1 MRC Laboratory of Molecular Biology, Cambridge, UK.
2 Department of Haematology, 2153 Cambridge University Hospitals NHS Foundation Trust , Cambridge, UK.
Innate Immun. 2018 Feb;24(2):112-121. doi: 10.1177/1753425918757898. Epub 2018 Feb 12.
Viral infection is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT), with up to one in four deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post-HSCT, the innate antiviral immune response is the first line of defense against invading viruses. Several novel innate viral-sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analyzed a panel of innate viral-sensor genes in HSCT patients, and assessed whether differences in innate antiviral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patients without active infections and healthy volunteers were highly homogenous. Although IFN-α expression was up-regulated in actively infected patients relative to controls, a corresponding up-regulation of innate viral sensor expression was not observed. IFN-α stimulation of patient PBMCs in vitro showed intact IFN-α signaling, but actively infected patients' PBMCs had reduced up-regulation of innate viral sensors. We show that the aberrant IFN-α responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor up-regulation in HSCT patients following viral infection.
病毒感染是异基因造血干细胞移植（HSCT）后发病率和死亡率的主要原因，多达四分之一的死亡直接与病毒疾病有关。在 HSCT 后等待淋巴细胞重建期间，先天抗病毒免疫反应是抵御入侵病毒的第一道防线。最近已经描述了几种新型先天病毒感应途径，但它们在人类中的生理重要性知之甚少。我们分析了一组 HSCT 患者的先天病毒传感器基因，并评估了先天抗病毒反应的差异是否可以解释对病毒感染易感性的差异。HSCT 患者中具有活性病毒感染、无活性感染的 HSCT 患者和健康志愿者的先天病毒传感器的表达水平高度均匀。虽然与对照组相比，活跃感染患者的 IFN-α 表达上调，但未观察到先天病毒传感器表达的相应上调。体外 IFN-α 刺激患者 PBMC 显示完整的 IFN-α 信号传导，但活跃感染患者的 PBMC 先天病毒传感器的上调减少。我们表明，HSCT 患者异常的 IFN-α 反应不是由于钙调神经磷酸酶抑制引起的。因此，我们的数据提出了在病毒感染后 HSCT 患者先天病毒传感器上调存在内在缺陷的可能性。
