Bat organoids reveal antiviral responses at epithelial surfaces

Bats can host viruses of pandemic concern without developing disease. The mechanisms underlying their exceptional resilience to viral infections are largely unresolved, necessitating the development of physiologically relevant and genetically tractable research models. Here, we developed respiratory and intestinal organoids that recapitulated the cellular diversity of the in vivo epithelium present in Rousettus aegyptiacus, the natural reservoir for the highly pathogenic Marburg virus (MARV). In contrast to human counterparts, bat organoids and mucosal tissue exhibited elevated constitutive expression of innate immune effectors, including type I interferon-ε (IFNε) and IFN-stimulated genes (ISGs). Upon infection with diverse zoonotic viruses, including MARV, bat organoids strongly induced type I and III IFN responses, which conferred robust antiviral protection. Type III IFNλ3 additionally displayed virus-independent self-amplification, acting as an ISG to enhance antiviral immunity. Our organoid platform reveals key features of bat epithelial antiviral immunity that may inform therapeutic strategies for viral disease resilience.

Description

Acknowledgements: We thank all members of the Penninger laboratory, J. Zuber (Research Institute of Molecular Pathology, Vienna) and S. Knapp (Medical University of Vienna) for their support and critical feedback on the presented work. We also thank the Vienna Biocenter Core Facilities (VBCF) for providing excellent scientific infrastructure and services, especially the BioOptics facility, the Molecular Biology Service, the VBCF Histology Facility, the next-generation sequencing facility (T. Grentzinger for preparing the 10x scRNA-seq libraries) and bioinformatic support (M. Novatchkova for providing help regarding the Souporcell pipeline). The laboratory of J.M.P. received funding from the Austrian Academy of Sciences, the Medical University of Vienna, the Vienna Science and Technology Fund (no. 10.47379/EICOV20002), the Austrian Science Fund Wittgenstein award (no. Z 271-B19), the Swedish Research Council (no. 2018-05766), the Fundació La Marató de TV3 (no. 202125-31), the T. Von Zastrow Foundation, the Canada 150 Research Chairs Program (no. F18-01336), the Canadian Institutes of Health Research COVID-19 grant nos. F20-02343 and F20-02015, and the Innovative Medicines Initiative 2 Joint Undertaking under grant no. 101005026. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations. We also gratefully acknowledge funding from the German Federal Ministry of Education and Research under the ‘Microbial Stargazing – Erforschung von Resilienzmechanismen von Mikroben und Menschen’ project (ref. 01KX2324).

Keywords

Intestinal Mucosa, Respiratory Mucosa, Organoids, Animals, Chiroptera, Humans, Interferons, Marburgvirus, Immunity, Innate

Journal Title

Nature Immunology

Journal ISSN

1529-2908
1529-2916

Volume Title

26

Publisher

Springer Science and Business Media LLC

Publisher DOI

https://doi.org/10.1038/s41590-025-02155-1

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) (101005026, 101005026, 101005026, 101005026, 101005026)
Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) (01KX2324)
Vetenskapsrådet (Swedish Research Council) (2018-05766)

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