bronchiolitis. Pediatr. Pulmonol. 33(6):449-52
18. Openshaw PJ. 2013. The mouse model of respiratory syncytial virus disease. Curr. Top. Microbiol. Immunol. 372:359-69
19. Carroll KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD, et al. 2009. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J. Allergy Clin. Immunol. 123(5):1055-61.e1
20. Sigurs N, Aljassim F, Kjellman B, Robinson PD, Sigurbergsson F, et al. 2010. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65(12):1045-52
21. Zanin M, Baviskar P, Webster R, Webby R. 2016. The interaction between respiratory pathogens and mucus. Cell Host Microbe. 19(2):159-68
22. Currier MG, Lee S, Stobart CC, Hotard AL, Villenave R, 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(5):e1005622
23. Stokes KL, Currier MG, Sakamoto K, Lee S, Collins PL, 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(18):10070-82
24. Smith CM, Kulkarni H, Radhakrishnan P, Rutman A, Bankart MJ, et al. 2014. Ciliary dyskinesia is an early feature of respiratory syncytial virus infection. Eur. Respir. J. 43(2):485-96
25. Currie SM, Gwyer Findlay E, McFarlane AJ, Fitch PM, Bottcher B, 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(6):2699-710
26. Sano H, Nagai K, Tsutsumi H, Kuroki Y. 2003. Lactoferrin and surfactant protein A exhibit distinct binding specificity to F protein and differently modulate respiratory syncytial virus infection. Eur. J. Immunol. 33(10):2894-902
27. LeVine AM, Gwozdz J, Stark J, Bruno M, Whitsett J, KorfhagenT. 1999. Surfactant protein-A enhances respiratory syncytial virus clearance in vivo. J. Clin. Investig. 103(7):1015-21
28. Kerr MH, Paton JY. 1999. Surfactant protein levels in severe respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 159(4 Part 1):1115-18
29. Ampuero S, Luchsinger V, Tapia L, Palomino MA, Larranaga CE. 2011. SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants. Infect. Genet. Evol. 11(6):1368-77
30. Lahti M. 2002. Surfactant protein D gene polymorphism associated with severe respiratory syncytial virus infection. Pediatr. Res. 51(6):696-99
31. Johnson SM, McNally BA, Ioannidis I, Flano E, Teng MN, et al. 2015. Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures. PLOS Pathog. 11(12):e1005318
32. Wright PF, Ikizler MR, Gonzales RA, Carroll KN, Johnson JE, Werkhaven JA. 2005. Growth of respiratory syncytial virus in primary epithelial cells from the human respiratory tract. J. Virol. 79(13):8651-654
33. Pastey MK, Crowe JE, Graham BS. 1999. RhoA interacts with the fusion glycoprotein of respiratory syncytial virus and facilitates virus-induced syncytium formation. J. Virol. 73(9):7262-270
34. Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, et al. 2015. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J. Exp. Med. 212(5):699-714
35. Bhoj VG, Sun Q, Bhoj EJ, Somers C, Chen X, et al. 2008. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. PNAS 105(37):14046-51
36. Demoor T, Petersen BC, Morris S, Mukherjee S, Ptaschinski C, et al. 2012. IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus. J. Immunol. 189(12):5942-53
37. Marr N, Turvey SE, Grandvaux N. 2013. Pathogen recognition receptor crosstalk in respiratory syncytial virus sensing: a host and cell type perspective. Trends Microbiol. 21(11):568-74
38. Borchers AT, Chang C, Gershwin ME, Gershwin LJ. 2013. Respiratory syncytial virus-a comprehensive review. Clin. Rev. Allergy Immunol. 45(3):331-79
39. Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, et al. 2007. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J. Infect. Dis. 196(6):826-34
40. Siezen CL, Bont L, Hodemaekers HM, Ermers MJ, Doornbos G, 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(4):333-35
41. Goritzka M, Durant LR, Pereira C, Salek-Ardakani S, Openshaw PJ, Johansson C. 2014. Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection. J. Virol. 88(11):6128-136
42. Durbin RK, Kotenko SV, Durbin JE. 2013. Interferon induction and function at the mucosal surface. Immunol. Rev. 255(1):25-39
43. Sun Y, Jain D, Koziol-White CJ, Genoyer E, Gilbert M, 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(9):e1005122
44. Villenave R, Broadbent L, Douglas I, Lyons JD, Coyle PV, et al. 2015. Induction and antagonism of antiviral responses in respiratory syncytial virus-infected pediatric airway epithelium. J. Virol. 89(24):12309-18
45. McNamara PS, Fonceca AM, Howarth D, Correia JB, Slupsky JR, 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(1):76-81
46. Hussell T, Bell TJ. 2014. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14(2):81-93
47. Reed JL, Brewah YA, Delaney T, Welliver T, Burwell T, et al. 2008. Macrophage impairment underlies airway occlusion in primary respiratory syncytial virus bronchiolitis. J. Infect. Dis. 198(12):1783-93
48. Pribul PK, Harker J, Wang B, Wang H, Tregoning JS, 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(9):4441-48
