Inflammatory Response in Influenza Virus Infection

描述（由申请方提供）：流感病毒感染引起每年一次的感染，其特征是突然出现症状，包括发热、肌痛、头痛、不适和寒战。最近，高致病性禽流感病毒在水禽中出现，随后人畜共患的人类感染引起了对人类大流行的担忧。人类的死亡率非常高，虽然致病原因尚不清楚，但涉及免疫失调。对流感病毒的免疫应答始于由1型干扰素和促炎细胞因子的释放组成的先天应答，但大多数研究表明，适应性应答对于病毒清除至关重要。然而，有证据表明，早期事件对控制病毒复制和启动适应性反应至关重要。我们最近的研究集中在感染流感病毒PR 8的小鼠中发生的非常早期的事件上。我们观察到延迟的炎症反应，我们归因于免疫拮抗剂蛋白NS 1的影响。一旦炎症被激活，在肺和血液中可以显示出高水平的细胞因子/趋化因子/生长因子。随后单核细胞流入肺部，并在整个感染过程中持续到达。骨髓和血液中的细胞表达干扰素信号，表明暴露于干扰素使其对病毒感染具有抵抗力。我们的数据表明，当它们暴露在病毒中时，它们的反应会更加强烈。在本申请中，我们建议完成对病毒感染后这些早期免疫事件的全面研究。我们将利用最近产生的I型和III型基因敲除小鼠（dKO）来分析干扰素非依赖性免疫途径，并通过扩展来分析干扰素信号传导对抗病毒免疫的重要性。此外，使用缺乏免疫拮抗剂蛋白NS 1的流感病毒感染dKO小鼠，我们将测量NS 1对干扰素非依赖性免疫的影响。目的3：研究高致病性禽流感病毒（HPAI）感染小鼠后免疫应答的早期事件。将研究细胞因子应答的失调，特别关注干扰素与炎性细胞因子的关系。最后，我们将尝试确定高致病性禽流感病毒对免疫激活的早期事件和T细胞反应的触发的影响。

DESCRIPTION (provided by applicant): Influenza virus infection causes yearly infections characterized by the abrupt onset of symptoms including fever, myalgia, headache, malaise and chills. Recently, highly pathogenic avian influenza viruses have arisen in aquatic birds and the subsequent zoonotic infections of humans have raised fear of a human pandemic. The fatality rate in humans is very high and while the reason for the virulence is not known, immune disregulation has been implicated. The immune response to the influenza virus begins with an innate response consisting of the release of type 1 interferon and proinflammatory cytokines but most studies show that an adaptive response is essential for viral clearance. However, evidence suggests that early events are crucial to control virus replication and initiate the adaptive response. We have focused our recent investigations on the very early events that occur in mice infected with influenza virus PR8. We have observed a delayed inflammatory response that we ascribe to the impact of the immune antagonist protein, NS1. Once inflammation has been activated high levels of cytokine/chemokines/growth factors can be demonstrated in the lungs and blood. This is followed by an influx of monocytes to the lungs that continue to arrive throughout the course of infection. Cells, in bone marrow and in blood, express an interferon signature indicating exposure to interferon that renders them resistant to virus infection. Our data suggest that they will respond much more vigorously when exposed to virus. In this application we propose to complete a comprehensive study of these early immune events following virus infection. We will take advantage of recently generated type I and type III knockout mice (dKO) to analyze the interferon independent immune pathway and by extension the importance of interferon signaling to anti-viral immunity. Moreover, using influenza virus lacking the immune antagonist protein, NS1, to infect dKO mice, we will measure the impact of NS1 on interferon independent immunity. In aim 3 we will study the early events in the immune response of mice following infection with highly pathogenic avian influenza virus (HPAI). The cytokine response will be studied for disregulation with a particular focus on the relationship of interferon to inflammatory cytokines. Finally, we will try to determine the impact that the HPAI virus has on the early events of immune activation and the triggering of the T cell response.