呼吸道流感病毒感染导致肠道菌群失衡的免疫学机制研究

Influenza is a respiratory disease which threatens to human health seriously. Clinically, the most common symptoms include cough, fever, headache, and weakness. These symptoms are often accompanied by gastroenteritis-like symptoms in many influenza patients, such as abdominal pain, nausea, vomiting, and diarrhea. In previous study, we found that respiratory influenza infection caused intestinal injury in mouse model, and Th17 cells were involved in this process. Moreover, influenza infection altered the intestinal microbiota composition, and antibiotic depletion of intestinal microbiota alleviated infection-induced intestinal injury. Thus, these results suggest that changes in the composition of intestinal microbiota caused by respiratory influenza infection are required for Th17 cell polarization and intestinal immune injury, but the underlying mechanism is not yet understood. Thus, the aim of this study is that, in the mouse model of respiratory influenza infection, using immunologic techniques such as immunohistochemical staining, multiparameter flow cytometry, ELISA, ELISPOT, cell transfer, antibody neutralization, as well as intestinal microbial depletion, transplantation, and diversity analysis to explore the immunological mechanism by which respiratory influenza infection destroy the balance of intestinal microbiota, which will provide theoretical basis for the prevention and treatment of influenza-related diseases.

流感是严重威胁人类健康的呼吸系统疾病。临床上，流感患者除有咳嗽，发热，头疼及虚弱等主要症状外，还时常伴有腹痛，恶心，呕吐及腹泻等类似肠胃疾病的症状。我们早期研究发现，在流感病毒呼吸道感染小鼠模型中，流感病毒感染能够通过诱导小肠Th17细胞的极化而导致肠道免疫损伤。在此过程中，小鼠肠道菌群的组成发生了改变；清除肠道细菌能够明显减轻肠道免疫损伤的程度，提示呼吸道流感病毒感染导致的肠道菌群失衡是诱导Th17细胞极化并进而导致肠道免疫损伤的重要原因，然而其具体的免疫学机制尚不清楚，值得进一步探索。因此，本研究旨在利用流感病毒感染小鼠模型作为研究平台，应用免疫组化，流式细胞术，ELISA，ELISPOT，细胞转输，抗体中和以及肠道共生菌的清除，植入和多样性分析等多种技术手段，探寻流感病毒感染导致肠道菌群稳态失衡的免疫学机制，为流感相关疾病的预防和治疗提供理论依据。

流感是比较常见的呼吸道感染疾病。临床上，流感患者除有咳嗽、发热、头疼和乏力等主要症状外，还时常会伴随有腹痛，恶心，呕吐和腹泻等类似肠胃炎的症状。然而，流感诱发类似肠胃炎疾病的免疫学机制尚不清楚。在本研究中，我们通过给小鼠滴鼻接种流感病毒建立感染模型，发现流感病毒感染在引起呼吸道粘膜免疫损伤的同时还会导致肠道粘膜免疫损伤，而对不属于粘膜组织的肝脏和肾脏组织却没有影响。在疾病过程中，肠道粘膜中有大量促炎症的Th17细胞聚集，IL-17A中和抗体处理能够显著地减轻肠道炎症损伤的程度。同时，小鼠肠道菌群的组成也发生了改变，抗生素处理清除肠道细菌能够显著地抑制Th17细胞的聚集并减轻肠道炎症损伤，提示肠道菌群的改变与Th17细胞的产生之间存在联系。进一步研究发现，流感病毒活化的肺脏T细胞在趋化因子的作用下特异地向肠道组织发生迁移并通过分泌炎性细胞因子改变肠道菌群的组成；改变的肠道菌群继而通过刺激肠道上皮细胞分泌细胞因子IL-15并最终促进Th17细胞的产生。本项研究不仅揭示了呼吸道粘膜免疫系统与肠道粘膜免疫系统之间的“纽带”，而且为研究跨脏器的免疫应答提供理论依据以及“共同的粘膜免疫系统”假说的成立提供证据。