title: Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children.
abstract: Newborn infants, including those born at term without congenital disorders, are at high risk of severe disease from respiratory syncytial virus (RSV) infection. Indeed, our current local surveillance data demonstrate that approximately half of children hospitalized with RSV were ≤3 mo old, and 74% were born at term. Informed by this clinical epidemiology, we investigated antiviral innate immune responses in early life, with the goal of identifying immunological factors underlying the susceptibility of infants and young children to severe viral lower respiratory tract infections. We compared RSV-induced innate cytokine production in blood mononuclear cells from neonates, young children aged 12-59 mo, and healthy adults. RSV-induced IFN-α production was primarily mediated by plasmacytoid dendritic cells (pDCs), and was significantly lower in term infants and young children < 5 y of age than in adults (p < 0.01). RSV-induced IFN-α production in human pDCs proceeded independently of endosomal TLRs, and human pDCs from healthy adult donors produced IFN-α in a retinoic acid-inducible gene I protein (RIG-I)-dependent manner. Of interest, young age and premature birth were independently associated with attenuated RIG-I-dependent IFN-α responses (p < 0.01). In contrast to IFN-α production, proinflammatory IL-6 responses to RSV were mediated by monocytes, appeared less dependent on RIG-I, and were significantly impaired only among preterm infants, not in term infants and young children. Our results suggest that human pDCs are less functional in early life, which may contribute to the increased susceptibility of infants and young children to severe RSV disease.
authors.affiliation: Department of Pediatrics, University of British Columbia and Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia V6H 3V4, Canada.
authors.forename: Nico
authors.initials: N
authors.lastname: Marr
authors.forename: Ting-I
authors.initials: TI
authors.lastname: Wang
authors.forename: Sarah H Y
authors.initials: SH
authors.lastname: Kam
authors.forename: Yuan Shen
authors.initials: YS
authors.lastname: Hu
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Sharma
authors.forename: Angie
authors.initials: A
authors.lastname: Lam
authors.forename: Joy
authors.initials: J
authors.lastname: Markowski
authors.forename: Alfonso
authors.initials: A
authors.lastname: Solimano
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Lavoie
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D000328:Adult; D000375:Aging / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004198:Disease Susceptibility; D011992:Endosomes / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D007231:Infant, Newborn / Q000276:immunology*; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000276:immunology*; D007297:Inpatients; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic; D018357:Respiratory Syncytial Virus Infections / Q000453:epidemiology / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases