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

重症 COVID-19 患者肺部和血液中对 SARS-CoV-2 的先天免疫反应

• 批准号: 10212766
• 负责人: Eliver Ghosn
• 金额: $ 35.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-24 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212766
• 关键词: 2019-nCoV; Adult Respiratory Distress Syndrome; Affect; Alveolar; Alveolar Macrophages; Antibodies; Antibody titer measurement; Antiviral Agents; Antiviral Response; Aspirate substance; Biological Assay; Blood; Blood specimen; Bone Marrow; Bronchoalveolar Lavage Fluid; COVID-19; Cells; Cessation of life; Coronavirus; Critical Illness; Data Set; Dendritic Cells; Development; Disease; Disease Outcome; Expression Profiling; Flow Cytometry; Follow-Up Studies; Funding; Gene Expression; Gene Expression Profile; Genes; Grant; Heterogeneity; Human; IL8 gene; Immune; Immunotherapy; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Influenza; Innate Immune Response; Innate Immune System; Intensive Care Units; Interferon Type I; Interferons; Investigation; Knowledge; Label; Lead; Life; Ligands; Lung; Lymphoid Cell; Measures; Membrane Proteins; Molecular; Myelogenous; Myeloid Cells; National Institute of Allergy and Infectious Disease; Neutrophil Infiltration; Oligonucleotides; Outcome; Patients; Phenotype; Play; Population; Public Health; RNA Viruses; Reporting; Research; Role; Sputum; Symptoms; T cell response; Tissues; Viral; Viral Antibodies; Virus; Virus Replication; Yolk Sac; base; cell type; chemokine; cytokine release syndrome; effective therapy; endotracheal; experience; fetal; high dimensionality; immunopathology; insight; interstitial; macrophage; monocyte; novel; novel coronavirus; pandemic disease; progenitor; receptor; recruit; respiratory; response; single-cell RNA sequencing; targeted treatment; treatment strategy

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.

概括 COVID-19 疾病是一种持续的全球流行病，由新型 β 冠状病毒 SARS-CoV 引起 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 可能导致肺部不受控制的过度炎症反应，并最终导致 一些患者会出现急性呼吸窘迫综合征（ARDS），而另一些患者则不会。由于快速 由于这种流行病的出现，关于肺部特定先天性的知识非常有限 对 SARS-CoV-2 的免疫反应可能导致 ARDS（在某些情况下甚至导致死亡），或者相反 引发保护性抗病毒反应（例如 I 型干扰素、干扰素刺激基因）。 人类先天免疫系统，特别是骨髓细胞，在启动“细胞因子”中的作用 据报道，“风暴”和全身性过度炎症，但具体是如何影响肺部的 巨噬细胞与浸润单核细胞对 SARS-CoV-2 的反应存在差异，以及各自的反应如何 骨髓亚群有助于保护性抗病毒反应或不受控制的过度反应 炎症和 ARDS 仍然未知。因此，对骨髓室的深入研究 ICU 重症 COVID-19 患者的肺部和血液中的数据对于更好地了解 ARDS 的启动和持续，最重要的是，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决特定的骨髓亚群， 包括肺内的肺泡和间质巨噬细胞、树突状细胞以及浸润性细胞 血液单核细胞，负责保护性抗病毒反应（例如 I 型干扰素、 干扰素刺激基因）和/或导致 ARDS 的异常高炎症反应 （例如，“细胞因子风暴”、中性粒细胞募集等）。通过这些研究，我们将开发新颖的 对人类先天免疫的分子编程和异质性的见解 对 SARS-CoV-2 感染的反应并确定潜在的靶基因，以提供有效的信息 治疗策略。

项目成果

Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes.

baritodinib减弱了由肺部膨胀单核细胞驱动的COVID-19的促炎阶段。

• DOI: 10.1016/j.celrep.2022.110945
• 发表时间: 2022-06-14
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Dobosh, Brian;Zandi, Keivan;Giraldo, Diego Moncada;Goh, Shu Ling;Musall, Kathryn;Aldeco, Milagros;LeCher, Julia;Giacalone, Vincent D.;Yang, Junkai;Eddins, Devon J.;Bhasin, Manoj;Ghosn, Eliver;Sukhatme, Vikas;Schinazi, Raymond F.;Tirouvanziam, Rabindra
• 通讯作者: Tirouvanziam, Rabindra

Hematopoietic Stem Cell Requirement for Macrophage Regeneration Is Tissue Specific.

• DOI: 10.4049/jimmunol.2100344
• 发表时间: 2021-12-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Eddins, Devon J.;Kosters, Astrid;Waters, Jeffrey;Sosa, Jasmine;Phillips, Megan;Yadava, Koshika;Herzenberg, Leonore A.;Kuipers, Hedwich F.;Ghosn, Eliver Eid Bou
• 通讯作者: Ghosn, Eliver Eid Bou