Activation of inflammatory programmed cell death by SARS-CoV-2

项目摘要 细胞程序性死亡是一种古老而有效的细胞内感染防御机制：激活 细胞对细胞内病原体的自杀反应消除了病原体的复制生态位， 免疫介导的杀伤。然而，当这些反应发生错误或过度时， 会导致组织破坏并加剧炎症。包括我们自己在内的许多团体的工作 显示肺部感染RNA病毒可通过称为 “坏死性凋亡”我们的初步数据证实，SARS-CoV-2感染肺上皮细胞， 死于坏死性凋亡这些发现，沿着其他初步数据包含在 这一提议使我们假设，坏死性凋亡引起的细胞死亡是感染的关键早期反应， 肺部感染了SARS冠状病毒2型我们进一步假设，虽然测量的坏死性反应有助于 消除SARS-CoV-2病毒，肺中过度的坏死性凋亡可导致有害的炎症反应， 病理我们将通过三个目标来测试这些假设：首先，我们将进行详细的 SARS-2感染小鼠缺乏坏死性凋亡关键成分免疫学和病理学特征 信号接下来，我们将使用我们实验室开发的小鼠模型来实验性地诱导小鼠的坏死性凋亡。 肺泡上皮细胞与SARS-2感染有关。最后，我们将使用人肺切片来评估细胞 完整人体组织对SARS-2感染的死亡反应。

Project Summary Programmed cell death is an ancient and effective defense mechanism against intracellular infection: activation of cellular suicide in response to intracellular pathogens eliminates pathogens’ replicative niches and exposes them to immune-mediated killing. However, when these responses occur incorrectly or overexuberantly, they can cause tissue destruction and exacerbate inflammation. Work from many groups including our own has shown that infection of the lung with RNA viruses can trigger cell death via the inflammatory process termed “necroptosis.” Our preliminary data confirm that infection of cells of the lung epithelium with SARS-CoV-2 leads to their death by necroptosis. These findings, along with additional preliminary data contained within the proposal, lead us to hypothesize that cell death by necroptosis is a key early response to infection of the lung with SARS-CoV-2. We further hypothesize that while a measured necroptotic response helps to eliminate SARS-CoV-2 virus, excessive necroptosis in the lung can lead to detrimental inflammatory pathology. We will test these hypotheses by focusing on three Aims: First, we will carry out detailed immunological and pathological profiling of SARS-2 infected mice lacking key components of necroptotic signaling. Next, we will use a mouse model developed in our lab to experimentally induce necroptosis in the alveolar epithelium in conjunction with SARS-2 infection. Finally, we will use human lung slices to assess cell death responses to SARS-2 infection in intact human tissue.