49. Kolli D, Gupta MR, Sbrana E, Velayutham TS, Chao H, 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(4):502-15
50. Makris S, Bajorek M, Culley FJ, Goritzka M, Johansson C. 2016. Alveolar macrophages can control respiratory syncytial virus infection in the absence of type I interferons. J. Innate Immun. 8:452-63
51. Gill MA, Palucka AK, Barton T, Ghaffar F, Jafri H, et al. 2005. Mobilization of plasmacytoid andmyeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. J. Infect. Dis. 191(7):1105-15
52. Smit JJ, Rudd BD, Lukacs NW. 2006. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. J. Exp. Med. 203(5):1153-59
53. Wang H, Peters N, Schwarze J. 2006. Plasmacytoid dendritic cells limit viral replication, pulmonary inflammation, and airway hyperresponsiveness in respiratory syncytial virus infection. J. Immunol. 177(9):6263-70
54. Schijf MA, Lukens MV, Kruijsen D, van Uden NO, Garssen J, 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(11):e81695
55. Owczarczyk AB, Schaller MA, Reed M, Rasky AJ, Lombard DB, Lukacs NW. 2015. Sirtuin 1 regulates dendritic cell activation and autophagy during respiratory syncytial virus-induced immune responses. J. Immunol. 195(4):1637-46
56. Reed M, Morris SH, Owczarczyk AB, Lukacs NW. 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(5):1118-30
57. Reed M, Morris SH, Jang S, Mukherjee S, Yue Z, Lukacs NW. 2013. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4Tcell responses and disease severity during respiratory syncytial virus infection. J. Immunol. 191(5):2526-37
58. Ptaschinski C, Mukherjee S, Moore ML, Albert M, Helin K, et al. 2015. RSV-inducedH3K4demethylase KDM5B leads to regulation of dendritic cell-derived innate cytokines and exacerbates pathogenesis in vivo. PLOS Pathog. 11(6):e1004978
59. Yao S, Jiang L, Moser EK, Jewett LB, Wright J, 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(4):746-59
60. Cannon MJ, Openshaw PJ, Askonas BA. 1988. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J. Exp. Med. 168(3):1163-68
61. Davidson S, Crotta S, McCabe TM, Wack A. 2014. Pathogenic potential of interferon αβ in acute influenza infection. Nat. Commun. 5:3864
62. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, et al. 2008. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J. Exp. Med. 205(13):3065-77
63. Kaiko GE, Phipps S, Angkasekwinai P, Dong C, Foster PS. 2010. NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25. J. Immunol. 185(8):4681-90
64. Huang H, Saravia J, You D, Shaw AJ, Cormier SA. 2015. Impaired gamma delta T cell-derived IL-17a and inflammasome activation during early respiratory syncytial virus infection in infants. Immunol. Cell Biol. 93(2):126-35
65. Dodd J, Riffault S, Kodituwakku JS, Hayday AC, Openshaw PJ. 2009. Pulmonary Vγ4+ γδT cells have proinflammatory and antiviral effects in viral lung disease. J. Immunol. 182(2):1174-81
66. Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, et al. 2015. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J. Clin. Investig. 125(2):571-82
67. Blum JS, Wearsch PA, Cresswell P. 2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443-73
68. Chiu C, Openshaw PJ. 2015. Antiviral B cell and T cell immunity in the lungs. Nat. Immunol. 16(1):18-26
69. Christiaansen AF, Knudson CJ, Weiss KA, Varga SM. 2014. The CD4 T cell response to respiratory syncytial virus infection. Immunol. Res. 59(1-3):109-17
70. Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, et al. 2015. RSV-specific airway residentmemoryCD8+ T cells and differential disease severity after experimental human infection. Nat. Commun. 6:10224
71. Liu J, Haddad EK, Marceau J, Morabito KM, Rao SS, et al. 2016. A numerically subdominantCD8Tcell response to matrix protein of respiratory syncytial virus controls infection with limited immunopathology. PLOS Pathog. 12(3):e1005486
72. De Bree GJ, Heidema J, van Leeuwen EM, van Bleek GM, Jonkers RE, et al. 2005. Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons. J. Infect. Dis. 191(10):1710-18
73. Knudson CJ, Weiss KA, Hartwig SM, Varga SM. 2014. The pulmonary localization of virus-specific T lymphocytes is governed by the tissue tropism of infection. J. Virol. 88(16):9010-16
74. DiNapoli JM, Murphy BR, Collins PL, Bukreyev A. 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
75. Ruckwardt TJ, Bonaparte KL, Nason MC, Graham BS. 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(7):3019-28
76. Fulton RB, Meyerholz DK, Varga SM. 2010. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J. Immunol. 185(4):2382-92
77. Durant LR, Makris S, Voorburg CM, Loebbermann J, Johansson C, Openshaw PJ. 2013. Regulatory T cells prevent Th2 immune responses and pulmonary eosinophilia during respiratory syncytial virus infection in mice. J. Virol. 87(20):10946-54
78. Loebbermann J, Thornton H, Durant L, Sparwasser T, Webster KE, et al. 2012. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol. 5(2):161-72
