Unlocking the secrets of bat immunity

Close-up of bat — Close-up Egyptian fruit bat, Rousettus aegyptiacus.

News

05/21/2025

Organoids unveil new defense mechanisms against zoonotic viruses

Bats are known as natural hosts for highly pathogenic viruses such as MERS- and SARS-related coronaviruses, as well as the Marburg and Nipah viruses. In contrast to the severe and often fatal disease outcomes these viruses cause in humans, bats generally do not show obvious signs of viral illness following infection. An international research team led by Dr. Max Kellner and Prof. Josef Penninger, Scientific Director of the Helmholtz Centre for Infection Research (HZI), has developed an innovative organoid research platform that allowed them to closely investigate the cellular antiviral defense mechanisms of mucosal epithelial tissues of bats. The results have now been published in Nature Immunology and could pave the way for the development of new therapies against viral diseases.

To investigate the innate immune defenses against viruses at the mucosal surfaces of bats, the research team developed organoids from the respiratory and intestinal tissue of Egyptian fruit bats (Rousettus aegyptiacus), the natural host of the highly pathogenic Marburg virus and other viruses known to be threats for humans. “Due to their unique lifestyle and low reproductive rates, bats are challenging animals to study. We therefore generated organoids from mucosal bat tissue, as these epithelial cell models proliferate well in culture and mimic the initial viral exposure—mucosal surfaces serve as entry points for many viruses into the body and orchestrate antiviral responses to infections,“ explains Max Kellner, who joined HZI in April 2025 as a junior research group leader to further investigate virus-host co-evolution.

The Egyptian fruit bat is the natural host of the highly pathogenic Marburg virus, which causes severe hemorrhagic fever in humans, leading to death in 30-90 % of infected individuals. Furthermore, there are no approved antiviral therapies or vaccines for Marburg virus disease to date. In close collaboration with Prof. Ali Mirazimi's team at the Karolinska Institute in Stockholm, the researchers successfully infected both bat organoids and human airway organoids with the Marburg virus in a high-security Biosafety Level 4 (S4) laboratory. Compared to the human models, bat organoids exhibited a significantly higher baseline antiviral immune activity even before infection.

“Our experiments on organoids showed that epithelial cells from Egyptian fruit bats, compared to those from humans, exhibit a significantly stronger baseline antiviral defense and an enhanced ability to induce innate immune responses to viral infections, particularly through the interferon system,” explains Max Kellner. “Interferons are a central component of the innate immune system and combat viral infections by activating hundreds of antiviral genes in cells. This likely enables bats to control viral replication early in infected mucosal tissues, while human cells are less effective at recognizing the Marburg virus in the early stages of infection, allowing uncontrolled replication and spread throughout the body.”

Bright-field microscopy of intestinal organoids from Egyptian fruit bats (Rousettus aegyptiacus)

Particularly, type III interferons appeared to play a crucial role in the mucosal antiviral immunity of Egyptian fruit bats: After infection with a variety of zoonotic viruses, bat organoids exhibited an exceptionally strong production of these interferons. Through additional type III interferon stimulation experiments and genetic modifications, such as the targeted knockout of the interferon system using CRISPR/Cas9, the strong antiviral activity of these interferons was confirmed. In addition, the researchers also discovered a self-amplifying gene regulatory mechanism of type III interferon expression, which provides long-lasting protection against viruses. “The results of this study suggest that bats can effectively prevent uncontrolled viral replication through a combination of various innate immune processes, thereby avoiding viral diseases,” says Josef Penninger. “For the development of antiviral therapies and the fight against future pandemics, understanding the resilience mechanisms of these animals against highly pathogenic viruses and the evolutionary adaptation of their immune systems is essential.”

In addition to the novel insights into the antiviral mechanisms of bat mucosal tissues, bat organoids will offer an innovative platform for more precise studies of the complex biology of bats at the genetic and molecular levels. The research team now plans to further develop the organoid models in terms of complexity and make them available to the scientific community. “It is particularly important to us to make our findings and the newly developed platform accessible to all researchers in the spirit of democratization,” says Josef Penninger. “Only by working together we can understand the complex mechanisms that evolution has shaped in animals like bats, and from this, develop new approaches for combating and treating viral diseases.”

Tissue samples for organoid generation were obtained from a breeding colony of Egyptian fruit bats at the Friedrich-Loeffler-Institut (FLI) in Greifswald. The majority of the research was conducted at the Medical University of Vienna and the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) at the Vienna BioCenter, in cooperation with the HZI.

Original publication

Max J. Kellner, Vanessa Monteil, Patrick Zelger, Gang Pei, Jie Jiao, Masahiro Onji, Komal Nayak, Matthias Zilbauer, Anne Balkema-Buschmann, Anca Dorhoi, Ali Mirazimi, Josef M. Penninger: Bat organoids reveal antiviral responses at epithelial surfaces. Nature Immunology, 2025, DOI: 10.1038/s41590-025-02155-1