title: Single-cell analysis shows that paracrine signaling by first responder cells shapes the interferon-β 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.
authors: Department of Neurology and Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Sonali
authors: S
authors: Patil
authors: Department of Neurology and Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Miguel
authors: M
authors: Fribourg
authors: Department of Neurology and Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Yongchao
authors: Y
authors: Ge
authors: Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
authors: Mona
authors: M
authors: Batish
authors: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
authors: Sanjay
authors: S
authors: Tyagi
authors: Department of Neurology and Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Fernand
authors: F
authors: Hayot
authors: Department of Neurology and Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. stuart.sealfon@mssm.edu.
authors: Stuart C
authors: SC
authors: Sealfon
mesh_terms: D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D008954:Models, Biological; D009522:Newcastle disease virus / Q000502:physiology*; D019899:Paracrine Communication / Q000276:immunology*; D059010:Single-Cell Analysis; D014779:Virus Replication
chemical_list: D016899:Interferon-beta