PLZF调控呼吸道合胞病毒感染打破哮喘免疫耐受的研究

婴幼儿重度呼吸道合胞病毒（RSV）感染显著增加了成人哮喘发生的风险。我们前期研究证实RSV感染能打破口服卵蛋白（OVA）诱导的小鼠免疫耐受（OT），通过RNA-seq检测发现在OT小鼠肺组织中PLZF的表达显著增高，而早期RSV感染能降低PLZF+细胞数量。但是PLZF对于耐受的调控机制还不清楚。我们假设早期RSV感染能通过减少PLZF+细胞的数量，改变其表型，并对恒定自然杀伤细胞（iNKT）细胞产生调控，从而打破耐受。本课题拟建立OT和哮喘小鼠模型，研究肺组织、肺门淋巴结中PLZF+细胞的数量、定位和表型变化，然后从细胞、动物水平，并运用过表达基因和基因敲除动物模型，研究RSV感染后PLZF+细胞的变化，以及PLZF对iNKT细胞分化的影响，探讨早期RSV感染通过抑制PLZF表达、打破耐受的机制。本研究成果将为RSV感染和哮喘提供新的干预靶点。

Severe respiratory syncytial virus (RSV) infection in infancy is associated with an increased prevalence of early childhood asthma. Our previous study has shown that RSV infection could impair oral tolerance (OT) and induce asthma in mice. Zbtb16 (encoding promyelocytic leukemia zinc finger, PLZF) in the lungs of the oral tolerance mice was significantly up-regulated detetmined by the RNA-seq analysis. Early RSV infection significantly reduced the number of PLZF+ cells in the lungs of tolerized mice. However, the concrete mechanism of PLZF regulating tolerance remains unclear. We hypothesized that early RSV infection could disrupt asthma tolerance by reducing PLZF-expressing cells, changing its phenotype, and regulating the differentiation of invariant natural killer T cells (iNKTs). First，the expression, location and phenotype changes of PLZF+ cells will be detected in the asthmatic and oral tolerance mice. The change of PLZF+ cells and differentiation of iNKTs after RSV infection will be determined in vitro and in vivo. The mechanism of RSV suppressing PLZF+ expression will also be studied using overexpressed PLZF transgenic and knock-out mice. The findings will provide novel interventional targets for RSV infection and asthma.