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

项目摘要 程序性细胞死亡是对抗细胞内感染的一种古老而有效的防御机制：激活 对细胞内病原体的细胞自杀反应消除病原体的复制生态位并暴露 免疫介导性杀戮。然而，当这些反应不正确或过度兴奋时，它们 会导致组织破坏并加剧炎症。包括我们自己在内的许多组织的工作都有 研究表明，感染rna病毒的肺部可以通过称为 “坏死性下垂。”我们的初步数据证实，SARS-CoV-2导致肺上皮细胞感染 导致他们死于坏死性下垂。这些发现，以及包含在 建议，使我们假设由坏死性下垂引起的细胞死亡是对感染的关键早期反应。 肺部感染SARS-CoV-2。我们进一步假设，虽然测量的坏死性反应有助于 消灭SARS-CoV-2病毒，肺部过度坏死性下垂可导致有害炎症 病理学。我们将围绕三个目标来检验这些假设：第一，我们将进行详细的 SARS-2感染小鼠缺乏坏死物关键成分的免疫学和病理学特征 发信号。接下来，我们将使用我们实验室开发的一种小鼠模型来实验性地诱导坏死性下垂 肺泡上皮细胞与SARS-2感染最后，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.