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

总结 COVID-19疾病是一种由新型β-冠状病毒SARS-CoV引起的持续全球大流行病， 2.对抗SARS-CoV-2的一个主要障碍是更好地了解人类先天免疫系统， 这些反应可能导致肺部不受控制的过度炎症，并最终导致 急性呼吸窘迫综合征（ARDS）在一些患者，但不是其他人。由于快速 由于这种流行病的出现，关于肺特异性先天性免疫缺陷的知识非常有限。 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 引发保护性抗病毒应答（例如，I型干扰素、干扰素刺激基因）。 人类先天免疫系统，特别是骨髓细胞，在启动“细胞因子”中的作用 风暴”和全身性炎症，但具体如何肺居民 巨噬细胞与浸润性单核细胞对SARS-CoV-2的不同反应，以及每种反应如何 髓系亚群有助于保护性抗病毒反应或不受控制的超 炎症和ARDS仍然未知。因此，对骨髓腔室的深入研究 重症监护室中严重COVID-19患者的肺部和血液中的含量对于更好地了解 ARDS的发生和持续，最重要的是， 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骨髓亚群， 包括肺内肺泡和间质巨噬细胞、树突状细胞以及浸润性 负责保护性抗病毒应答的血液单核细胞（例如，I型干扰素， 干扰素刺激的基因）和/或导致ARDS的异常高度炎症反应 (e.g.,“细胞因子风暴”、中性粒细胞募集等）。通过这些研究，我们将开发新的 深入了解人类先天免疫的分子编程和异质性 SARS-CoV-2感染的反应，并确定潜在的靶基因，以告知有效的 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.