Role of neutrophil chemoattractant CXCL5 in SARS-CoV-2 infection-induced lung inflammatory innate immune response in an in vivo hACE2 transfection mouse model

Autor: Long Ding Liu, Yan Li Chen, Jia Li Li, Jing Li, Lei Guo, Ze Ning Yang, Yan Liang, Heng Li, Hui Wen Zheng, Hai Jing Shi
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Chemokine CXCL5
Chemokine
Neutrophils
viruses
Pathogenesis
0302 clinical medicine
lcsh:Zoology
lcsh:QL1-991
Mice
Knockout
lung infection
Ecology
neutrophil
Articles
sars-cov-2
medicine.anatomical_structure
CXCL5
030220 oncology & carcinogenesis
Cytokines
Angiotensin-Converting Enzyme 2
medicine.symptom
Coronavirus Infections
mouse model
Pneumonia
Viral
Mice
Transgenic
Inflammation
Peptidyl-Dipeptidase A
Biology
Virus
Cell Line
Betacoronavirus
03 medical and health sciences
medicine
Animals
Humans
Pandemics
Ecology
Evolution
Behavior and Systematics
Innate immune system
Lung
ace2
COVID-19
Immunity
Innate
respiratory tract diseases
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Viral Receptor
Immunology
cxcl5
biology.protein
Animal Science and Zoology
Zdroj: Zoological Research, Vol 41, Iss 6, Pp 621-631 (2020)
Zoological Research
ISSN: 2095-8137
DOI: 10.24272/j.issn.2095-8137.2020.118
Popis: Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.了解严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的发病机制，阐明宿主的抗病毒免疫功能，是开发疫苗和抗病毒药物的关键。小鼠作为模式动物因其方便获取和操作并能够进行遗传编辑，广泛用于传染病动物模型。然而研究表明正常成年小鼠对SARS-CoV-2病毒并不敏感。因此，我们建立了一种肺部转染SARS-CoV-2病毒受体人血管紧张素转换酶2（human angiotensin-converting enzyme 2, hACE2）的小鼠模型，以期在正常小鼠上快速建立SARS-CoV-2的感染模型。基于该模型， hACE2受体转染小鼠在转染2天后感染SARS-CoV-2病毒。与对照小鼠相比，感染后在hACE2受体转染小鼠肺部可检测到病毒核酸和蛋白、肺部病理改变、天然免疫细胞浸润和炎症因子增高。进一步研究表明，中性粒细胞是病毒感染后最早也是数量最多浸润肺部的白细胞。此外，利用CXCL5基因敲除小鼠建立hACE2受体转染小鼠模型，该小鼠感染SARS-CoV-2病毒后嗜中性粒细胞募集入感染肺组织显著下调，同时降低了感染肺部的炎症反应。CXCL5的敲除并未影响到病毒感染后肺部的清除，提示了该因子作为潜在的控制SARS-CoV-2病毒感染肺炎的靶标。.
Databáze: OpenAIRE
Externí odkaz: