Research ArticleImmunology

Single-cell analysis shows that paracrine signaling by first responder cells shapes the interferon-β response to viral infection

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Sci. Signal.  10 Feb 2015:
Vol. 8, Issue 363, pp. ra16
DOI: 10.1126/scisignal.2005728

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Taking the time to respond

One of the earliest responses of cells to viral infection is expression of the gene encoding interferon-β (Ifnb1). Within a population of cells exposed to virus, the overall immune response is shaped by the percentage of cells that become infected, the proportion of those infected cells that initially express Ifnb1, and the extent of Ifnb1 expression per cell. Patil et al. used single-cell imaging to quantify the amounts of Ifnb1 and viral mRNAs in infected human dendritic cells over time. Mathematical simulations of viral infection indicated that differences in the timing of Ifnb1 induction in individual cells contributed to the dynamics of the population. Indeed, further experiments showed that the earliest responders released paracrine signals that controlled the timing of the antiviral response of the remaining cells within the population. These results have implications for understanding how individual immune cells coordinate the extent of the immune response to viral infection.

Abstract

Immune responses to viral infection are stochastic processes, which initiate in a limited number of cells that then propagate the response. A key component of the response to viral infection entails the synthesis and secretion of type I interferons (IFNs), including the early induction of the gene encoding IFN-β (Ifnb1). With single-cell analysis and mathematical modeling, we investigated the mechanisms underlying how increases in the amount of Ifnb1 mRNA per cell and in the numbers of cells expressing Ifnb1 calibrate the response to viral infection. We used single-cell, single-molecule assays to quantify the early induction of Ifnb1 expression (the Ifnb1 response) in human monocyte-derived dendritic cells infected with Newcastle disease virus, thus retaining the physiological stoichiometry of transcriptional regulators to both alleles of the Ifnb1 gene. We applied computational methods to extract the stochastic features that underlie the cell-to-cell variations in gene expression over time. Integration of simulations and experiments identified the role of paracrine signaling in increasing the number of cells that express Ifnb1 over time and in calibrating the immune response to viral infection.

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