流感病毒继发呼吸道细菌共感染是导致人和动物死亡率大幅上升的主要原因之一，但共感染发生的机制尚不明确。我们的前期研究发现，宿主蛋白CypA在A型流感病毒感染后显著上调，并且CypA能够增强A组链球菌对人肺泡上皮（A549）细胞的粘附，上调粘附受体integrin α5的表达，提示CypA可能参与调控流感病毒继发呼吸道细菌共感染过程。本项目拟利用CypA敲低的A549和猪气管上皮细胞、CypA敲除小鼠的骨髓来源巨噬细胞、CypA敲除小鼠及SPF猪建立多种细胞和动物模型，检测CypA在流感病毒感染后对细菌粘附及粘附受体表达的影响，确定CypA的抑制剂CsA能否阻断细菌粘附，并进一步探索CypA在流感病毒感染过程中通过哪些信号通路调控细菌粘附，明确其作用靶点和作用机制。本研究将从流感病毒感染相关宿主蛋白的角度阐明流感病毒继发呼吸道细菌共感染的分子机制，旨在为共感染阻断药物的研究提供理论依据。

Influenza virus-induced secondary bacterial infection in respiratory tract is one of the prime reasons for high mortality during the epidemic of influenza in human and animals. However, the mechanisms of virus-bacteria coinfection remain unclear. Our preliminary studies showed that the host protein CypA was upregulated upon influenza A virus infection, and CypA was critical for enhancing group A streptococcus (GAS) adherence to human lung epithelial cells (A549 cells) and upregulating the expression of integrin α5, a major GAS binding receptor, indicating that CypA is likely to involve in the regulation of influenza virus-induced secondary bacterial infection. In this study, we propose to establish several in vitro and in vivo models of influenza virus-induced secondary bacterial infection by using CypA knock-down A549 and new born pig tracheal epithelial (NPTr) cells, bone marrow-derived macrophage (BMDM) cells from CypA knock-out mice, CypA knock-out mice, and SPF pigs to investigate the effect of CypA on bacterial adherence and adhesion receptors expression. The effect of CsA on blocking bacterial adherence will also be evaluated. We will further determine the CypA-associated signaling pathways to regulate bacterial adherence and the target proteins of CypA during influenza virus-bacterial coinfection. The proposed study will contribute to further understanding the molecular mechanisms of influenza virus-induced secondary bacterial infection and provide targets for designing anti-coinfection drugs.