Cadar Dániel, Horváth Balázs, Rissman Melanie, Baum Heike, Bialonski Alexandra, Heung Michelle, Lawrence Philip, Balkema-Buschmann Anne, Rodríguez Estefanía, Escudero-Pérez Beatriz
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany; Erasmus Medical Center, Rotterdam, The Netherlands.
Adv Virus Res. 2025;122:19-59. doi: 10.1016/bs.aivir.2025.03.006. Epub 2025 Apr 19.
Bats are the reservoir hosts for a diverse range of viruses, including some that are highly pathogenic to humans, yet they generally harbor these pathogens without showing symptoms. This unique tolerance to viral infection makes them a critical model to study virus-host interactions and immune responses. Immunological in vivo studies in bats are however often hampered by low reproducibility, a lack of specific reagents, limited access to adequate facilities and availability of inbred bat colonies to perform experiments. In order to overcome these challenges, we have developed a bat xenograft mouse model by intravenously engrafting mice with Rousettus aegyptiacus bone marrow (bat immune system mice; BIS-mice). R. aegyptiacus is of special interest since it is the reservoir host of Marburg virus (MARV). Here we show that MARV does not cause morbidity in bat-engrafted mice, while Ebola virus (EBOV) seems to be highly lethal in this model. Further transcriptome analysis of MARV and EBOV infected BIS-mice revealed that the infection route significantly influences gene expression profiles in host tissues. Additionally, distinct gene expression patterns were observed in BIS-mice when comparing EBOV and MARV infection, underscoring virus-specific timing and intensity of immune gene activation, with MARV typically inducing earlier and more sustained antiviral responses compared to EBOV, which triggers a pronounced inflammatory response. This study demonstrates, for the first time, the use of BIS-mice to study filovirus immunopathogenesis. Additionally, it establishes a crucial foundation for generating bat species-specific immune mouse models, enabling in-depth characterization of bat-borne viruses and promoting translational research in this field.
蝙蝠是多种病毒的宿主，其中一些病毒对人类具有高度致病性，但它们通常携带这些病原体而不表现出症状。这种对病毒感染的独特耐受性使它们成为研究病毒与宿主相互作用及免疫反应的关键模型。然而，蝙蝠的体内免疫学研究常常受到低再现性、缺乏特异性试剂、难以获得足够的设施以及缺乏用于实验的近交蝙蝠群体的限制。为了克服这些挑战，我们通过将埃及果蝠骨髓静脉移植到小鼠体内（蝙蝠免疫系统小鼠；BIS小鼠），开发了一种蝙蝠异种移植小鼠模型。埃及果蝠特别引人关注，因为它是马尔堡病毒（MARV）的宿主。在这里，我们表明MARV不会在移植了蝙蝠的小鼠中引起发病，而埃博拉病毒（EBOV）在这个模型中似乎具有高度致死性。对感染MARV和EBOV的BIS小鼠进行的进一步转录组分析表明，感染途径显著影响宿主组织中的基因表达谱。此外，在比较EBOV和MARV感染时，在BIS小鼠中观察到了不同的基因表达模式，突出了免疫基因激活的病毒特异性时间和强度，与引发明显炎症反应的EBOV相比，MARV通常诱导更早且更持续的抗病毒反应。这项研究首次证明了使用BIS小鼠来研究丝状病毒免疫发病机制。此外，它为生成蝙蝠物种特异性免疫小鼠模型奠定了关键基础，能够深入表征蝙蝠传播的病毒，并促进该领域的转化研究。
