白细胞介素-13降低气道上皮对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的易感性，但通过类花生酸信号通路在体内增加疾病严重程度。
IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling.
作者信息
Ghimire Shreya, Xue Biyun, Li Kun, Gannon Ryan M, Wohlford-Lenane Christine L, Thurman Andrew L, Gong Huiyu, Necker Grace C, Zheng Jian, Meyerholz David K, Perlman Stanley, McCray Paul B, Pezzulo Alejandro A
机构信息
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Stead Family Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
出版信息
EBioMedicine. 2025 Sep 15;120:105920. doi: 10.1016/j.ebiom.2025.105920.
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 A 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.
背景
一旦呼吸衰竭发生，可用于预防病毒诱导的肺部疾病进展（包括2019冠状病毒病，即COVID - 19）的治疗方法益处有限。已获批和新出现的细胞因子信号调节抗体的疗效存在差异，且受病程和患者特异性炎症模式影响。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
使用单细胞和批量RNA测序方法，在体外原代人呼吸道上皮（HAE）细胞以及体内小鼠适应性严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染模型中，研究2型细胞因子白细胞介素13（IL-13）对SARS-CoV-2结合/进入、复制及宿主反应的作用。此外，使用免疫荧光、组织病理学、免疫组织化学和液相色谱-串联质谱（LC-MS/MS）分析对反应进行定量。
研究结果
IL-13在体外通过减少表达血管紧张素转换酶2（ACE2）的纤毛细胞数量，而非通过中和气道表面液体或干扰素介导的抗病毒作用，保护气道上皮细胞免受SARS-CoV-2感染。相比之下，IL-13使小鼠疾病严重程度恶化；其作用由类花生酸信号介导，且在缺乏磷脂酶A2G2D酶的小鼠中被消除。
阐释
IL-13诱导的炎症对COVID-19发病机制的多个步骤有不同影响。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，它会增强体内疾病进展。阻断IL-13和/或类花生酸信号可能对预防进展为严重的呼吸道病毒诱导的肺部疾病具有保护作用。
资助
卡弗信托COVID-19资助；囊性纤维化基金会爱荷华州RDP；美国国立卫生研究院（NIH）1R01HL163024；K01HL140261；NIH R01AI129269；NIH P01AI060699；NIH资助P30 DK-54759；囊性纤维化基金会PEZZUL20A1-KB；斯特德家族基金会。
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