Role of Cell-to-Cell Variability in Activating a Positive Feedback Antiviral Response in Human Dendritic Cells

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.在人单核细胞衍生树突状细胞（human monocyte-derived dendritic cells）感染新城疫病毒（Newcastle disease virus）后的最初数小时内，IFNB1的诱导水平极低，且分泌的I型干扰素（type I interferon）响应低于酶联免疫吸附测定（ELISA）的检测下限。但此时已有诸多干扰素诱导基因被激活，例如DDX58（RIGI）——该基因可通过识别病毒RNA诱导IFNB1的表达。我们探究了仅少量受感染细胞早期诱导IFNB1，是否会导致干扰素分泌水平偏低，进而促使所有细胞激活干扰素响应基因。为此，我们构建了基于智能体的数学模型（agent-based mathematical model），以分析IFNB1与DDX58的时间动态变化。模拟结果显示，少量早期应答细胞可为DDX58-IFNB1正反馈环路的高效可控激活提供机制支撑。该模型预测的单细胞响应分布，经单细胞mRNA检测得到了实验验证。研究结果表明，细胞间显著的异质性在早期固有免疫应答中发挥关键作用，且这种异质性对于基于IFNB1的正反馈环路的高效激活不可或缺。