79. Lee DC, Harker JA, Tregoning JS, Atabani SF, Johansson C, 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(17):8790-98
80. Delgado MF, Coviello S, Monsalvo AC, Melendi GA, Hernandez JZ, 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(1):34-41
81. Polack FP, Teng MN, Collins PL, Prince GA, Exner M, et al. 2002. A role for immune complexes in enhanced respiratory syncytial virus disease. J. Exp. Med. 196(6):859-65
82. Loebbermann J, Durant L, Thornton H, Johansson C, Openshaw PJ. 2013. Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells. PNAS 110(8):2987-92
83. Krishnamoorthy N, Khare A, Oriss TB, Raundhal M, Morse C, et al. 2012. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18(10):1525-30
84. Loebbermann J, Schnoeller C, Thornton H, Durant L, Sweeney NP, et al. 2012. IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice. PLOS ONE 7(2):e32371
85. Sun L, Cornell TT, LeVine A, Berlin AA, Hinkovska-Galcheva V, et al. 2013. Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation. Clin. Exp. Immunol. 172(2):263-79
86. Weiss KA, Christiaansen AF, Fulton RB, Meyerholz DK, Varga SM. 2011. Multiple CD4+ Tcell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. J. Immunol. 187(6):3145-54
87. Sun J, Cardani A, Sharma AK, Laubach VE, Jack RS, et al. 2011. Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLOS Pathog. 7(8):e1002173
88. Shao HY, Huang JY, Lin YW, Yu SL, Chitra E, 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
89. Nagata DE, Ting HA, Cavassani KA, Schaller MA, Mukherjee S, et al. 2015. Epigenetic control of Foxp3 by SMYD3H3K4histonemethyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal Immunol. 8(5):1131-43
90. Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, 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(9):1040-49
91. Chiu C, Ellebedy AH, Wrammert J, Ahmed R. 2015. B cell responses to influenza infection and vaccination. Curr. Top. Microbiol. Immunol. 386:381-98
92. Couch RB, Kasel JA. 1983. Immunity to influenza in man. Annu. Rev. Microbiol. 37:529-49
93. Barclay WS, al-Nakib W, Higgins PG, Tyrrell DA. 1989. The time course of the humoral immune response to rhinovirus infection. Epidemiol. Infect. 103(3):659-69
94. Agoti CN, Mwihuri AG, Sande CJ, Onyango CO, Medley GF, 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(10):1532-41
95. Hall CB, Walsh EE, Long CE, Schnabel KC. 1991. Immunity to and frequency of reinfection with respiratory syncytial virus. J. Infect. Dis. 163(4):693-98
96. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, et al. 2016. Trained immunity: a program of innate immune memory in health and disease. Science 352(6284):aaf1098
97. Crouse J, Kalinke U, Oxenius A. 2015. Regulation of antiviral T cell responses by type I interferons. Nat. Rev. Immunol. 15(4):231-42
98. Spann KM, Tran KC, Collins PL. 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(9):5353-62
99. Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. 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(8):4363-69. Erratum. 2004. J. Virol. 78(12):6705
100. Ling Z, Tran KC, Teng MN. 2009. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J. Virol. 83(8):3734-42
101. Elliott J, Lynch OT, Suessmuth Y, Qian P, Boyd CR, et al. 2007. Respiratory syncytial virusNS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J. Virol. 81(7):3428-36
102. Whelan JN, Tran KC, van Rossum DB, Teng MN. 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
103. Ren J, Liu T, Pang L, Li K, Garofalo RP, et al. 2011. A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virusNS1 protein. J. Gen. Virol. 92(Part 9):2153-59
104. Krug RM. 2015. Functions of the influenza A virus NS1 protein in antiviral defense. Curr. Opin. Virol. 12:1-6
105. Teijaro JR. 2016. Type I interferons in viral control and immune regulation. Curr. Opin. Virol. 16:31-40
106. Munir S, LeNouen C, Luongo C, Buchholz UJ, Collins PL, Bukreyev A. 2008. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppressmaturation of human dendritic cells. J. Virol. 82(17):8780-96
107. Agarwal P, Raghavan A, Nandiwada SL, Curtsinger JM, Bohjanen PR, 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(3):1695-704
108. Gonzalez PA, Prado CE, Leiva ED, Carreno LJ, Bueno SM, et al. 2008. Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells. PNAS 105(39):14999-5004
109. Rallabhandi P, Phillips RL, Boukhvalova MS, Pletneva LM, Shirey KA, 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(4):e00218-12
110. Oshansky CM, Zhang W, Moore E, Tripp RA. 2009. The host response and molecular pathogenesis associated with respiratory syncytial virus infection. Future Microbiol. 4(3):279-97
111. Chirkova T, Lin S, Oomens AG, Gaston KA, Boyoglu-Barnum S, et al. 2015. CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells. J. Gen. Virol. 96(9):2543-56
