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

Marcel A. Schijf, Michael V. Lukens, Debby Kruijsen, Nathalie O. P. van Uden, Johan Garssen, Frank E. J. Coenjaerts, Belinda van't Land, Grada M. van Bleek*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Scopus)
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Abstract

Innate immune responses elicited upon virus exposure are crucial for the effective eradication of viruses, the onset of adaptive immune responses and for establishing proper immune memory. Respiratory syncytial virus (RSV) is responsible for a high disease burden in neonates and immune compromised individuals, causing severe lower respiratory tract infections. During primary infections exuberant innate immune responses may contribute to disease severity. Furthermore, immune memory is often insufficient to protect during RSV re-exposure, which results in frequent symptomatic reinfections. Therefore, identifying the cell types and pattern recognition receptors (PRRs) involved in RSV-specific innate immune responses is necessary to understand incomplete immunity against RSV. We investigated the innate cellular response triggered upon infection of epithelial cells and peripheral blood mononuclear cells. We show that CD14(+) myeloid cells and epithelial cells are the major source of IL-8 and inflammatory cytokines, IL-6 and TNF-alpha, when exposed to live RSV Three routes of RSV-induced IFN-alpha production can be distinguished that depend on the cross-talk of different cell types and the presence or absence of virus specific antibodies, whereby pDC are the ultimate source of IFN-alpha. RSV-specific antibodies facilitate direct TLR7 access into endosomal compartments, while in the absence of antibodies, infection of monocytes or epithelial cells is necessary to provide an early source of type I interferons, required to engage the IFN-alpha,beta receptor (IFNAR)-mediated pathway of IFN-alpha production by pDC. However, at high pDC density infection with RSV causes IFN-alpha production without the need for a second party cell. Our study shows that cellular context and immune status are factors affecting innate immune responses to RSV. These issues should therefore be addressed during the process of vaccine development and other interventions for RSV disease.

Original languageEnglish
Article numbere81695
Number of pages18
JournalPLoS ONE
Volume8
Issue number11
DOIs
Publication statusPublished - 26-Nov-2013
Externally publishedYes

Keywords

  • PLASMACYTOID DENDRITIC CELLS
  • TOLL-LIKE RECEPTORS
  • NF-KAPPA-B
  • PATTERN-RECOGNITION RECEPTORS
  • INNATE IMMUNITY
  • RIG-I
  • PROINFLAMMATORY CYTOKINES
  • NONSTRUCTURAL PROTEINS
  • ANTIVIRAL RESPONSES
  • INDUCED ACTIVATION

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