IP-10介导Teff/Treg失衡在H7N9病毒致急性肺损伤中的作用机制研究

H7N9 avian influenza is a dangerous disease with high mortality. Its main characteristic is severe pneumonia caused by acute lung injury. Our previous study found that expression level of interferon induced protein 10 (IP-10) was significantly associated with severity of disease and was able to predict progression and prognosis of the disease directly. Pathologic tissue showed a large number of T cells accumulated in the lungs of patients with H7N9. It is currently known that effector T cell (Teff) and regulatory T cell (Treg) imbalance plays an important role in organ injury and IP-10 may be involved in chemotaxis of Teff and Treg. Therefore, in this study, we assume that IP-10 is involved in the development of acute lung injury by mediating Teff and Treg imbalance. We aim to clarify the dose-effect relationship between IP-10 expression and cell injury degree by constructing alveolar epithelial cell line with IP-10 gene interference and overexpression and infecting H7N9 virus. We would also infect wild type and IP-10 gene knockout mice with H7N9 in order to construct acute lung injury model, and analyze the exact mechanism of acute lung injury caused by IP-10-mediated Teff and Treg imbalance, providing novel ways for treatment of H7N9 avian influenza.

H7N9禽流感病情凶险，病死率高，其主要临床特征为急性肺损伤导致的重症肺炎。我们前期研究发现：干扰素诱导蛋白10（IP-10）表达水平与病程严重程度显著相关，可直接预测疾病的进展和预后，且病理组织提示H7N9患者肺部出现大量T细胞聚集，目前已知效应T细胞（Teff）和调节性T细胞（Treg）比例失衡在靶器官损伤中发挥了重要作用，且IP-10可参与趋化Teff与Treg。因此本研究推测IP-10通过介导Teff和Treg平衡失调参与急性肺损伤的发生发展。本项目拟通过构建IP-10基因干扰及过表达肺泡上皮细胞株并感染H7N9病毒，明确IP-10表达水平变化与细胞损伤程度的量效关系。并经H7N9病毒感染野生型及IP-10基因敲除小鼠构建急性肺损伤模型，进一步分析IP-10通过介导Teff/Treg失衡导致急性肺损伤的确切作用机制，为H7N9禽流感治疗提供新思路。

H7N9禽流感等急性呼吸道传染病感染导致的急性肺损伤病情危重、病死率高，是新突发传染病防治面临的重大科学问题。本课题发现IP-10在H7N9禽流感导致急性肺损伤的发生发展中起着重要作用。初步揭示了H7N9病毒感染过程关键效应T细胞Th17和Tc17的变化规律，发现了H7N9禽流感病毒急性感染期Th17和Tc17的数量下调，从而导致IL-17A分泌和免疫应答下降，且恢复期Th17和Tc17数量的回升，并与疾病的转归高度相关。首次明确早期抗病毒的临床效果，发现2天之内服用抗病毒药物能显著降低H7N9禽流感患者病死率。全面揭示H7N9禽流感感染的死亡危险因素，发现年龄、抗病毒药物服用时间、继发感染是影响H7N9患者死亡的独立危险因素。在新冠疫情中，课题组迅速将建立的各类技术平台用于开展新型冠状病毒的相关研究，发现在新冠患者的血清IP-10表达水平与疾病严重程度相关，并精确揭示了新冠患者在疾病进程中的病毒载量动态变化规律，发现病毒持续时间、病毒载量与疾病严重程度显著相关，相关研究成果为卫生行政部门制定相关政策提供了科学依据。本课题已在BMJ、Clin Infect Dis等国际顶级医学期刊发表了相关论文7篇，单篇最高影响因子30.223，一篇入选ESI高被引论文和Hot论文。协助培养研究生2名，获国家科技进步奖特等奖、教育部技术发明奖二等奖各1项。