112. Jeong KI, Piepenhagen PA, Kishko M, DiNapoli JM, Groppo RP, 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(6):e0130517
113. Moore EC, Barber J, Tripp RA. 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
114. Chirkova T, Boyoglu-Barnum S, Gaston KA, Malik FM, Trau SP, et al. 2013. Respiratory syncytial virus G protein CX3C motif impairs human airway epithelial and immune cell responses. J. Virol. 87(24):13466-79
115. Haynes LM, Caidi H, Radu GU, Miao C, Harcourt JL, 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(3):439-47
116. Cespedes PF, Bueno SM, Ramirez BA, Gomez RS, Riquelme SA, et al. 2014. Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. PNAS 111(31):E3214-23
117. Bosch AA, Biesbroek G, Trzcinski K, Sanders EA, Bogaert D. 2013. Viral and bacterial interactions in the upper respiratory tract. PLOS Pathog. 9(1):e1003057
118. Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH, et al. 2014. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am. J. Respir. Crit. Care Med. 190(3):298-308
119. Biesbroek G, Tsivtsivadze E, Sanders EA, Montijn R, Veenhoven RH, et al. 2014. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am. J. Respir. Crit. Care Med. 190(11):1283-92
120. Pendse M, Hooper LV. 2016. Immunology: Mum's microbes boost baby's immunity. Nature 533(7601):42-43
121. Gomez de Aguero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y, et al. 2016. The maternal microbiota drives early postnatal innate immune development. Science 351(6279): 1296-302
122. Teo SM, Mok D, Pham K, Kusel M, Serralha M, et al. 2015. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell HostMicrobe 17(5):704-15
123. Vissing NH, Chawes BL, Bisgaard H. 2013. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am. J. Respir. Crit. Care Med. 188(10):1246-52
124. Hasegawa K, Linnemann RW, Mansbach JM, Ajami NJ, Espinola JA, et al. 2016. The fecal microbiota profile and bronchiolitis in infants. Pediatrics 138(1):e20160218
125. de Steenhuijsen Piters WA, Heinonen S, Hasrat R, Bunsow E, Smith B, et al. 2016. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 194(9):1104-15
126. Stensballe LG, Hjuler T, Andersen A, Kaltoft M, Ravn H, 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(8):1165-71
127. Stark JM, Stark MA, Colasurdo GN, LeVine AM. 2006. Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection. J. Med. Virol. 78(6):829-38
128. Goulding J, Godlee A, Vekaria S, Hilty M, Snelgrove R, Hussell T. 2011. Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. J. Infect. Dis. 204(7):1086-94
129. Didierlaurent A, Goulding J, Patel S, Snelgrove R, Low L, et al. 2008. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205(2):323-29
130. Mella C, Suarez-Arrabal MC, Lopez S, Stephens J, Fernandez S, et al. 2013. Innate immune dysfunction is associated with enhanced disease severity in infants with severe respiratory syncytial virus bronchiolitis. J. Infect. Dis. 207(4):564-73
131. Garcia C, Soriano-Fallas A, Lozano J, Leos N, Gomez AM, 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(1):86-89
132. Tulic MK, Hurrelbrink RJ, Prele CM, Laing IA, Upham JW, et al. 2007. Tlr4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J. Immunol. 179(1):132-40
133. Mandelberg A, Tal G, Naugolny L, Cesar K, Oron A, 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(1):48-52
134. Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, et al. 2004. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J. Infect. Dis. 189(11):2057-63
135. Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, et al. 2007. Association ofTLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J. Immunol. 179(5):3171-77
136. Paulus SC, Hirschfeld AF, Victor RE, Brunstein J, Thomas E, Turvey SE. 2007. Common human Toll-like receptor 4 polymorphisms-role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin. Immunol. 123(3):252-57
137. Kresfelder TL, Janssen R, Bont L, Pretorius M, Venter M. 2011. Confirmation of an association between single nucleotide polymorphisms in theVDRgene with respiratory syncytial virus related disease in South African children. J. Med. Virol. 83(10):1834-40
138. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, et al. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1(5):398-401
139. Kallal LE, Hartigan AJ, Hogaboam CM, Schaller MA, Lukacs NW. 2010. Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology. J. Immunol. 185(7):4137-47
140. Goritzka M, Pereira C, Makris S, Durant LR, Johansson C. 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
141. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC, et al. 2013. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLOS Med. 10(11):e1001549
142. Marr N, Wang TI, Kam SH, Hu YS, Sharma AA, 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(3):948-57
