Innate immune responses to SARS-CoV-2 in the lung and blood of patients with severe COVID-19

摘要 新冠肺炎病是一种持续的全球大流行，由一种新的贝塔冠状病毒SARS-CoV- 2.抗击SARS-CoV-2的一个主要障碍是更好地了解人类的先天免疫 可导致肺内失控的高炎症反应，最终导致 一些患者患有急性呼吸窘迫综合征(ARDS)，而另一些患者则没有。由于速度很快 这场大流行的出现，对肺部特有的先天疾病的了解非常有限 对SARS-CoV-2的免疫反应可能导致ARDS(在某些情况下死亡)或相反 诱导保护性抗病毒反应(例如，I型干扰素、干扰素刺激基因)。 人类先天免疫系统，特别是髓系细胞在启动一种“细胞因子”中的作用 风暴“和全身性高炎症已有报道，但具体是如何驻留在肺 巨噬细胞与浸润性单核细胞对SARS-CoV-2的不同反应及其各自的机制 髓系亚群有助于保护性抗病毒反应或失控的高 炎症和ARDS仍不清楚。因此，对髓质室的深入研究 ICU重症新冠肺炎患者的肺和血液中的变化对进一步了解 ARDS的启动和持续，以及最重要的是，有助于开发更有效的 和靶向治疗。 我们项目的主要目标是在单细胞水平上解析特定的髓系亚群， 包括驻留在肺泡和间质的巨噬细胞、树突状细胞以及浸润性 负责保护性抗病毒反应的单核细胞(例如，I型干扰素， 干扰素刺激基因)和/或导致ARDS的异常炎症反应 (如“细胞因子风暴”、中性粒细胞募集等)。通过这些研究，我们将开发出新的 对人类先天免疫的分子编程和异质性的洞察 对SARS-CoV-2感染的应答并识别潜在的靶基因以告知有效 治疗策略。

SUMMARY COVID-19 disease is an ongoing global pandemic caused by a new beta-coronavirus SARS-CoV- 2. A major obstacle to battling SARS-CoV-2 is a better understanding of the human innate immune responses that can lead to an uncontrolled hyper-inflammation in the lung and, ultimately, to an acute respiratory distress syndrome (ARDS) in some patients but not others. Due to the rapid emergence of this pandemic, very limited knowledge is available on the lung-specific innate immune responses to SARS-CoV-2 that could lead to ARDS (and in some cases death) or instead elicit a protective antiviral response (e.g., type-I interferons, interferon-stimulated genes). The role of the human innate immune system, particularly the myeloid cells, in initiating a “cytokine storm” and generalized hyper-inflammation has been reported, but specifically how lung-resident macrophages vs. infiltrating monocytes differentially respond to SARS-CoV-2 and how each myeloid subset contribute to either protective antiviral responses or uncontrolled hyper- inflammation and ARDS remain unknown. Hence, an in-depth study of the myeloid compartment in the lung and blood of severe COVID-19 patients in ICU is critical to better understand the initiation and persistence of ARDS and, most importantly, to the development of more efficient and targeted therapy. Our project’s primary objective is to resolve, at a single-cell level, the specific myeloid subsets, including lung-resident alveolar and interstitial macrophages, dendritic cells, as well as infiltrating blood monocytes, that are responsible for protective antiviral responses (e.g., type-I interferons, interferon-stimulated genes) and/or aberrant hyper-inflammatory responses that lead to ARDS (e.g., “cytokine storm”, neutrophil recruitment, etc.). Through these studies, we will develop novel insights into the molecular programming and heterogeneity of the human innate immune responses to SARS-CoV-2 infection and identify potential target genes to inform effective treatment strategies.