Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America.
PLoS One. 2011 Feb 8;6(2):e16614. doi: 10.1371/journal.pone.0016614.
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.
在新城疫病毒感染人单核细胞来源的树突状细胞的最初几个小时内，IFNβ1 的诱导非常低，分泌型 I 型干扰素反应低于 ELISA 检测限。然而，此时许多干扰素诱导基因被激活，例如 DDX58（RIGI），它响应病毒 RNA 诱导 IFNβ1。我们研究了感染细胞中只有一小部分早期诱导 IFNβ1 是否会导致低水平 IFN 分泌，然后诱导所有细胞中 IFN 反应基因。我们开发了基于代理的数学模型来探索 IFNβ1 和 DDX58 的时间动态。模拟表明，少数早期反应细胞为 DDX58-IFNβ1 正反馈回路的有效和受控激活提供了一种机制。该模型预测了单细胞反应的分布，这些分布通过单细胞 mRNA 测量得到了证实。结果表明，大的细胞间变异性在早期固有免疫反应中起着重要作用，这种变异性对于基于 IFNβ1 的反馈回路的有效激活是必不可少的。