143. Cormier SA, Shrestha B, Saravia J, Lee GI, Shen L, et al. 2014. Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection. J. Virol. 88(16):9350-60
144. Remot A, Descamps D, Jouneau L, Laubreton D, Dubuquoy C, 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(4):874-84
145. Han J, Dakhama A, Jia Y, Wang M, Zeng W, et al. 2012. Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. J. Allergy Clin. Immunol. 130(5):1175-86.e9
146. Yamaguchi Y, Harker JA, Wang B, Openshaw PJ, Tregoning JS, Culley FJ. 2012. Preexposure to CpG protects against the delayed effects of neonatal respiratory syncytial virus infection. J. Virol. 86(19):10456-61
147. Chu HY, Steinhoff MC, Magaret A, Zaman K, Roy E, et al. 2014. Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh. J. Infect. Dis. 210(10):1582-89
148. Vissers M, Ahout IM, de Jonge MI, Ferwerda G. 2015. Mucosal IgG levels correlate better with respiratory syncytial virus load and inflammation than plasma IgG levels. Clin. Vaccine Immunol. 23(3):243-45
149. Ogilvie MM, Vathenen AS, Radford M, Codd J, Key S. 1981. Maternal antibody and respiratory syncytial virus infection in infancy. J. Med. Virol. 7(4):263-71
150. Glezen WP, Paredes A, Allison JE, Taber LH, Frank AL. 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(5):708-15
151. Ochola R, Sande C, Fegan G, Scott PD, Medley GF, et al. 2009. The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya. PLOS ONE 4(12):e8088
152. Piedra PA, Jewell AM, Cron SG, Atmar RL, Glezen WP. 2003. Correlates of immunity to respiratory syncytial virus (RSV) associated-hospitalization: establishment of minimum protective threshold levels of serum neutralizing antibodies. Vaccine 21(24):3479-82
153. Stensballe LG, Ravn H, Kristensen K, Agerskov K, Meakins T, et al. 2009. Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. J. Allergy Clin. Immunol. 123(2):398-403
154. Nyiro JU, Sande C, Mutunga M, Kiyuka PK, Munywoki PK, et al. 2015. Quantifyingmaternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya. Vaccine 33(15):1797-801
155. Dunn SR, Ryder AB, Tollefson SJ, Xu M, Saville BR, Williams JV. 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(10):1654-56
156. De Sierra TM, Kumar ML, Wasser TE, Murphy BR, Subbarao EK. 1993. Respiratory syncytial virusspecific immunoglobulins in preterm infants. J. Pediatr. 122(5 Part 1):787-91
157. Okoko BJ, Wesumperuma LH, Ota MO, Pinder M, Banya W, et al. 2001. The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a ruralWest African population. J. Infect. Dis. 184(5):627-32
158. Atwell JE, Thumar B, Robinson LJ, Tobby R, Yambo P, 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(3):423-31
159. McIntosh K, McQuillin J, Gardner PS. 1979. Cell-free and cell-bound antibody in nasal secretions from infants with respiratory syncytial virus infection. Infect. Immun. 23(2):276-81
160. McIntosh K, Masters HB, Orr I, Chao RK, Barkin RM. 1978. The immunologic response to infection with respiratory syncytial virus in infants. J. Infect. Dis. 138(1):24-32
161. Sande CJ, Cane PA, Nokes DJ. 2014. The association between age and the development of respiratory syncytial virus neutralising antibody responses following natural infection in infants. Vaccine 32(37):4726-29
162. Shinoff JJ, O'Brien KL, Thumar B, Shaw JB, Reid R, et al. 2008. Young infants can develop protective levels of neutralizing antibody after infection with respiratory syncytial virus. J. Infect. Dis. 198(7):1007-15
163. Williams JV, Weitkamp JH, Blum DL, LaFleur BJ, Crowe JE. 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(2-3):407-14
164. Ohuma EO, Okiro EA, Ochola R, Sande CJ, Cane PA, 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(9):794-802
165. Sande CJ, Mutunga MN, Okiro EA, Medley GF, Cane PA, Nokes DJ. 2013. Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort. J. Med. Virol. 85(11):2020-25
166. Murphy BR, Alling DW, Snyder MH, Walsh EE, Prince GA, 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(5):894-98
167. Kanswal S, Katsenelson N, Selvapandiyan A, Bram RJ, Akkoyunlu M. 2008. Deficient TACI expression on B lymphocytes of newborn mice leads to defective Ig secretion in response to BAFF or APRIL. J. Immunol. 181(2):976-90
168. Reed JL, Welliver TP, Sims GP, McKinney L, Velozo L, et al. 2009. Innate immune signals modulate antiviral and polyreactive antibody responses during severe respiratory syncytial virus infection. J. Infect. Dis. 199(8):1128-138
169. Tregoning JS, Wang BL, McDonald JU, Yamaguchi Y, Harker JA, et al. 2013. Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection. PNAS 110(14):5576-81
170. McNamara PS, Ritson P, Selby A, Hart CA, Smyth RL. 2003. Bronchoalveolar lavage cellularity in infants with severe respiratory syncytial virus bronchiolitis. Arch. Dis. Child 88(10):922-26
171. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, et al. 2009. Neonatal innate TLRmediated responses are distinct from those of adults. J. Immunol. 183(11):7150-60
172. Legg JP, Hussain IR, Warner JA, Johnston SL, Warner JO. 2003. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis. Am. J. Respir. Crit. Care Med. 168(6):633-39
173. Aberle JH, Aberle SW, Dworzak MN, Mandl CW, Rebhandl W, 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(4):1263-68
174. Kristjansson S, Bjarnarson SP, Wennergren G, Palsdottir AH, Arnadottir T, 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(4):805-11
175. Semple MG, Dankert HM, Ebrahimi B, Correia JB, Booth JA, et al. 2007. Severe respiratory syncytial virus bronchiolitis in infants is associated with reduced airway interferon gamma and substance P. PLOS ONE 2(10):e1038
176. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, et al. 2000. Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year followup study. Am. J. Respir. Crit. Care Med. 161(5):1518-23
177. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, et al. 2001. Local interferon-gamma levels during respiratory syncytial virus lower respiratory tract infection are associated with disease severity. J. Infect. Dis. 184(3):355-58
178. Hoebee B, Bont L, Rietveld E, van Oosten M, Hodemaekers HM, et al. 2004. Influence of promoter variants of interleukin-10, interleukin-9, and tumor necrosis factor-aa genes on respiratory syncytial virus bronchiolitis. J. Infect. Dis. 189(2):239-47
179. Hoebee B, Rietveld E, Bont L, Oosten MV, Hodemaekers HM, et al. 2003. Association of severe respiratory syncytial virus bronchiolitis with interleukin-4 and interleukin-4 receptor apolymorphisms. J. Infect. Dis. 187(1):2-11
180. Ermers MJ, Hoebee B, Hodemaekers HM, Kimman TG, Kimpen JL, Bont L. 2007. IL-13 genetic polymorphism identifies children with late wheezing after respiratory syncytial virus infection. J. Allergy Clin. Immunol. 119(5):1086-91
181. Fonceca AM, Flanagan BF, Trinick R, Smyth RL, McNamara PS. 2012. Primary airway epithelial cultures from children are highly permissive to respiratory syncytial virus infection. Thorax 67(1):42-48
182. Villenave R, Thavagnanam S, Sarlang S, Parker J, Douglas I, et al. 2012. In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo. PNAS 109(13):5040-45
183. Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K, 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
184. Lee HC, Headley MB, Loo YM, Berlin A, Gale M, 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(5):1187-96.e5
185. Yang SH, Chu MA, Park HJ, Lee KH, Kim WT, Chung HL. 2012. Increased nasal interleukin-33 in the infants with acute respiratory syncytial virus bronchiolitis. Pediatr. Allergy Respir. Dis. 22(4):383
186. Culley FJ, Pollott J, Openshaw PJ. 2002. Age at first viral infection determines the pattern of T cellmediated disease during reinfection in adulthood. J. Exp. Med. 196(10):1381-86
187. Saravia J, You D, Shrestha B, Jaligama S, Siefker D, et al. 2015. Respiratory syncytial virus disease is mediated by age-variable IL-33. PLOS Pathog. 11(10):e1005217
188. Faber TE, Schuurhof A, Vonk A, Koppelman GH, Hennus MP, et al. 2012. IL1RLl gene variants and nasopharyngeal IL1RL-alpha levels are associated with severe RSV bronchiolitis: a multicenter cohort study. PLOS ONE 7(5):e34364
189. Geerdink RJ, Pillay J, Meyaard L, Bont L. 2015. Neutrophils in respiratory syncytial virus infection: a target for asthma prevention. J. Allergy Clin. Immunol. 136(4):838-47
190. Stoppelenburg AJ, de Roock S, Hennus MP, Bont L, Boes M. 2014. Elevated Th17 response in infants undergoing respiratory viral infection. Am. J. Pathol. 184(5):1274-79
191. Stoppelenburg AJ, Salimi V, Hennus M, Plantinga M, Huis in't Veld R, et al. 2013. Local IL-17a potentiates early neutrophil recruitment to the respiratory tract during severe RSV infection. PLOS ONE 8(10):e78461
192. Lukens MV, van de Pol AC, Coenjaerts FE, Jansen NJ, Kamp VM, et al. 2010. A systemic neutrophil response precedes robust CD8+ T-cell activation during natural respiratory syncytial virus infection in infants. J. Virol. 84(5):2374-83
193. McNamara PS, Flanagan BF, Baldwin LM, Newland P, Hart CA, Smyth RL. 2004. Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet 363(9414):1031-37
194. Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC, et al. 2010. Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls. Pediatr. Pulmonol. 45(6):608-13
195. Dodd JS, Lum E, Goulding J, Muir R, Van Snick J, Openshaw PJ. 2009. IL-9 regulates pathology during primary and memory responses to respiratory syncytial virus infection. J. Immunol. 183(11):7006-13
196. Raiden S, Pandolfi J, Payaslian F, Anderson M, Rivarola N, 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(7):865-68
197. Korppi M, Nuolivirta K, Lauhkonen E, Holster A, Terasjarvi J, et al. 2017. IL-10 gene polymorphism is associated with preschool atopy and early-life recurrent wheezing after bronchiolitis in infancy. Pediatr. Pulmonol. 52(1):14-20
