Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children

Nico Marr, Ting I. Wang, Sarah H.Y. Kam, Yuan Shen Hu, Ashish A. Sharma, Angie Lam, Joy Markowski, Alfonso Solimano, Pascal M. Lavoie, Stuart E. Turvey

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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 L3 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-A 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-A production in human pDCs proceeded independently of endosomal TLRs, and human pDCs from healthy adult donors produced IFN-A 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-A responses (p <0.01). In contrast to IFN-A 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.

Original languageEnglish
Pages (from-to)948-957
Number of pages10
JournalJournal of Immunology
Volume192
Issue number3
DOIs
Publication statusPublished - 1 Feb 2014

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Marr, N., Wang, T. I., Kam, S. H. Y., Hu, Y. S., Sharma, A. A., Lam, A., Markowski, J., Solimano, A., Lavoie, P. M., & Turvey, S. E. (2014). Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children. Journal of Immunology, 192(3), 948-957. https://doi.org/10.4049/jimmunol.1302007