IL-13降低对气道上皮SARS-CoV-2感染的易感性,但通过类二十烷信号传导在体内增加疾病严重程度。

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Shreya Ghimire, Biyun Xue, Kun Li, Ryan M Gannon, Christine L Wohlford-Lenane, Andrew L Thurman, Huiyu Gong, Grace C Necker, Jian Zheng, David K Meyerholz, Stanley Perlman, Paul B McCray, Alejandro A Pezzulo
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引用次数: 0

摘要

背景:一旦发生呼吸衰竭,用于预防病毒引起的肺部疾病(包括2019冠状病毒病(COVID-19))进展的现有治疗方法的益处有限。已批准的和新出现的细胞因子信号调节抗体的疗效是可变的,受病程和患者特异性炎症模式的影响。因此,了解炎症在病毒感染周期中的作用对于有效使用细胞因子调节剂至关重要。方法:采用单细胞和大量rna测序方法,在体外原代HAE细胞和小鼠适应性SARS-CoV-2感染模型中研究2型细胞因子IL-13在SARS-CoV-2结合/进入、复制和宿主反应中的作用。此外,通过免疫荧光、组织病理学、免疫组织化学和LC-MS/MS测定对反应进行量化。研究结果:IL-13通过降低表达ace2的纤毛细胞的丰度而不是通过在气道表面液体中中和或干扰素介导的抗病毒作用来保护气道上皮细胞免受SARS-CoV-2的体外感染。相反,IL-13加重了小鼠的疾病严重程度;这种作用是由类二十烷酸信号介导的,在缺乏磷脂酶A2酶PLA2G2D的小鼠中被消除。解释:il -13诱导的炎症对COVID-19发病的多个步骤有不同的影响。il -13诱导的炎症可能对初始SARS-CoV-2气道上皮感染具有保护作用;然而,它会促进体内疾病的进展。阻断IL-13和/或类二十烷酸信号可能对严重呼吸道病毒诱导的肺部疾病的进展具有保护作用。资助:Carver Trust COVID-19赠款;CF基金会爱荷华州RDP;国家卫生研究院1 r01hl163024;K01HL140261;NIH R01AI129269;NIH P01AI060699;NIH Grant P30 DK-54759;囊性纤维化基金会PEZZUL20A1-KB;斯特德家族基金会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling.

Background: Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signalling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents.

Methods: The role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response was investigated in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo using single-cell and bulk RNA-sequencing approaches. Additionally, the responses were quantified using immunofluorescence, histopathology, immunohistochemistry and LC-MS/MS assays.

Findings: IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2-expressing ciliated cells rather than by neutralisation in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened disease severity in mice; the effects were mediated by eicosanoid signalling and were abolished in mice deficient in the phospholipase A2 enzyme PLA2G2D.

Interpretation: IL-13-induced inflammation differentially affects multiple steps of COVID-19 pathogenesis. IL-13-induced inflammation may be protective against initial SARS-CoV-2 airway epithelial infection; however, it enhances disease progression in vivo. Blockade of IL-13 and/or eicosanoid signalling may be protective against progression to severe respiratory virus-induced lung diseases.

Funding: Carver Trust COVID-19 Grant; CF Foundation Iowa RDP; NIH 1R01HL163024; K01HL140261; NIH R01AI129269; NIH P01AI060699; NIH Grant P30 DK-54759; Cystic Fibrosis Foundation PEZZUL20A1-KB; Stead Family Foundation.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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