新鉴定PA-X“host-shutoff”功能区调控H7N9禽流感病毒毒力的机制

流感病毒感染宿主后，导致宿主蛋白合成的快速下降，这一过程称为“host-shutoff”。流感病毒可通过该活性调控病毒的毒力。前期我们通过对不同亚型流感病毒PA-X基因的大数据分析和功能验证，在PA-X基因上鉴定了一个新的“host-shutoff”功能区，其显著增强H7N9病毒对小鼠的毒力。然而，该功能区调控H7N9病毒毒力的机制还不清楚。本项目首先评价功能区对H7N9病毒毒力相关生物学特性的影响；然后探索功能区“host-shutoff”作用特点；最后鉴定决定功能区“host-shutoff”活性的关键宿主因子，并明确其在功能区调控H7N9病毒毒力中的作用。从而从病毒因素和宿主因素全面解析新鉴定PA-X“host-shutoff”功能区调控H7N9病毒毒力的机制。研究将拓展对PA-X“host-shutoff”如何利用宿主机器调节宿主蛋白表达从而调控流感病毒毒力的理解。

Influenza virus infection results in a rapid decline of global host protein synthesis in infected cells, a process known as host-shutoff. Influenza virus can regulate viral virulence through this activity. By thoroughly comparing all the available PA-X sequences and verification of the PA-X host-shutoff ability, we successfully identified a new functional domain for PA-X host-shutoff activity. This novel host-shutoff functional domain significantly increases the virulence of H7N9 virus in mice. However, the potential mechanism underlying this phenomenon is unknown. In this proposal, we will first investigate the effect of the newly identified functional domain on the virulence-associated biological characteristics of H7N9 influenza virus. Then, we will explore the host-shutoff characteristics of the functional domain. Last, we will identify the crucial host factor associated with the host-shutoff characteristics of the functional domain and evaluate the role of the host factor in functional domain-mediated modulation of H7N9 virus virulence. Thus, the mechanism for regulation of H7N9 virus virulence by the novel host-shutoff functional domain in PA-X will be systematically illustrated from the level of both virus and the host. This proposal will advance our understanding of how PA-X explores host machinery to modulate host protein expression and finally affects viral virulence through host-shutoff activity.