Transcriptional signatures of Ebola and Marburg virus infection in a bat-immune-system (BIS) mouse model.

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.