title: Role of cell-to-cell variability in activating a positive feedback antiviral response in human dendritic cells.
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.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Hu
authors.forename: German
authors.initials: G
authors.lastname: Nudelman
authors.forename: Yishai
authors.initials: Y
authors.lastname: Shimoni
authors.forename: Madhu
authors.initials: M
authors.lastname: Kumar
authors.forename: Yaomei
authors.initials: Y
authors.lastname: Ding
authors.forename: Carolina
authors.initials: C
authors.lastname: López
authors.forename: Fernand
authors.initials: F
authors.lastname: Hayot
authors.forename: James G
authors.initials: JG
authors.lastname: Wetmur
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D018448:Models, Immunological; D009000:Monocytes / Q000166:cytology; D009522:Newcastle disease virus / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D013269:Stochastic Processes
chemical_list: D012333:RNA, Messenger; D011971:Receptors, Immunologic; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases