天然免疫反应是宿主抵御病原微生物入侵的第一道防线。Cyclophilin A（CypA，亲环素A）是一种肽基脯氨酰顺/反异构酶，具有多种生物学功能。我们的前期研究结果发现，CypA不仅能够通过促进A型流感病毒M1蛋白的泛素化降解来抑制病毒的复制，而且通过正调控RLR介导的I型干扰素的产生来抑制病毒的复制。TLR通路在宿主抗流感病毒天然免疫反应中同样发挥了重要作用。初步研究结果表明，CypA能够负调控TLR信号通路, 因此推测CypA可能是天然免疫反应的一个双向调控因子。然而，CypA对TLR介导的天然免疫反应的调控机制尚不清楚。本项目拟利用CypA敲除细胞系、敲除小鼠和转基因小鼠以及转基因猪，深入揭示CypA在TLR通路的作用靶点和作用机理，同时确定CypA在小鼠和猪的动物模型上抗A型流感病毒的能力，进而阐明CypA对TLR介导的抗流感病毒天然免疫的调控机制，为动物抗病毒育种提供理论依据。

Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase with many biological functions. Our previous studies indicate that CypA inhibits influenza A virus replication by accelerating ubiquitin-proteasome degradation of M1 protein. We further discovered that CypA inhibits virus replication by promoting RIG-I-mediated type-I IFN production. TLR signaling pathway also participates in the innate immune response against influenza A virus. Our recent studies implied that CypA inhibited TLR signaling pathway, while the molecular mechanism is still unclear. In this proposal, we will further investigate the mechanism of how CypA regulates TLR-mediated immune response by using CypA-deficient cells, CypA knockout/transgenic mice, and CypA transgenic pig. We will also evaluate the antiviral function of CypA against influenza A virus in murine and porcine models. Our study will provide new insights of the roles of CypA in host antiviral innate immunity.