细胞外人源化IFNAR免疫小鼠模型用于分析人干扰素α及其亚型。

IF 8.4 2区 医学 Q1 IMMUNOLOGY Emerging Microbes & Infections Pub Date : 2024-12-01 Epub Date: 2024-01-22 DOI:10.1080/22221751.2023.2287681
Yumeng Li, Asha Ashuo, Menghan Hao, Yaming Li, Jianyu Ye, Jiangxia Liu, Ting Hua, Zhong Fang, Jianhua Li, Zhenghong Yuan, Jieliang Chen
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引用次数: 0

摘要

I型干扰素(IFN-Is)在包括慢性乙型肝炎病毒(HBV)感染在内的各种疾病的免疫防御和治疗中起着关键作用。所有IFN- is信号都是通过IFN-α受体1 (IFNAR1)和IFNAR2亚基组成的IFN- i异二聚体受体复合体传递的,但IFN- i亚型之间抗病毒和免疫调节反应的差异在很大程度上仍然未知。由于IFN-IFNAR相互作用是物种特异性的,小鼠对人类IFN-I表现出较弱的反应。为了更充分地表征人IFN-α及其亚型在体内的作用,采用基因靶向策略在C57BL/6N菌株中产生细胞外人源化IFNAR1/2 (IFNAR1/2 - hec)的基因敲入小鼠。IfnarhEC小鼠对人IFN-I有积极反应,内源性小鼠IFN-I信号在杂合小鼠中保持活跃(IfnarhEC/+)。对ifna - hec小鼠和离体细胞的分析表明,人IFN-α2和α14亚型对JAK-STAT信号的激活和免疫应答有不同的影响。与IFN-α2相比,IFN-α14诱导STAT1/2和IFN刺激基因的更大激活,协同诱导IFN-α和-γ信号,诱导更多抗原特异性CD8+ T细胞。此外,使用临床使用的聚乙二醇化hIFN-α2治疗后,具有HBV复制的IFNAR-hEC小鼠显示出长期的病毒抑制。这些结果表明,IFNAR-hEC小鼠可能有助于阐明人类IFN-Is的抗病毒和免疫调节功能,并进行临床前研究。更好地了解IFN-α亚型的不同活性可以为改进IFN为基础的治疗的发展提供见解。
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An extracellular humanized IFNAR immunocompetent mouse model for analyses of human interferon alpha and subtypes.

Type I interferons (IFN-Is) have key roles in immune defense and treatments for various diseases, including chronic hepatitis B virus (HBV) infection. All IFN-Is signal through a shared IFN-I heterodimeric receptor complex comprising IFN-α receptor 1 (IFNAR1) and IFNAR2 subunits, but differences in antiviral and immunomodulatory responses among IFN-I subtypes remain largely unknown. Because the IFN-IFNAR interactions are species-specific, mice exhibit weak responses to human IFN-I. To more fully characterize the actions of human IFN-α and its subtypes in vivo, a gene targeting strategy was employed to generate gene knock-in mice with extracellular-humanized IFNAR1/2 (IFNAR-hEC) in the C57BL/6N strain. IFNAR-hEC mice actively responded to human IFN-I, and endogenous mouse IFN-I signalling remained active in heterozygous mice (IfnarhEC/+). Analyses of IFNAR-hEC mice and isolated cells showed that human IFN-α2 and α14 subtypes exerted differential effect on the activation of JAK-STAT signalling and immune responses. Compared with IFN-α2, IFN-α14 induced greater activation of STAT1/2 and IFN-stimulated genes, synergistically elicited IFN-α and -γ signalling, and induced higher numbers of antigen-specific CD8+ T cells. Moreover, IFNAR-hEC mice with HBV replication displayed long-term viral suppression upon treatment with the clinically-used PEGylated hIFN-α2. These results indicate that IFNAR-hEC mice may be useful for elucidating antiviral and immunomodulatory functions of human IFN-Is and for conducting preclinical studies. A better understanding of the distinct activities of IFN-α subtypes can provide insights concerning the development of improved IFN-based therapy.

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来源期刊
Emerging Microbes & Infections
Emerging Microbes & Infections IMMUNOLOGY-MICROBIOLOGY
CiteScore
26.20
自引率
2.30%
发文量
276
审稿时长
20 weeks
期刊介绍: Emerging Microbes & Infections is a peer-reviewed, open-access journal dedicated to publishing research at the intersection of emerging immunology and microbiology viruses. The journal's mission is to share information on microbes and infections, particularly those gaining significance in both biological and clinical realms due to increased pathogenic frequency. Emerging Microbes & Infections is committed to bridging the scientific gap between developed and developing countries. This journal addresses topics of critical biological and clinical importance, including but not limited to: - Epidemic surveillance - Clinical manifestations - Diagnosis and management - Cellular and molecular pathogenesis - Innate and acquired immune responses between emerging microbes and their hosts - Drug discovery - Vaccine development research Emerging Microbes & Infections invites submissions of original research articles, review articles, letters, and commentaries, fostering a platform for the dissemination of impactful research in the field.
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