健康人群对禽流感病毒的交叉T细胞免疫反应及分子机制

Human infection cases of avian influenza A viruses, i.e. H5N1, H7N9 were continuously reported in China and/or other adjacent countries/regions in recent years. In the meantime, the prevalence of 2009 pandemic influenza A (H1N1) virus (2009 pH1N1) still retains in north hemisphere since its first identification in April 2009, and became one of the major seasonal influeza viruses in China and other countries. The memory T cells induced by the primary influenza virus infecion are illuminated to have a pivotal role in rapid recovery of secondary infection of the similar influenza virus. However, it is still not determined yet the cross-reactivity and the protective effect of seasonal influenza infection-induced specific-T cell responses to the avian influenza in China. Previouly, we have identified cross-T cell responses against the 2009 pH1N1 among the seasonal influenza (such as Brisbane/07(H1N1) and Brisbane/07(H3N2)) infected-populations. In this study, we will further investigate the characterization and mechanism of the cross-T cell responses to avian influenza virus, e.g. H5N1, H6N1, H7N9, H9N2, and H10N8 and determine their roles in the anti-avian influenza protection. Furthermore, we will perform the X-ray crystallographic strategy to determine the structural basis of the cross-T cell responses to peptides from different influenza viruses. Our findings will illuminate the mechanism of the cross-T cell responses against different avian influenza A viruses and are beneficial for the development of T cell-based universal vaccines for influenza viruses.

近年来，禽流感病毒如H5N1和H7N9等感染人病例在我国及周边国家不断出现。而季节性流感在每年冬春季节也在人群中流行，如2009甲型H1N1流感病毒已经成为我国北方及北美地区的季节性流感之一。病毒感染引发的特异性T细胞在抵抗再次感染中发挥重要的保护作用。基于我国不同流感流行现状，感染季节性流感的人群体内是否事先存在针对禽流感病毒的交叉细胞免疫反应及保护作用？申请人对2009甲型流感等不同季节性流感病毒之间的交叉T细胞免疫进行的研究发现保守性T细胞表位具有免疫优势。本研究拟进一步探讨2009甲型流感病毒感染康复人群对H5N1、H6N1、H7N9、H9N2以及H10N8等禽流感的交叉T细胞反应的机制以及在抗流感保护力中发挥的作用；另一方面，通过X射线晶体学手段研究中国优势HLA分子呈递突变流感表位的结构学基础。为针对人群的禽流感T细胞免疫水平检测以及基于T细胞通用疫苗的研发提供材料和理论基础。

季节性流感病毒每年在人群中造成一定的流行，尤其在最近的2017-18流行季，季节性流感感染人数远超往年，且呈现甲型H1N1、H3N2以及两种乙型流感混合流行的趋势。与此同时，H5N1、H7N9和H9N2等禽流感病毒亦威胁人类健康。在人体针对病毒的免疫反应中，T细胞识别的病毒表位相对保守，因而不同流感之间发生交叉反应的可能性较大。本研究主要借助细胞免疫学和X射线晶体学等手段，针对2009甲型流感病毒感染康复人群对H7N9等禽流感的交叉T细胞反应的机制进行研究。我们发现季节性流感病毒感染康复人群不存在针对禽流感病毒的血清学交叉，而健康人群确实存在一定水平的针对H7N9禽流感病毒的交叉细胞免疫水平，但是这种细胞免疫水平明显低于人群对2009 pH1N1的细胞免疫水平，甚至低于人群对H5N1禽流感病毒交叉免疫水平。同时，我们又在病毒水平上验证了这种对于不同禽流感的细胞免疫交叉的趋势。为了探究造成这种不同程度的免疫反应的分子机制，我们锁定一系列免疫优势单肽，并将MHC-多肽复合物纯化结晶，从已解析的结构上分析了突变带来的这种潜在识别差异。同时我们对H7N9重症感染病例的T细胞免疫特征、免疫保护和损伤机制、以及传播规律进行了深入而系统的研究，取得系列成果，为针对人群的季节性流感病毒和禽流感病毒的T细胞免疫水平检测以及基于T细胞通用疫苗的研发提供材料和理论基础。同时，利用针对流感病毒建立的T细胞免疫检测技术，我们揭示了MERS-CoV等新发和再发病毒的T细胞免疫分子机制，为疫苗研发和诊疗方案制定提供了理论基础。