Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
Institute of Virology Münster, University of Münster, Von-Esmarch-Straße 56, 48149, Münster, Germany.
BMC Genom Data. 2024 Feb 15;25(1):19. doi: 10.1186/s12863-024-01203-3.
Influenza virus infections represent a major global health problem. The dynamin-like GTPase MX1 is an interferon-dependent antiviral host protein that confers resistance to influenza virus infections. Infection models in mice are an important experimental system to understand the host response and susceptibility to developing severe disease following influenza infections. However, almost all laboratory mouse strains carry a non-functional Mx1 gene whereas humans have a functional MX1 gene. Most studies in mice have been performed with strains carrying a non-functional Mx1 gene. It is therefore very important to investigate the host response in mouse strains with a functional Mx1 gene.
Here, we analyzed the host response to influenza virus infections in two congenic mouse strains carrying the functional Mx1 gene from the A2G strain. B6.A2G-Mx1(B6-Mx1) mice are highly resistant to influenza A virus (IAV) H1N1 infections. On the other hand, D2(B6).A2G-Mx1(D2-Mx1) mice, although carrying a functional Mx1 gene, were highly susceptible, exhibited rapid weight loss, and died. We performed gene expression analysis using RNAseq from infected lungs at days 3 and 5 post-infection (p.i.) of both mouse strains to identify genes and pathways that were differentially expressed between the two mouse strains. The susceptible D2-Mx1 mice showed a high viral replication already at day 3 p.i. and exhibited a much higher number of differentially expressed genes (DEGs) and many DEGs had elevated expression levels compared to B6-Mx1 mice. On the other hand, some DEGs were specifically up-regulated only in B6-Mx1 mice at day 3 p.i., many of which were related to host immune response functions.
From these results, we conclude that at early times of infection, D2-Mx1 mice showed a very high and rapid replication of the virus, which resulted in lung damage and a hyperinflammatory response leading to death. We hypothesize that the activation of certain immune response genes was missing and that others, especially Mx1, were expressed at a time in D2-Mx1 mice when the virus had already massively spread in the lung and were thus not able anymore to protect them from severe disease. Our study represents an important addition to previously published studies in mouse models and contributes to a better understanding of the molecular pathways and genes that protect against severe influenza disease.
流感病毒感染是一个全球性的重大健康问题。动力蛋白样 GTP 酶 MX1 是一种干扰素依赖性抗病毒宿主蛋白，可抵抗流感病毒感染。在小鼠中进行的感染模型是了解宿主反应和对流感感染后发生严重疾病易感性的重要实验系统。然而，几乎所有的实验室小鼠品系都携带一种无功能的 Mx1 基因，而人类则有一个功能正常的 MX1 基因。大多数在携带无功能 Mx1 基因的小鼠中进行的研究。因此，研究携带功能性 Mx1 基因的小鼠品系中的宿主反应非常重要。
在这里，我们分析了两种带有功能性 A2G 株 Mx1 基因的同源小鼠品系对流感病毒感染的宿主反应。B6.A2G-Mx1（B6-Mx1）小鼠对甲型流感病毒（IAV）H1N1 感染高度抵抗。另一方面，尽管携带功能性 Mx1 基因，但 D2（B6）.A2G-Mx1（D2-Mx1）小鼠高度易感，体重迅速减轻，并死亡。我们使用感染后第 3 天和第 5 天的感染肺组织的 RNAseq 进行基因表达分析，以鉴定两种小鼠品系之间差异表达的基因和途径。易感的 D2-Mx1 小鼠在感染后第 3 天就表现出高病毒复制，并表现出更多数量的差异表达基因（DEGs），许多 DEGs 的表达水平明显高于 B6-Mx1 小鼠。另一方面，一些 DEGs 仅在感染后第 3 天的 B6-Mx1 小鼠中特异性上调，其中许多与宿主免疫反应功能有关。
从这些结果可以得出结论，在感染的早期，D2-Mx1 小鼠表现出非常高且快速的病毒复制，导致肺损伤和过度炎症反应，导致死亡。我们假设某些免疫反应基因的激活缺失，而其他基因，特别是 Mx1，在 D2-Mx1 小鼠中表达的时间是病毒已经在肺部大量传播的时候，因此无法再保护它们免受严重疾病的侵害。我们的研究是对先前在小鼠模型中进行的研究的重要补充，有助于更好地了解保护机体免受严重流感疾病的分子途径和基因。
