Role of cell-to-cell variability in activating a positive feedback antiviral response in human dendritic cells

PLoS One. 2011 Feb 8;6(2):e16614. doi: 10.1371/journal.pone.0016614.

Abstract

In the first few hours following Newcastle disease viral infection of human monocyte-derived dendritic cells, the induction of IFNB1 is extremely low and the secreted type I interferon response is below the limits of ELISA assay. However, many interferon-induced genes are activated at this time, for example DDX58 (RIGI), which in response to viral RNA induces IFNB1. We investigated whether the early induction of IFNBI in only a small percentage of infected cells leads to low level IFN secretion that then induces IFN-responsive genes in all cells. We developed an agent-based mathematical model to explore the IFNBI and DDX58 temporal dynamics. Simulations showed that a small number of early responder cells provide a mechanism for efficient and controlled activation of the DDX58-IFNBI positive feedback loop. The model predicted distributions of single cell responses that were confirmed by single cell mRNA measurements. The results suggest that large cell-to-cell variation plays an important role in the early innate immune response, and that the variability is essential for the efficient activation of the IFNB1 based feedback loop.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology*
  • Feedback, Physiological*
  • Gene Expression Regulation / immunology
  • Humans
  • Immunity, Innate
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Models, Immunological*
  • Monocytes / cytology
  • Newcastle disease virus / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stochastic Processes

Substances

  • RNA, Messenger
  • Interferon-beta
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases