Type I interferon receptor signalling deficiency results in dysregulated innate immune responses to SARS-CoV-2 in mice.
Type I interferon receptor signalling deficiency results in dysregulated innate immune responses to SARS-CoV-2 in mice.
复制标题
I 型干扰素受体信号传导缺陷导致小鼠对 SARS-CoV-2 的先天免疫反应失调。
DOI：
10.1002/eji.202249913
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发表时间：
2022
影响因子：
5.4
通讯作者：
Ogger PP
中科院分区：
文献类型：
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作者：
Ogger PP
SARS-CoV-2是一种新出现的冠状病毒，引起呼吸道冠状病毒病(新冠肺炎)的全球大流行。I型干扰素途径在抗病毒防御中特别重要，最近的研究发现I型干扰素刺激SARS-CoV-2的早期炎症反应。在这里，我们使用SARS-CoV-2感染的小鼠模型，通过鼻内转导野生型(WT)和I型干扰素受体-1缺陷(Ifnar1-/-)小鼠的hACE2促进病毒进入，研究I型干扰素信号和先天免疫反应在SARS-CoV-2感染中的作用。我们的数据表明，I型干扰素信号对于诱导对SARS-CoV-2的抗病毒效应应答、控制病毒复制和预防疾病加重至关重要。此外，hACE2-Ifnar1-/-小鼠增加了趋化运动CxCl1的基因表达和中性粒细胞的气道渗透，减少和延迟了单核细胞募集趋化因子CCL2的产生。hACE2-Ifnar1-/-小鼠在SARS-CoV-2感染后表现出炎性髓系细胞向肺内募集的改变，从Ly6C+细胞转变为Ly6C表达细胞。总之，我们的发现表明，I型干扰素信号缺陷导致对SARS-CoV-2感染的先天免疫反应失调。
SARS‐CoV‐2 is a newly emerged coronavirus, causing the global pandemic of respiratory coronavirus disease (COVID‐19). The type I interferon (IFN) pathway is of particular importance for anti‐viral defense and recent studies identified that type I IFNs drive early inflammatory responses to SARS‐CoV‐2. Here, we use a mouse model of SARS‐CoV‐2 infection, facilitating viral entry by intranasal recombinant Adeno‐Associated Virus (rAAV) transduction ofhACE2in wildtype (WT) and type I IFN receptor‐1 deficient (Ifnar1–/–)mice, to study the role of type I IFN signalling and innate immune responses during SARS‐CoV‐2 infection. Our data show that type I IFN signalling is essential for inducing anti‐viral effector responses to SARS‐CoV‐2, control of virus replication, and to prevent enhanced disease. Furthermore,hACE2‐Ifnar1–/–mice had increased gene expression of the chemokineCxcl1and airway infiltration of neutrophils as well as reduced and delayed production of monocyte‐recruiting chemokine CCL2.hACE2‐Ifnar1–/–mice showed altered recruitment of inflammatory myeloid cells to the lung upon SARS‐CoV‐2 infection, with a shift from Ly6C+to Ly6C–expressing cells. Together, our findings suggest that type I IFN signalling deficiency results in a dysregulated innate immune response to SARS‐CoV‐2 infection.