Multi-dimensional comparison of differentially pathogenic coronaviruses (CoV) in human lung tissue

项目总结： SARS-CoV-2是一种新的冠状病毒，也是当前全球大流行的原因。这场疫情始于 2019年12月，现已席卷全球。SARS-CoV-2是一种呼吸道病原体， 引发新冠肺炎，它已经导致全球260多万人死亡，超过538,000人 截至2021年3月，仅在美国就有死亡病例。SARS-CoV-2感染人类的主要病理变化 是在肺里。在这个建议中，我们试图通过感染来研究冠状病毒感染后的早期事件。 体外培养人肺组织。为了了解SARS-CoV-2导致如此严重的 疾病结局，我们将比较两种冠状病毒株，SARS-CoV-2(高致病性)和 人类感染NL63(轻度致病)。在目标1中，我们将确定病毒复制动力学的差异， 感染细胞类型和炎症反应。在目标2中，我们将描述宿主对感染的反应 使用基于质谱学的蛋白质组学。了解这些复杂的病毒：人类体内的宿主成分 系统以及冠状病毒之间的这些差异将导致对体内易感性和 确定用于治疗开发的新药靶点。

PROJECT SUMMARY: SARS-CoV-2 is a novel coronavirus and the cause of the current global pandemic. This outbreak started in December of 2019 and has now spread over the entire world. SARS-CoV-2 is a respiratory pathogen that causes COVID-19, which has been the cause of more than 2.6 million deaths worldwide, with over 538,000 deaths in the US alone as of March 2021. The primary pathology caused by SARS-CoV-2 infection in humans is in the lungs. In this proposal, we seek to study the early events following coronavirus infection by infecting human lung tissue ex vivo. In order to understand the mechanism by which SARS-CoV-2 causes such severe disease outcomes, we will compare two coronavirus strains, SARS-CoV-2 (which is highly pathogenic) and NL63 (which is mildly pathogenic) in humans. In Aim 1, we will identify differences in viral replication kinetics, infected cell types, and the inflammatory response. In Aim 2, we will characterize the host response to infection using mass spectrometry-based proteomics. Understanding these complex virus:host components in a human system and how these differ between coronaviruses will lead to new hypotheses for in vivo susceptibility and identify new drug targets for therapeutic development.