流感病毒表面的血凝素蛋白（HA）是病毒启动感染的决定性蛋白，其在细胞中的合成及降解效率直接影响病毒粒子的感染性与传播性。在前期研究中，我们发现HA蛋白在胞内合成过程中能够同时被蛋白酶体和溶酶体降解，并报道了蛋白酶体降解HA的机理及抗病毒效应，而溶酶体降解HA蛋白的机制及其背后的生物学意义尚不明确。目前我们已证实，HA蛋白能够在感染细胞中形成凝集小体，该凝集小体可通过自噬途径被细胞溶酶体降解，抑制溶酶体的降解可显著增加细胞功能性HA的数量。本项目拟在此基础上，首先构建不同的基因修饰细胞系，鉴定在HA凝集小体形成及降解过程中，发挥关键作用的宿主分子；之后在基因修饰细胞系中查看HA凝集小体通路对病毒复制的影响；最后构建相应的基因修饰小鼠，在体内验证干预HA凝集小体的合成和降解可以调控流感病毒的复制。本项目将揭示细胞通过凝集小体途径影响流感病毒复制的分子机制，并为新型抗病毒药物开发奠定基础。

Hemagglutinin (HA) of influenza virus is required for viral particles to infect host cells, therefore, HA biosynthesis and degradation are important determinants of viral infectivity and transmission. We have found that HAs are degraded by both proteasomal and lysosomal pathways in host cells and previously reported on the molecular mechanism and anti-viral effect of proteasomal degradation（J Virol. 2017，pii: e01690-17）. However, the mechanism and biological significance of lysosome-mediated HA degradation is still unknown. Our current data demonstrate that influenza virus infection leads to the formation of HA aggresomes. These HA aggresomes are targeted to lysosome for degradation through an autophagic pathway, and inhibition of lysosomal degradation increases the amount of functional HAs. In this proposal, first, we will generate different genetically modified cell lines to screen the host molecules which are critical in the formation and degradation of HA aggresomes. Then, the mechanism by which the formation and degradation of HA aggresomes influence virus replication will be examined by using genetically modified cell lines. Lastly, based on the results of in vitro study, we will establish genetically modified mice to study whether the formation and degradation of HA aggresomes can modulate virus replication in vivo. This project will clarify the molecular mechanism of how the HA aggresomes affect influenza virus replication, and provide new insight for anti-viral drug design.