Department of Pediatrics, Radboud University Medical Centre, Nijmegen, Netherlands.
Eur J Immunol. 2012 Oct;42(10):2727-35. doi: 10.1002/eji.201242396. Epub 2012 Aug 20.
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, with remarkable variability in disease severity. An exaggerated proinflammatory response and influx of leukocytes is part of the pathogenesis of severe RSV disease. Here, we show an increase in proinflammatory cytokine production by human immune cells after stimulation with RSV and muramyl dipeptide (MDP), which is recognized by nucleotide-binding oligomerization domain containing 2 (NOD2). PBMCs from Crohn's disease patients homozygous for the 3020insC mutation in the NOD2 gene did not show a synergistic response to stimulation with RSV and MDP, suggesting that NOD2 is essential for the observed synergy. Further experiments aimed at identifying the viral ligand indicated that viral RNA plays an essential role in the recognition of RSV. Stimulation with RSV or Poly(I:C) induced IFN-β expression, which resulted in an increased expression of the viral receptors TLR3 and RIG-I, as well as an increased NOD2 expression. Our data indicate that IFN-β induction by viral RNA is an essential first step in the increased proinflammatory response to MDP. We hypothesize that the enhanced proinflammatory response to MDP following RSV infection may be an important factor in determining the outcome of the severity of disease.
呼吸道合胞病毒（RSV）是导致婴儿下呼吸道感染的主要原因，其疾病严重程度的差异很大。过度的促炎反应和白细胞浸润是严重 RSV 疾病发病机制的一部分。在这里，我们显示人类免疫细胞在受到 RSV 和 muramyl dipeptide（MDP）刺激后产生促炎细胞因子的增加，MDP 被核苷酸结合寡聚结构域包含 2（NOD2）识别。来自 NOD2 基因 3020insC 突变纯合子的克罗恩病患者的 PBMC 对 RSV 和 MDP 的刺激没有表现出协同反应，表明 NOD2 对于观察到的协同作用是必需的。进一步旨在确定病毒配体的实验表明，病毒 RNA 在 RSV 的识别中起关键作用。用 RSV 或 Poly(I:C) 刺激诱导 IFN-β 的表达，导致病毒受体 TLR3 和 RIG-I 的表达增加，以及 NOD2 的表达增加。我们的数据表明，病毒 RNA 诱导的 IFN-β 是对 MDP 产生增强的促炎反应的必要的第一步。我们假设 RSV 感染后对 MDP 的增强的促炎反应可能是决定疾病严重程度结果的重要因素。
