Abstract
BackgroundCell-to-cell variability in mRNA and proteins has been observed in many biological systems, including the human innate immune response to viral infection. Most of these studies have focused on variability that arises from (a) intrinsic stochastic fluctuations in gene expression and (b) extrinsic sources (e.g. fluctuations in transcription factors). The main focus of our study is the effect of extracellular signaling on enhancing intrinsic stochastic fluctuations. As a new source of noise, the communication between cells with fluctuating numbers of components has received little attention. We use agent-based modeling to study this contribution to noise in a system of human dendritic cells responding to viral infection.ResultsOur results, validated by single-cell experiments, show that in the transient state cell-to-cell variability in an interferon-stimulated gene (DDX58) arises from the interplay between the spatial randomness of the cellular sources of the interferon and the temporal stochasticity of its own production. The numerical simulations give insight into the time scales on which autocrine and paracrine signaling act in a heterogeneous population of dendritic cells upon viral infection. We study the effect of different factors that influence the magnitude of the cell-to-cell-variability of the induced gene, including the cell density, multiplicity of infection, and the time scale over which the cellular sources begin producing the cytokine.ConclusionsWe propose a mechanism of noise propagation through extracellular communication and establish conditions under which the mechanism is operative. The cellular stochasticity of gene induction, which we investigate, is not limited to the specific interferon-induced gene we have studied; a broad distribution of copy numbers across cells is to be expected for other interferon-stimulated genes. This can lead to functional consequences for the system-level response to a viral challenge.
Highlights
Cell-to-cell variability in mRNA and proteins has been observed in many biological systems, including the human innate immune response to viral infection
Our investigation is motivated by our previous experimental work on the innate immune response of dendritic cells (DCs) to viral infection, which showed large cell-to-cell variability of IFN-β mRNA [10] as well as of DDX58 [18], a gene induced as a result of interferon secretion and cognate receptor binding
We describe the results of our simulation of the effect of extracellular signaling on noise with reference to the experimental measurements in Newcastle disease virus (NDV) infected DCs [18,20]
Summary
Cell-to-cell variability in mRNA and proteins has been observed in many biological systems, including the human innate immune response to viral infection Most of these studies have focused on variability that arises from (a) intrinsic stochastic fluctuations in gene expression and (b) extrinsic sources (e.g. fluctuations in transcription factors). The question arises whether the broad, non-Poisson experimental distribution of DDX58 is related to the temporally sporadic IFN-β production At first glance this seems unlikely, because in the extracellular medium, homogenization of secreted cytokines is expected to occur. Our work shows that there is a period of approximately 10 hours where the spatial heterogeneity of infection (only a fraction of cells is infected) and the temporal stochasticity of interferon induction create an environment where genes induced by interferon signaling are very noisy as well
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