198. Ruckwardt TJ, Malloy AM, Morabito KM, Graham BS. 2014. Quantitative and qualitative deficits in neonatal lung-migratory dendritic cells impact the generation of theCD8+ Tcell response. PLOS Pathog. 10(2):e1003934
199. Ruckwardt TJ, Malloy AM, Gostick E, Price DA, Dash P, 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(12):e1002377
200. PrabhuDas M, Adkins B, Gans H, King C, Levy O, et al. 2011. Challenges in infant immunity: implications for responses to infection and vaccines. Nat. Immunol. 12(3):189-94
201. Sumino K, Tucker J, Shahab M, Jaffee KF, Visness CM, 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(5):1267-73.e1
202. De Almeida Nagata DE, Demoor T, Ptaschinski C, Ting HA, Jang S, et al. 2014. IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis. Am. J. Pathol. 184(6):1807-18
203. Dakhama A, Park JW, Taube C, Joetham A, Balhorn A, 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(3):1876-83
204. Tregoning JS, Yamaguchi Y, Harker J, Wang B, Openshaw PJ. 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(8):4115-24
205. You D, Saravia J, Siefker D, Shrestha B, Cormier SA. 2016. Crawling with virus: translational insights from a neonatal mouse model on the pathogenesis of respiratory syncytial virus in infants. J. Virol. 90(1):2-4
206. Harker JA, Yamaguchi Y, Culley FJ, Tregoning JS, Openshaw PJ. 2014. Delayed sequelae of neonatal respiratory syncytial virus infection are dependent on cells of the innate immune system. J. Virol. 88(1):604-11
207. Lee YM, Miyahara N, Takeda K, Prpich J, Oh A, 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(2):208-18
208. Eichinger KM, Egana L, Orend JG, Resetar E, Anderson KB, et al. 2015. Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice. Respir. Res. 16:122
209. Harker JA, Lee DC, Yamaguchi Y, Wang B, Bukreyev A, et al. 2010. Delivery of cytokines by recombinant virus in early life alters the immune response to adult lung infection. J. Virol. 84(10):5294-302
210. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, et al. 2013. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N. Engl. J. Med. 368(19):1791-99
211. O'Brien KL, Chandran A, Weatherholtz R, Jafri HS, Griffin MP, 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(12):1398-408
212. Pala P, Bjarnason R, Sigurbergsson F, Metcalfe C, Sigurs N, Openshaw PJ. 2002. Enhanced IL-4 responses in children with a history of respiratory syncytial virus bronchiolitis in infancy. Eur. Respir. J. 20(2):376-82
213. Van der Sande MA, Kidd IM, Goetghebuer T, Martynoga RA, Magnusen A, 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(10):1430-35
214. Schauer U, Hoffjan S, Rothoeft T, Bartz H, Konig S, et al. 2004. Severe respiratory syncytial virus infections and reduced interferon-gamma generation in vitro. Clin. Exp. Immunol. 138(1):102-9
215. Renzi PM, Turgeon JP, Yang JP, Drblik SP, Marcotte JE, et al. 1997. Cellular immunity is activated and a Th-2 response is associated with early wheezing in infants after bronchiolitis. J. Pediatr. 130(4):584-93
216. Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL. 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(1):70-76
217. Schuurhof A, Janssen R, de Groot H, Hodemaekers HM, de Klerk A, et al. 2011. Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze. Respir. Res. 12:121
218. Ermers MJ, Janssen R, Onland-Moret NC, Hodemaekers HM, Rovers MM, et al. 2011. IL10 family member genes IL19 and IL20 are associated with recurrent wheeze after respiratory syncytial virus bronchiolitis. Pediatr. Res. 70(5):518-23
219. Eberl G. 2016. Immunity by equilibrium. Nat. Rev. Immunol. 16(8):524-32
220. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, et al. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289(2):179-86
221. Fleming DM, Taylor RJ, Lustig RL, Schuck-Paim C, Haguinet F, 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
222. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. 2005. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352(17):1749-59
223. Falsey AR, McElhaney JE, Beran J, van Essen GA, Duval X, 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(12):1873-81
224. Walsh EE, Peterson DR, Falsey AR. 2004. Risk factors for severe respiratory syncytial virus infection in elderly persons. J. Infect. Dis. 189(2):233-38
225. Duncan CB, Walsh EE, Peterson DR, Lee FE, Falsey AR. 2009. Risk factors for respiratory failure associated with respiratory syncytial virus infection in adults. J. Infect. Dis. 200(8):1242-46
226. Lee N, Lui GC, Wong KT, Li TC, Tse EC, et al. 2013. High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin. Infect. Dis. 57(8):1069-77
227. Lee N, Chan MC, Lui GC, Li R, Wong RY, et al. 2015. High viral load and respiratory failure in adults hospitalized for respiratory syncytial virus infections. J. Infect. Dis. 212(8):1237-40
228. Malloy AM, Falsey AR, Ruckwardt TJ. 2013. Consequences of immature and senescent immune responses for infection with respiratory syncytial virus. Curr. Top. Microbiol. Immunol. 372:211-31
229. Kollmann TR, Levy O, Montgomery RR, Goriely S. 2012. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37(5):771-83
230. Shaw AC, Goldstein DR, Montgomery RR. 2013. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13(12):875-87
231. Pillai PS, Molony RD, Martinod K, Dong H, Pang IK, et al. 2016. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352(6284):463-66
232. Boraschi D, Aguado MT, Dutel C, Goronzy J, Louis J, et al. 2013. The gracefully aging immune system. Sci. Transl. Med. 5(185):185ps8
233. Looney RJ, Falsey AR, Walsh E, Campbell D. 2002. Effect of aging on cytokine production in response to respiratory syncytial virus infection. J. Infect. Dis. 185(5):682-85
234. Cherukuri A, Patton K, Gasser RA, Zuo F, Woo J, et al. 2013. Adults 65 years old and older have reduced numbers of functionalmemoryTcells to respiratory syncytial virus fusion protein. Clin. Vaccine Immunol. 20(2):239-47
235. Cusi MG, Martorelli B, Di Genova G, Terrosi C, Campoccia G, Correale P. 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
236. Zhang Y, Wang Y, Gilmore X, Xu K, Wyde PR, Mbawuike IN. 2002. An aged mouse model for RSV infection and diminished CD8+ CTL responses. Exp. Biol. Med. 227(2):133-40
237. Wong TM, Boyapalle S, Sampayo V, Nguyen HD, Bedi R, et al. 2014. Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology. PLOS ONE 9(2):e88764
238. Fulton RB, Weiss KA, Pewe LL, Harty JT, Varga SM. 2013. Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection. J. Virol. 87(23):12694-700
239. Falsey AR, Walsh EE. 1998. Relationship of serum antibody to risk of respiratory syncytial virus infection in elderly adults. J. Infect. Dis. 177(2):463-66
240. Luchsinger V, Piedra PA, Ruiz M, Zunino E, Martinez MA, et al. 2012. Role of neutralizing antibodies in adults with community-acquired pneumonia by respiratory syncytial virus. Clin. Infect. Dis. 54(7):905-12
241. Walsh EE, Falsey AR. 2004. Age related differences in humoral immune response to respiratory syncytial virus infection in adults. J. Med. Virol. 73(2):295-99
242. Agius G, Dindinaud G, Biggar RJ, Peyre R, Vaillant V, et al. 1990. An epidemic of respiratory syncytial virus in elderly people: clinical and serological findings. J. Med. Virol. 30(2):117-27
243. Murata Y, Lightfoote PM, Biear JN, Falsey AR, Walsh EE. 2010. Humoral response to the central unglycosylated region of the respiratory syncytial virus attachment protein. Vaccine 28(38):6242-46
244. Siegrist CA, Aspinall R. 2009. B-cell responses to vaccination at the extremes of age. Nat. Rev. Immunol. 9(3):185-94
245. Mohr E, Siegrist CA. 2016. Vaccination in early life: standing up to the challenges. Curr. Opin. Immunol. 41:1-8
246. Anderson LJ, Dormitzer PR, Nokes DJ, Rappuoli R, Roca A, Graham BS. 2013. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine 31(Suppl. 2):B209-15
247. Widjaja I, Wicht O, Luytjes W, Leenhouts K, Rottier PJ, et al. 2016. Characterization of epitopespecific anti-respiratory syncytial virus (anti-RSV) antibody responses after natural infection and after vaccination with formalin-inactivated RSV. J. Virol. 90(13):5965-77
248. Munoz FM. 2015. Respiratory syncytial virus in infants: Ismaternal vaccination a realistic strategy? Curr. Opin. Infect. Dis. 28(3):221-24
249. Anderson LJ. 2013. Respiratory syncytial virus vaccine development. Semin. Immunol. 25(2):160-71
250. Kachikis A, Englund JA. 2016. Maternal immunization: optimizing protection for themother and infant. J. Infect. 72(Suppl.):S83-90
251. Munoz F. 2003. Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant women. Vaccine 21(24):3465-67
252. Brandt C, Power UF, Plotnicky-Gilquin H, Huss T, Nguyen T, et al. 1997. Protective immunity against respiratory syncytial virus in early life aftermurinematernal or neonatal vaccinationwith the recombinant G fusion protein BBG2Na. J. Infect. Dis. 176(4):884-91
253. Sharma A, Wendland R, Sung B, Wu W, Grunwald T, Worgall S. 2014. Maternal immunization with chimpanzee adenovirus expressing RSV fusion protein protects against neonatal RSV pulmonary infection. Vaccine 32(43):5761-68
254. Graham BS. 2016. Vaccines against respiratory syncytial virus: The time has finally come. Vaccine 34(30):3535-41
255. Meijboom MJ, Pouwels KB, Luytjes W, Postma MJ, Hak E. 2013. RSV vaccine in development: assessing the potential cost-effectiveness in the Dutch elderly population. Vaccine 31(52):6254-60
256. Del Giudice G, Weinberger B, Grubeck-Loebenstein B. 2015. Vaccines for the elderly. Gerontology 61(3):203-10
257. Valkenburg SA, Venturi V, Dang TH, Bird NL, Doherty PC, et al. 2012. Early priming minimizes the age-related immune compromise of CD8+ T cell diversity and function. PLOS Pathog. 8(2):e1002544